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1
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Pang L, Tian C, Wang Q, Zhao Z, Pan B, Luo Z, Wu S, Li X, Fan J. An Integrating Microfluidic System for Concentration Gradient Generation of Exosomes and Exosome-Assisted Single-Cell-Derived Tumor-Sphere Formation. ACS Sens 2025; 10:678-688. [PMID: 39866075 DOI: 10.1021/acssensors.4c01542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
To enhance exploration on tumor stem-like cells (TSCs) without altering their cellular biological characteristics, researchers advocate for application of single-cell-derived tumor-spheres (STSs). TSCs are regulated by their surrounding microenvironment, making it crucial to simulate a tumor microenvironment to facilitate STS formation. Recently, exosomes that originated from the tumor microenvironment have emerged as a promising approach for mimicking the tumor microenvironment. In the tumor microenvironment, various associated cells (such as fibroblasts, endothelial cells, and immune cells) play crucial roles. Utilizing exosomes derived from these cells enabled us to simulate the tumor microenvironment and promote STS formation. Herein, we have developed an integrated microfluidic platform to generate serial concentration gradients and evaluate the effects of multiple exosomes on STS formation. To demonstrate the feasibility of our approach, we generated serial concentration gradients of exosomes derived from two different cell types (HUVEC and NIH/3T3 cells) and assessed their effects on STS formation. Subsequently, we investigated the drug resistance of STSs treated with free doxorubicin and doxorubicin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles. Our findings revealed that the serial concentration gradients of mixed exosomes could be successfully generated, leading to an enhanced formation rate and size of STSs. Compared to exosomes derived from one cell type, the mixed exosomes exhibited superior promotion of STS formation. Additionally, nanomedicines demonstrated a reduction in the drug resistance of TSCs compared to free drug treatment, particularly in smaller and/or more deformable TSCs. This platform provides an innovative approach for STS formation enhancement and tumor microenvironment simulation.
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Affiliation(s)
- Long Pang
- School of Basic Medical Science, Xi'an Key Laboratory of Pathogenic Microorganism and Tumor Immunity, Xi'an Medical University, Xi'an 710021, China
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
| | - Chang Tian
- Public Health School, Anhui University of Science & Technology, Huainan, Anhui 232001, China
| | - Qirui Wang
- School of Basic Medical Science, Xi'an Key Laboratory of Pathogenic Microorganism and Tumor Immunity, Xi'an Medical University, Xi'an 710021, China
| | - Zhaohua Zhao
- School of Basic Medical Science, Xi'an Key Laboratory of Pathogenic Microorganism and Tumor Immunity, Xi'an Medical University, Xi'an 710021, China
| | - Bofeng Pan
- School of Basic Medical Science, Xi'an Key Laboratory of Pathogenic Microorganism and Tumor Immunity, Xi'an Medical University, Xi'an 710021, China
| | - Zichun Luo
- School of Basic Medical Science, Xi'an Key Laboratory of Pathogenic Microorganism and Tumor Immunity, Xi'an Medical University, Xi'an 710021, China
| | - Shuqiang Wu
- Oncology Department of Xi'an Fengcheng Hospital, Xi'an 710021, China
| | - Xueping Li
- School of Basic Medical Science, Xi'an Key Laboratory of Pathogenic Microorganism and Tumor Immunity, Xi'an Medical University, Xi'an 710021, China
| | - Jianglin Fan
- School of Basic Medical Science, Xi'an Key Laboratory of Pathogenic Microorganism and Tumor Immunity, Xi'an Medical University, Xi'an 710021, China
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
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Verona F, Di Bella S, Schirano R, Manfredi C, Angeloro F, Bozzari G, Todaro M, Giannini G, Stassi G, Veschi V. Cancer stem cells and tumor-associated macrophages as mates in tumor progression: mechanisms of crosstalk and advanced bioinformatic tools to dissect their phenotypes and interaction. Front Immunol 2025; 16:1529847. [PMID: 39981232 PMCID: PMC11839637 DOI: 10.3389/fimmu.2025.1529847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Accepted: 01/17/2025] [Indexed: 02/22/2025] Open
Abstract
Cancer stem cells (CSCs) are a small subset within the tumor mass significantly contributing to cancer progression through dysregulation of various oncogenic pathways, driving tumor growth, chemoresistance and metastasis formation. The aggressive behavior of CSCs is guided by several intracellular signaling pathways such as WNT, NF-kappa-B, NOTCH, Hedgehog, JAK-STAT, PI3K/AKT1/MTOR, TGF/SMAD, PPAR and MAPK kinases, as well as extracellular vesicles such as exosomes, and extracellular signaling molecules such as cytokines, chemokines, pro-angiogenetic and growth factors, which finely regulate CSC phenotype. In this scenario, tumor microenvironment (TME) is a key player in the establishment of a permissive tumor niche, where CSCs engage in intricate communications with diverse immune cells. The "oncogenic" immune cells are mainly represented by B and T lymphocytes, NK cells, and dendritic cells. Among immune cells, macrophages exhibit a more plastic and adaptable phenotype due to their different subpopulations, which are characterized by both immunosuppressive and inflammatory phenotypes. Specifically, tumor-associated macrophages (TAMs) create an immunosuppressive milieu through the production of a plethora of paracrine factors (IL-6, IL-12, TNF-alpha, TGF-beta, CCL1, CCL18) promoting the acquisition by CSCs of a stem-like, invasive and metastatic phenotype. TAMs have demonstrated the ability to communicate with CSCs via direct ligand/receptor (such as CD90/CD11b, LSECtin/BTN3A3, EPHA4/Ephrin) interaction. On the other hand, CSCs exhibited their capacity to influence immune cells, creating a favorable microenvironment for cancer progression. Interestingly, the bidirectional influence of CSCs and TME leads to an epigenetic reprogramming which sustains malignant transformation. Nowadays, the integration of biological and computational data obtained by cutting-edge technologies (single-cell RNA sequencing, spatial transcriptomics, trajectory analysis) has significantly improved the comprehension of the biunivocal multicellular dialogue, providing a comprehensive view of the heterogeneity and dynamics of CSCs, and uncovering alternative mechanisms of immune evasion and therapeutic resistance. Moreover, the combination of biology and computational data will lead to the development of innovative target therapies dampening CSC-TME interaction. Here, we aim to elucidate the most recent insights on CSCs biology and their complex interactions with TME immune cells, specifically TAMs, tracing an exhaustive scenario from the primary tumor to metastasis formation.
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Affiliation(s)
- Francesco Verona
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, Italy
| | - Sebastiano Di Bella
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, Italy
| | - Roberto Schirano
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | - Camilla Manfredi
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | - Francesca Angeloro
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Giulia Bozzari
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, Italy
| | - Matilde Todaro
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
- Azienda Ospedaliera Universitaria Policlinico “Paolo Giaccone” (AOUP), Palermo, Italy
| | - Giuseppe Giannini
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
- Istituto Pasteur, Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome, Italy
| | - Giorgio Stassi
- Department of Precision Medicine in Medical, Surgical and Critical Care, University of Palermo, Palermo, Italy
| | - Veronica Veschi
- Department of Molecular Medicine, University La Sapienza, Rome, Italy
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3
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Wang Q, Hu T, Zhang Q, Zhang Y, Dong X, Jin Y, Li J, Guo Y, Guo F, Chen Z, Zhong P, Yang Y, Ma Y. Fusobacterium nucleatum promotes colorectal cancer through neogenesis of tumor stem cells. J Clin Invest 2025; 135:e181595. [PMID: 39656543 PMCID: PMC11785920 DOI: 10.1172/jci181595] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 12/05/2024] [Indexed: 02/04/2025] Open
Abstract
Intestinal stem cells are crucial for maintaining intestinal homeostasis, yet their transformation into tumor stem cells in the context of microbial infection remains poorly understood. Fusobacterium nucleatum is frequently associated with the onset and progression of colorectal cancer (CRC). In this study, we uncovered that F. nucleatum colonized the depths of gut crypts in both patients with CRC and mouse models. Through single-cell sequencing analysis, we demonstrated that F. nucleatum infection reprogrammed crypt cells and activated lymphocyte antigen 6 complex, locus A+ ( LY6A+, also known as stem cell antigen 1 [Sca-1]) revival stem cells (RSCs), promoting their hyperproliferation and subsequent transformation into tumor stem cells, which accelerated intestinal carcinogenesis. Mechanistically, we identified LY6A as a glycosylphosphatidylinositol-anchored (GPI-anchored) membrane receptor for F. nucleatum. Upon binding, F. nucleatum induced the upregulation of ribosomal protein S14 (RPS14) via the LY6A receptor, driving RSC hyperactivity and tumorigenic conversion. Functional studies showed that genetic ablation of Ly6a in intestinal epithelial cells or Rps14 in LY6A+ RSCs substantially reduced F. nucleatum colonization and tumorigenesis. Moreover, analysis of clinical CRC cohorts revealed a strong correlation between F. nucleatum infection, RSC expansion, and elevated RPS14 expression in tumor tissues. These findings highlight an alternative F. nucleatum/LY6A/RPS14 signaling axis as a critical driver of CRC progression and propose potential therapeutic targets for effective CRC intervention.
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Affiliation(s)
- Qinying Wang
- Department of Colorectal Surgery and
- Department of Cancer Institute, Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Tingting Hu
- Department of Colorectal Surgery and
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qinyuan Zhang
- Department of Colorectal Surgery and
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yichi Zhang
- Department of Colorectal Surgery and
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaoxu Dong
- Department of Colorectal Surgery and
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yutao Jin
- Department of Colorectal Surgery and
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jinming Li
- Department of Colorectal Surgery and
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yangyang Guo
- Department of Colorectal Surgery and
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fanying Guo
- Department of Colorectal Surgery and
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ziying Chen
- Department of Colorectal Surgery and
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Peijie Zhong
- Department of Colorectal Surgery and
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yongzhi Yang
- Department of Colorectal Surgery and
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yanlei Ma
- Department of Colorectal Surgery and
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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4
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Muthuraman N, Thomas A, Samuel Ram T, Mohankumar KM, Abraham P. Is There Any Difference in Stem Cell Population between Type I and Type II Endometrial Cancer? A Pilot Study. JOURNAL OF MOTHER AND CHILD 2025; 29:10-19. [PMID: 40433700 DOI: 10.34763/jmotherandchild.20252901.d-24-00041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 03/07/2025] [Indexed: 05/29/2025]
Abstract
BACKGROUND The incidence of endometrial cancer is increasing globally. Cancer stem cells are now considered the driving force for tumour recurrence and metastasis. We studied whether the proportion of cancer stem cell population and stemness gene expression differ in type I and type II endometrial cancer. MATERIALS AND METHODS Type I and type II endometrial tumour tissues were obtained from patients who underwent hysterectomy. The tumour tissue was digested using collagenase, and we established a primary culture. In the primary cultures established from these two types of cancer, we used flow cytometry to measure the proportion of the cancer stem cell population expressing CD 133 and CXCR4 on its surface. We also looked for the expression of genes related to stemness, regulators of stemness, and markers of metastasis in both these cancer types. RESULTS We found that the proportion of cancer stem cell population that expresses CD133 and CXCR4 was higher in type II endometrial cancer than in type I endometrial cancer. Also, genes (Nanog, ALDH, EZH2) related to stemness and aberrant transcriptome were found to be upregulated in type II endometrial cancer. CONCLUSION Our study demonstrates that the proportion of stem cells in type 2 endometrial cancer is higher than in type I endometrial cancer. The findings of this study should lead us to investigate with a larger sample size and see if the increase in the stem cell population in type II endometrial cancer may be the reason for its poor prognosis.
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Affiliation(s)
- N Muthuraman
- Associate Professor, Department of Biochemistry, Christian Medical College, Vellore, Tamil Nadu, India
| | - Anitha Thomas
- Professor, Department of Gynecologic Oncology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Thomas Samuel Ram
- Professor, Department of Radiotherapy, Christian Medical College, Vellore, Tamil Nadu, India
| | - K M Mohankumar
- Scientist, Centre for Stem Cell Research (CSCR), Bagayam, Vellore, Tamil Nadu, India
| | - Premila Abraham
- Associate Professor, Department of Biochemistry, Christian Medical College, Vellore, Tamil Nadu, India
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5
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Shankari G, Raji R, Prabhu D, Jeyakanthan J, Gopinath SCB. Progressive Dynamics of Cancer Stem Cells in Oral Squamous Cell Carcinoma. Curr Cancer Drug Targets 2025; 25:113-117. [PMID: 39279115 DOI: 10.2174/0115680096340994240906111400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 07/31/2024] [Accepted: 08/09/2024] [Indexed: 09/18/2024]
Affiliation(s)
- Gopalakrishnan Shankari
- Center for Bioinformatics, Karpagam Academy of Higher Education, Karpagam, India
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, 641021, India
| | - Rajmichael Raji
- Structural Biology and Biocomputing Lab, Department of Bioinformatics, Alagappa University, Karaikudi, 630003, India
| | - Dhamodharan Prabhu
- Center for Bioinformatics, Karpagam Academy of Higher Education, Karpagam, India
- Department of Biotechnology, Karpagam Academy of Higher Education, Coimbatore, 641021, India
| | - Jeyaraman Jeyakanthan
- Structural Biology and Biocomputing Lab, Department of Bioinformatics, Alagappa University, Karaikudi, 630003, India
| | - Subash C B Gopinath
- Center for Global Health Research, Saveetha Medical College & Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, 602105, Tamil Nadu, India
- Faculty of Chemical Engineering & Technology and Institute of Nano Electronic Engineering, 02600 Arau, Perlis, Malaysia
- Department of Technical Sciences, Western Caspian University, Baku, AZ 1075, Azerbaijan
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6
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Oppel F, Gendreizig S, Martinez-Ruiz L, Florido J, López-Rodríguez A, Pabla H, Loganathan L, Hose L, Kühnel P, Schmidt P, Schürmann M, Neumann JM, Viyof Ful F, Scholtz LU, Ligum D, Brasch F, Niehaus K, Escames G, Busche T, Kalinowski J, Goon P, Sudhoff H. Mucosa-like differentiation of head and neck cancer cells is inducible and drives the epigenetic loss of cell malignancy. Cell Death Dis 2024; 15:724. [PMID: 39358322 PMCID: PMC11446932 DOI: 10.1038/s41419-024-07065-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 09/07/2024] [Accepted: 09/11/2024] [Indexed: 10/04/2024]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a highly malignant disease with high death rates that have remained substantially unaltered for decades. Therefore, new treatment approaches are urgently needed. Human papillomavirus-negative tumors harbor areas of terminally differentiated tissue that are characterized by cornification. Dissecting this intrinsic ability of HNSCC cells to irreversibly differentiate into non-malignant cells may have tumor-targeting potential. We modeled the cornification of HNSCC cells in a primary spheroid model and analyzed the mechanisms underlying differentiation by ATAC-seq and RNA-seq. Results were verified by immunofluorescence using human HNSCC tissue of distinct anatomical locations. HNSCC cell differentiation was accompanied by cell adhesion, proliferation stop, diminished tumor-initiating potential in immunodeficient mice, and activation of a wound-healing-associated signaling program. Small promoter accessibility increased despite overall chromatin closure. Differentiating cells upregulated KRT17 and cornification markers. Although KRT17 represents a basal stem cell marker in normal mucosa, we confirm KRT17 to represent an early differentiation marker in HNSCC tissue. Cornification was frequently found surrounding necrotic areas in human tumors, indicating an involvement of pro-inflammatory stimuli. Indeed, inflammatory mediators activated the differentiation program in primary HNSCC cells. In HNSCC tissue, distinct cell differentiation states were found to create a common tissue architecture in normal mucosa and HNSCCs. Our data demonstrate a loss of cell malignancy upon faithful HNSCC cell differentiation, indicating that targeted differentiation approaches may be therapeutically valuable. Moreover, we describe KRT17 to be a candidate biomarker for HNSCC cell differentiation and early tumor detection.
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Affiliation(s)
- Felix Oppel
- Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Bielefeld, Germany.
| | - Sarah Gendreizig
- Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Bielefeld, Germany
| | - Laura Martinez-Ruiz
- Institute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada, Granada, Spain
- Department of Physiology, Faculty of Medicine, University of Granada, Granada, Spain
- Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Investigación Biosanitaria (Ibs), Granada, San Cecilio University Hospital, Granada, Spain
| | - Javier Florido
- Institute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada, Granada, Spain
- Department of Physiology, Faculty of Medicine, University of Granada, Granada, Spain
- Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Investigación Biosanitaria (Ibs), Granada, San Cecilio University Hospital, Granada, Spain
| | - Alba López-Rodríguez
- Institute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada, Granada, Spain
- Department of Physiology, Faculty of Medicine, University of Granada, Granada, Spain
- Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Investigación Biosanitaria (Ibs), Granada, San Cecilio University Hospital, Granada, Spain
| | - Harkiren Pabla
- Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Bielefeld, Germany
| | - Lakshna Loganathan
- Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Bielefeld, Germany
| | - Leonie Hose
- Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Bielefeld, Germany
| | - Philipp Kühnel
- Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Bielefeld, Germany
| | - Pascal Schmidt
- Center for Biotechnology (CeBiTec), University Hospital OWL of Bielefeld University, Bielefeld, Germany
| | - Matthias Schürmann
- Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Bielefeld, Germany
| | - Judith Martha Neumann
- Proteome and Metabolome Research, Center for Biotechnology (CeBiTec), Faculty of Biology, Bielefeld University, Bielefeld, Germany
| | - Flavian Viyof Ful
- Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Bielefeld, Germany
| | - Lars Uwe Scholtz
- Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Bielefeld, Germany
| | - Dina Ligum
- Department of Pathology, Klinikum Bielefeld, Bielefeld, Germany
| | - Frank Brasch
- Department of Pathology, Klinikum Bielefeld, Bielefeld, Germany
| | - Karsten Niehaus
- Proteome and Metabolome Research, Center for Biotechnology (CeBiTec), Faculty of Biology, Bielefeld University, Bielefeld, Germany
| | - Germaine Escames
- Institute of Biotechnology, Biomedical Research Center, Health Sciences Technology Park, University of Granada, Granada, Spain
- Department of Physiology, Faculty of Medicine, University of Granada, Granada, Spain
- Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Investigación Biosanitaria (Ibs), Granada, San Cecilio University Hospital, Granada, Spain
| | - Tobias Busche
- Center for Biotechnology (CeBiTec), University Hospital OWL of Bielefeld University, Bielefeld, Germany
| | - Jörn Kalinowski
- Center for Biotechnology (CeBiTec), University Hospital OWL of Bielefeld University, Bielefeld, Germany
| | - Peter Goon
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore
| | - Holger Sudhoff
- Department of Otolaryngology, Head and Neck Surgery, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Bielefeld, Germany.
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7
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H-Alcántara A, Kourani O, Marcos-Jiménez A, Martínez-Núñez P, Herranz-Martín E, Fuentes P, Toribio ML, Muñoz-Calleja C, Iglesias T, Campanero MR. Glutathione overproduction mediates lymphoma initiating cells survival and has a sex-dependent effect on lymphomagenesis. Cell Death Dis 2024; 15:534. [PMID: 39068166 PMCID: PMC11283572 DOI: 10.1038/s41419-024-06923-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 07/30/2024]
Abstract
Lymphoid tumor patients often exhibit resistance to standard therapies or experience relapse post-remission. Relapse is driven by Tumor Initiating Cells (TICs), a subset of tumor cells capable of regrowing the tumor and highly resistant to therapy. Growing cells in 3D gels is a method to discern tumorigenic cells because it strongly correlates with tumorigenicity. The finding that TICs, rather than differentiated tumor cells, grow in 3D gels offers a unique opportunity to unveil TIC-specific signaling pathways and therapeutic targets common to various cancer types. Here, we show that culturing lymphoid cells in 3D gels triggers reactive oxygen species (ROS) production, leading to non-tumor lymphoid cell death while enabling the survival and proliferation of a subset of lymphoma/leukemia cells, TICs or TIC-like cells. Treatment with the antioxidant N-acetylcysteine inhibits this lethality and promotes the growth of primary non-tumor lymphoid cells in 3D gels. A subset of lymphoma cells, characterized by an increased abundance of the antioxidant glutathione, escape ROS-induced lethality, a response not seen in non-tumor cells. Reducing glutathione production in lymphoma cells, either through pharmacological inhibition of glutamate cysteine ligase (GCL), the enzyme catalyzing the rate-limiting step in glutathione biosynthesis, or via knockdown of GCLC, the GCL catalytic subunit, sharply decreased cell growth in 3D gels and xenografts. Tumor cells from B-cell lymphoma/leukemia patients and λ-MYC mice, a B-cell lymphoma mouse model, overproduce glutathione. Importantly, pharmacological GCL inhibition hindered lymphoma growth in female λ-MYC mice, suggesting that this treatment holds promise as a therapeutic strategy for female lymphoma/leukemia patients.
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Affiliation(s)
- Alberto H-Alcántara
- Cell-cell communication and inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Madrid, Spain
| | - Omar Kourani
- Cell-cell communication and inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Madrid, Spain
| | - Ana Marcos-Jiménez
- Immunology Department, Instituto de Investigación Sanitaria Princesa, Hospital Universitario de la Princesa, Madrid, Spain
| | - Patricia Martínez-Núñez
- Cell-cell communication and inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Madrid, Spain
| | - Estela Herranz-Martín
- Cell-cell communication and inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Madrid, Spain
| | - Patricia Fuentes
- Immune System Development and Function Unit, CBM, CSIC-UAM, Madrid, Spain
| | - María L Toribio
- Immune System Development and Function Unit, CBM, CSIC-UAM, Madrid, Spain
| | - Cecilia Muñoz-Calleja
- Immunology Department, Instituto de Investigación Sanitaria Princesa, Hospital Universitario de la Princesa, Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC) Madrid, Madrid, Spain
- Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| | - Teresa Iglesias
- Department of Neurological Diseases and Aging, Instituto de Investigaciones Biomédicas Sols-Morreale, CSIC-UAM, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) Madrid, Madrid, Spain
| | - Miguel R Campanero
- Cell-cell communication and inflammation Unit, Centro de Biología Molecular Severo Ochoa (CBM), CSIC-UAM, Madrid, Spain.
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
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8
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Peng Z, Wang S, Wen D, Mei Z, Zhang H, Liao S, Lv L, Li C. FEN1 upregulation mediated by SUMO2 via antagonizing proteasomal degradation promotes hepatocellular carcinoma stemness. Transl Oncol 2024; 44:101916. [PMID: 38513457 PMCID: PMC10966306 DOI: 10.1016/j.tranon.2024.101916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 01/22/2024] [Accepted: 02/15/2024] [Indexed: 03/23/2024] Open
Abstract
PURPOSE Metastasis of hepatocellular carcinoma (HCC) critically impacts the survival prognosis of patients, with the pivotal role of hepatocellular carcinoma stem cells in initiating invasive metastatic behaviors. The Flap Endonuclease 1 (FEN1) is delineated as a metallonuclease, quintessential for myriad cellular processes including DNA replication, DNA synthesis, DNA damage rectification, Okazaki fragment maturation, baseexcision repair, and the preservation of genomic stability. Furthermore, it has been recognized as an oncogene in a diverse range of malignancies. Our antecedent research has highlighted a pronounced overexpression of protein FEN1 in hepatocellular carcinoma, where it amplifies the invasiveness and metastatic potential of liver cancer cells. However, its precise role in liver cancer stem cells (LCSCs) remains an enigma and requires further investigation. METHODS To rigorously evaluate the stemness attributes of LCSCs, we employed sphere formation assays and flow cytometric evaluations. Both CD133+ and CD133- cell populations were discerningly isolated utilizing immunomagnetic bead separation techniques. The expression levels of pertinent genes were assayed via real-time quantitative PCR (RT-qPCR) and western blot analyses, while the expression profiles in hepatocellular carcinoma tissues were gauged using immunohistochemistry. Subsequent immunoprecipitation, in conjunction with mass spectrometry, ascertained the concurrent binding of proteins FEN1 and Small ubiquitin-related modifier 2 (SUMO2) in HCC cells. Lastly, the impact of SUMO2 on proteasomal degradation pathway of FEN1 was validated by supplementing MG132. RESULTS Our empirical findings substantiate that protein FEN1 is profusely expressed in spheroids and CD133+ cells. In vitro investigations demonstrate that the upregulation of protein FEN1 unequivocally augments the stemness of LCSCs. In a congruent in vivo context, elevation of FEN1 noticeably enhances the tumorigenic potential of LCSCs. Conversely, inhibiting protein FEN1 resulted in a marked reduction in LCSC stemness. From a mechanistic perspective, there exists a salient positive correlation between the protein expression of FEN1 and SUMO2 in liver cancer tissues. Furthermore, the level of SUMO2-mediated modification of FEN1 is pronouncedly elevated in LCSCs. Interestingly, SUMO2 has the ability to bind to FEN1, leading to a inhibition in the proteasomal degradation pathway of FEN1 and an enhancement in its protein expression. However, it is noteworthy that this interaction does not affect the mRNA level of FEN1. CONCLUSION In summation, our research elucidates that protein FEN1 is an effector in augmenting the stemness of LCSCs. Consequently, strategic attenuation of protein FEN1 might proffer a pioneering approach for the efficacious elimination of LCSCs.
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Affiliation(s)
- Zhenxiang Peng
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Linjiang Road, Yuzhong District, Chongqing 400010, PR China
| | - Shuling Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Linjiang Road, Yuzhong District, Chongqing 400010, PR China
| | - Diguang Wen
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Linjiang Road, Yuzhong District, Chongqing 400010, PR China
| | - Zhechuan Mei
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Linjiang Road, Yuzhong District, Chongqing 400010, PR China.
| | - Hao Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Linjiang Road, Yuzhong District, Chongqing 400010, PR China.
| | - Shengtao Liao
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Linjiang Road, Yuzhong District, Chongqing 400010, PR China.
| | - Lin Lv
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Linjiang Road, Yuzhong District, Chongqing 400010, PR China.
| | - Chuanfei Li
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Linjiang Road, Yuzhong District, Chongqing 400010, PR China.
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Zhao Y, Zhang B, Ma Y, Guo M, Zhao F, Chen J, Wang B, Jin H, Zhou F, Guan J, Zhao Q, Liu Q, Wang H, Zhao F, Wang X. Distinct molecular profiles drive multifaceted characteristics of colorectal cancer metastatic seeds. J Exp Med 2024; 221:e20231359. [PMID: 38502057 PMCID: PMC10949939 DOI: 10.1084/jem.20231359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 10/10/2023] [Accepted: 02/08/2024] [Indexed: 03/20/2024] Open
Abstract
Metastasis of primary tumors remains a challenge for early diagnosis and prevention. The cellular properties and molecular drivers of metastatically competent clones within primary tumors remain unclear. Here, we generated 10-16 single cell-derived lines from each of three colorectal cancer (CRC) tumors to identify and characterize metastatic seeds. We found that intrinsic factors conferred clones with distinct metastatic potential and cellular communication capabilities, determining organ-specific metastasis. Poorly differentiated or highly metastatic clones, rather than drug-resistant clones, exhibited poor clinical prognostic impact. Personalized genetic alterations, instead of mutation burden, determined the occurrence of metastatic potential during clonal evolution. Additionally, we developed a gene signature for capturing metastatic potential of primary CRC tumors and demonstrated a strategy for identifying metastatic drivers using isogenic clones with distinct metastatic potential in primary tumors. This study provides insight into the origin and mechanisms of metastasis and will help develop potential anti-metastatic therapeutic targets for CRC patients.
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Affiliation(s)
- Yuanyuan Zhao
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
- Institute for Intelligent Healthcare, Tsinghua University, Beijing, China
| | - Bing Zhang
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yiming Ma
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mengmeng Guo
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
| | - Fuqiang Zhao
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianan Chen
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bingzhi Wang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hua Jin
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
| | - Fulai Zhou
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
| | - Jiawei Guan
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
| | - Qian Zhao
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
| | - Qian Liu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongying Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fangqing Zhao
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China
- Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
| | - Xia Wang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
- Institute for Intelligent Healthcare, Tsinghua University, Beijing, China
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10
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Borlongan MC, Saha D, Wang H. Tumor Microenvironment: A Niche for Cancer Stem Cell Immunotherapy. Stem Cell Rev Rep 2024; 20:3-24. [PMID: 37861969 DOI: 10.1007/s12015-023-10639-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/02/2023] [Indexed: 10/21/2023]
Abstract
Tumorigenic Cancer Stem Cells (CSCs), often called tumor-initiating cells (TICs), represent a unique subset of cells within the tumor milieu. They stand apart from the bulk of tumor cells due to their exceptional self-renewal, metastatic, and differentiation capabilities. Despite significant progress in classifying CSCs, these cells remain notably resilient to conventional radiotherapy and chemotherapy, contributing to cancer recurrence. In this review, our objective is to explore novel avenues of research that delve into the distinctive characteristics of CSCs within their surrounding tumor microenvironment (TME). We will start with an overview of the defining features of CSCs and then delve into their intricate interactions with cells from the lymphoid lineage, namely T cells, B cells, and natural killer (NK) cells. Furthermore, we will discuss their dynamic interplay with myeloid lineage cells, including macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs). Moreover, we will illuminate the crosstalk between CSCs and cells of mesenchymal origin, specifically fibroblasts, adipocytes, and endothelial cells. Subsequently, we will underscore the pivotal role of CSCs within the context of the tumor-associated extracellular matrix (ECM). Finally, we will highlight pre-clinical and clinical studies that target CSCs within the intricate landscape of the TME, including CAR-T therapy, oncolytic viruses, and CSC-vaccines, with the ultimate goal of uncovering novel avenues for CSC-based cancer immunotherapy.
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Affiliation(s)
- Mia C Borlongan
- College of Medicine, California Northstate University, 9700 West Taron Drive, Elk Grove, CA, 95757, USA
| | - Dipongkor Saha
- Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, California Northstate University, 9700 West Taron Drive, Elk Grove, CA, 95757, USA.
| | - Hongbin Wang
- College of Medicine, California Northstate University, 9700 West Taron Drive, Elk Grove, CA, 95757, USA.
- Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, California Northstate University, 9700 West Taron Drive, Elk Grove, CA, 95757, USA.
- Master Program of Pharmaceutical Sciences College of Graduate Studies, Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, Department of Basic Science College of Medicine, California Northstate University, 9700 West Taron Drive, Elk Grove, CA, 95757, USA.
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11
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Wurm AA, Brilloff S, Kolovich S, Schäfer S, Rahimian E, Kufrin V, Bill M, Carrero ZI, Drukewitz S, Krüger A, Hüther M, Uhrig S, Oster S, Westphal D, Meier F, Pfütze K, Hübschmann D, Horak P, Kreutzfeldt S, Richter D, Schröck E, Baretton G, Heining C, Möhrmann L, Fröhling S, Ball CR, Glimm H. Signaling-induced systematic repression of miRNAs uncovers cancer vulnerabilities and targeted therapy sensitivity. Cell Rep Med 2023; 4:101200. [PMID: 37734378 PMCID: PMC10591033 DOI: 10.1016/j.xcrm.2023.101200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 06/21/2023] [Accepted: 08/25/2023] [Indexed: 09/23/2023]
Abstract
Targeted therapies are effective in treating cancer, but success depends on identifying cancer vulnerabilities. In our study, we utilize small RNA sequencing to examine the impact of pathway activation on microRNA (miRNA) expression patterns. Interestingly, we discover that miRNAs capable of inhibiting key members of activated pathways are frequently diminished. Building on this observation, we develop an approach that integrates a low-miRNA-expression signature to identify druggable target genes in cancer. We train and validate our approach in colorectal cancer cells and extend it to diverse cancer models using patient-derived in vitro and in vivo systems. Finally, we demonstrate its additional value to support genomic and transcriptomic-based drug prediction strategies in a pan-cancer patient cohort from the National Center for Tumor Diseases (NCT)/German Cancer Consortium (DKTK) Molecularly Aided Stratification for Tumor Eradication (MASTER) precision oncology trial. In conclusion, our strategy can predict cancer vulnerabilities with high sensitivity and accuracy and might be suitable for future therapy recommendations in a variety of cancer subtypes.
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Affiliation(s)
- Alexander A Wurm
- Mildred Scheel Early Career Center, National Center for Tumor Diseases (NCT/UCC) Dresden, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany.
| | - Silke Brilloff
- Mildred Scheel Early Career Center, National Center for Tumor Diseases (NCT/UCC) Dresden, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Sofia Kolovich
- Mildred Scheel Early Career Center, National Center for Tumor Diseases (NCT/UCC) Dresden, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Silvia Schäfer
- Mildred Scheel Early Career Center, National Center for Tumor Diseases (NCT/UCC) Dresden, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Elahe Rahimian
- Mildred Scheel Early Career Center, National Center for Tumor Diseases (NCT/UCC) Dresden, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Vida Kufrin
- Mildred Scheel Early Career Center, National Center for Tumor Diseases (NCT/UCC) Dresden, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Marius Bill
- Mildred Scheel Early Career Center, National Center for Tumor Diseases (NCT/UCC) Dresden, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany; Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Zunamys I Carrero
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany
| | - Stephan Drukewitz
- German Cancer Consortium (DKTK), Dresden, Germany; Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Institute of Human Genetics, University of Leipzig, Leipzig, Germany
| | - Alexander Krüger
- German Cancer Consortium (DKTK), Dresden, Germany; Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Melanie Hüther
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Sebastian Uhrig
- Computational Oncology Group, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany
| | - Sandra Oster
- German Cancer Consortium (DKTK), Dresden, Germany; Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Dana Westphal
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Friedegund Meier
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Skin Cancer Center at the University Cancer Centre Dresden and National Center for Tumor Diseases, Dresden, Germany
| | - Katrin Pfütze
- German Cancer Consortium (DKTK), Heidelberg, Germany; Sample Processing Laboratory, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany
| | - Daniel Hübschmann
- Computational Oncology Group, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany
| | - Peter Horak
- German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany
| | - Simon Kreutzfeldt
- German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany
| | - Daniela Richter
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany
| | - Evelin Schröck
- German Cancer Consortium (DKTK), Dresden, Germany; Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Institute for Clinical Genetics, University Hospital Carl Gustav Carus at Technische Universität Dresden, Dresden, Germany; ERN GENTURIS, Hereditary Cancer Syndrome Center Dresden, Dresden, Germany
| | - Gustavo Baretton
- German Cancer Consortium (DKTK), Dresden, Germany; Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Christoph Heining
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany
| | - Lino Möhrmann
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany
| | - Stefan Fröhling
- German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany
| | - Claudia R Ball
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany; Technische Universität Dresden, Faculty of Biology, Dresden, Germany
| | - Hanno Glimm
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany; Translational Functional Cancer Genomics, National Center for Tumor Diseases (NCT) Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany
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12
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Kasprzak A. Prognostic Biomarkers of Cell Proliferation in Colorectal Cancer (CRC): From Immunohistochemistry to Molecular Biology Techniques. Cancers (Basel) 2023; 15:4570. [PMID: 37760539 PMCID: PMC10526446 DOI: 10.3390/cancers15184570] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/04/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common and severe malignancies worldwide. Recent advances in diagnostic methods allow for more accurate identification and detection of several molecular biomarkers associated with this cancer. Nonetheless, non-invasive and effective prognostic and predictive testing in CRC patients remains challenging. Classical prognostic genetic markers comprise mutations in several genes (e.g., APC, KRAS/BRAF, TGF-β, and TP53). Furthermore, CIN and MSI serve as chromosomal markers, while epigenetic markers include CIMP and many other candidates such as SERP, p14, p16, LINE-1, and RASSF1A. The number of proliferation-related long non-coding RNAs (e.g., SNHG1, SNHG6, MALAT-1, CRNDE) and microRNAs (e.g., miR-20a, miR-21, miR-143, miR-145, miR-181a/b) that could serve as potential CRC markers has also steadily increased in recent years. Among the immunohistochemical (IHC) proliferative markers, the prognostic value regarding the patients' overall survival (OS) or disease-free survival (DFS) has been confirmed for thymidylate synthase (TS), cyclin B1, cyclin D1, proliferating cell nuclear antigen (PCNA), and Ki-67. In most cases, the overexpression of these markers in tissues was related to worse OS and DFS. However, slowly proliferating cells should also be considered in CRC therapy (especially radiotherapy) as they could represent a reservoir from which cells are recruited to replenish the rapidly proliferating population in response to cell-damaging factors. Considering the above, the aim of this article is to review the most common proliferative markers assessed using various methods including IHC and selected molecular biology techniques (e.g., qRT-PCR, in situ hybridization, RNA/DNA sequencing, next-generation sequencing) as prognostic and predictive markers in CRC.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Swiecicki Street 6, 60-781 Poznan, Poland
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13
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Luo Z, Wang B, Luo F, Guo Y, Jiang N, Wei J, Wang X, Tseng Y, Chen J, Zhao B, Liu J. Establishment of a large-scale patient-derived high-risk colorectal adenoma organoid biobank for high-throughput and high-content drug screening. BMC Med 2023; 21:336. [PMID: 37667332 PMCID: PMC10478412 DOI: 10.1186/s12916-023-03034-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 08/15/2023] [Indexed: 09/06/2023] Open
Abstract
BACKGROUND Colorectal adenoma (CA), especially high-risk CA (HRCA), is a precancerous lesion with high prevalence and recurrence rate and accounts for about 90% incidence of sporadic colorectal cancer cases worldwide. Currently, recurrent CA can only be treated with repeated invasive polypectomies, while safe and promising pharmaceutical invention strategies are still missing due to the lack of reliable in vitro model for CA-related drug screening. METHODS We have established a large-scale patient-derived high-risk colorectal adenoma organoid (HRCA-PDO) biobank containing 37 PDO lines derived from 33 patients and then conducted a series of high-throughput and high-content HRCA drug screening. RESULTS We established the primary culture system with the non-WNT3a medium which highly improved the purity while maintained the viability of HRCA-PDOs. We also proved that the HRCA-PDOs replicated the histological features, cellular diversity, genetic mutations, and molecular characteristics of the primary adenomas. Especially, we identified the dysregulated stem genes including LGR5, c-Myc, and OLFM4 as the markers of adenoma, which are well preserved in HRCA-PDOs. Based on the HRCA-PDO biobank, a customized 139 compound library was applied for drug screening. Four drugs including metformin, BMS754807, panobinostat and AT9283 were screened out as potential hits with generally consistent inhibitory efficacy on HRCA-PDOs. As a representative, metformin was discovered to hinder HRCA-PDO growth in vitro and in vivo by restricting the stemness maintenance. CONCLUSIONS This study established a promising HRCA-PDO biobank and conducted the first high-throughput and high-content HRCA drug screening in order to shed light on the prevention of colorectal cancer.
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Affiliation(s)
- Zhongguang Luo
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Bangting Wang
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Feifei Luo
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Yumeng Guo
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Ning Jiang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Jinsong Wei
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Xin Wang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Yujen Tseng
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Jian Chen
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Bing Zhao
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China.
- Institute of Organoid Technology, Kunming Medical University, Kunming, 650500, China.
| | - Jie Liu
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China.
- Institute of Biomedical Sciences and Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
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14
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Wang MY, Wang XW, Zhao WX, Li Y, Cai ML, Wang KX, Xi XM, Zhao C, Zhou HM, Shao RG, Xia GM, Zhang YF, Zhao WL. Enhanced binding of β-catenin and β-TrCP mediates LMPt's anti-CSCs activity in colorectal cancer. Biochem Pharmacol 2023; 212:115577. [PMID: 37137416 DOI: 10.1016/j.bcp.2023.115577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 04/25/2023] [Accepted: 04/25/2023] [Indexed: 05/05/2023]
Abstract
Cancer stem cells (CSCs), a subpopulation of tumor cells with the features of self-renewal, tumor initiation, and insensitivity to common physical and chemical agents, are the key to cancer relapses, metastasis, and resistance. Accessible CSCs inhibitory strategies are primarily based on small molecule drugs, yet toxicity limits their application. Here, we report a liposome loaded with low toxicity and high effectiveness of miriplatin, lipo-miriplatin (LMPt) with high miriplatin loading, and robust stability, exhibiting a superior inhibitory effect on CSCs and non-CSCs. LMPt predominantly inhibits the survival of oxaliplatin-resistant (OXA-resistant) cells composed of CSCs. Furthermore, LMPt directly blocks stemness features of self-renewal, tumor initiation, unlimited proliferation, metastasis, and insensitivity. In mechanistic exploration, RNA sequencing (RNA-seq) revealed that LMPt downregulates the levels of pro-stemness proteins and that the β-catenin-mediated stemness pathway is enriched. Further research shows that either in adherent cells or 3D-spheres, the β-catenin-OCT4/NANOG axis, the vital pathway to maintain stemness, is depressed by LMPt. The consecutive activation of the β-catenin pathway induced by mutant β-catenin (S33Y) and OCT4/NANOG overexpression restores LMPt's anti-CSCs effect, elucidating the key role of the β-catenin-OCT4/NANOG axis. Further studies revealed that the strengthened binding of β-catenin and β-TrCP initiates ubiquitination and degradation of β-catenin induced by LMPt. In addition,the ApcMin/+transgenicmouse model, in which colon tumors are spontaneously formed, demonstrates LMPt's potent anti-non-CSCs activity in vivo.
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Affiliation(s)
- Meng-Yan Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Xiao-Wei Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Wen-Xia Zhao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Yang Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Mei-Lian Cai
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Ke-Xin Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Xiao-Ming Xi
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Cong Zhao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Hui-Min Zhou
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Rong-Guang Shao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China.
| | - Gui-Min Xia
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China.
| | - Ye-Fan Zhang
- Department of Hepatobiliary Surgery/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Wu-Li Zhao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China.
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15
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Candiello E, Reato G, Verginelli F, Gambardella G, D Ambrosio A, Calandra N, Orzan F, Iuliano A, Albano R, Sassi F, Luraghi P, Comoglio PM, Bertotti A, Trusolino L, Boccaccio C. MicroRNA 483-3p overexpression unleashes invasive growth of metastatic colorectal cancer via NDRG1 downregulation and ensuing activation of the ERBB3/AKT axis. Mol Oncol 2023. [PMID: 36862005 DOI: 10.1002/1878-0261.13408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 02/07/2023] [Accepted: 02/27/2023] [Indexed: 03/03/2023] Open
Abstract
In colorectal cancer, the mechanisms underlying tumor aggressiveness require further elucidation. Taking advantage of a large panel of human metastatic colorectal cancer xenografts and matched stem-like cell cultures (m-colospheres), here we show that the overexpression of microRNA 483-3p (miRNA-483-3p; also known as MIR-483-3p), encoded by a frequently amplified gene locus, confers an aggressive phenotype. In m-colospheres, endogenous or ectopic miRNA-483-3p overexpression increased proliferative response, invasiveness, stem cell frequency, and resistance to differentiation. Transcriptomic analyses and functional validation found that miRNA-483-3p directly targets NDRG1, known as a metastasis suppressor involved in EGFR family downregulation. Mechanistically, miRNA-483-3p overexpression induced the signaling pathway triggered by ERBB3, including AKT and GSK3β, and led to the activation of transcription factors regulating epithelial-mesenchymal transition (EMT). Consistently, treatment with selective anti-ERBB3 antibodies counteracted the invasive growth of miRNA-483-3p-overexpressing m-colospheres. In human colorectal tumors, miRNA-483-3p expression inversely correlated with NDRG1 and directly correlated with EMT transcription factor expression and poor prognosis. These results unveil a previously unrecognized link between miRNA-483-3p, NDRG1, and ERBB3-AKT signaling that can directly support colorectal cancer invasion and is amenable to therapeutic targeting.
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Affiliation(s)
- Ermes Candiello
- Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy
| | - Gigliola Reato
- Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy.,Department of Oncology, University of Turin Medical School, Italy
| | - Federica Verginelli
- Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy
| | - Gennaro Gambardella
- Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.,Department of Chemical Materials and Industrial Engineering, University of Naples Federico II, Italy
| | - Antonio D Ambrosio
- Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy
| | - Noemi Calandra
- Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy.,Department of Oncology, University of Turin Medical School, Italy
| | - Francesca Orzan
- Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy
| | | | - Raffaella Albano
- Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy
| | - Francesco Sassi
- Translational Cancer Medicine, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy
| | - Paolo Luraghi
- Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy
| | | | - Andrea Bertotti
- Department of Oncology, University of Turin Medical School, Italy.,Translational Cancer Medicine, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy
| | - Livio Trusolino
- Department of Oncology, University of Turin Medical School, Italy.,Translational Cancer Medicine, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy
| | - Carla Boccaccio
- Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy.,Department of Oncology, University of Turin Medical School, Italy
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16
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Biswas PK, Park SR, An J, Lim KM, Dayem AA, Song K, Choi HY, Choi Y, Park KS, Shin HJ, Kim A, Gil M, Saha SK, Cho SG. The Orphan GPR50 Receptor Regulates the Aggressiveness of Breast Cancer Stem-like Cells via Targeting the NF-kB Signaling Pathway. Int J Mol Sci 2023; 24:ijms24032804. [PMID: 36769125 PMCID: PMC9917945 DOI: 10.3390/ijms24032804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 01/28/2023] [Accepted: 01/28/2023] [Indexed: 02/05/2023] Open
Abstract
The expression of GPR50 in CSLC and several breast cancer cell lines was assessed by RT-PCR and online platform (UALCAN, GEPIA, and R2 gene analysis). The role of GPR50 in driving CSLC, sphere formation, cell proliferation, and migration was performed using shGPR50 gene knockdown, and the role of GPR50-regulated signaling pathways was examined by Western blotting and Luciferase Assay. Herein, we confirmed that the expression of G protein-coupled receptor 50 (GPR50) in cancer stem-like cells (CSLC) is higher than that in other cancer cells. We examined that the knockdown of GPR50 in CSLC led to decreased cancer properties, such as sphere formation, cell proliferation, migration, and stemness. GPR50 silencing downregulates NF-kB signaling, which is involved in sphere formation and aggressiveness of CSLC. In addition, we demonstrated that GPR50 also regulates ADAM-17 activity by activating NOTCH signaling pathways through the AKT/SP1 axis in CSLC. Overall, we demonstrated a novel GPR50-mediated regulation of the NF-κB-Notch signaling pathway, which can provide insights into CSLC progression and prognosis, and NF-κB-NOTCH-based CSLC treatment strategies.
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Affiliation(s)
- Polash Kumar Biswas
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center (MCRC), Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
- Division of Biological Sciences, University of Montana, Missoula, MT 59812, USA
| | - Sang Rok Park
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center (MCRC), Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Jongyub An
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center (MCRC), Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Kyung Min Lim
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center (MCRC), Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Ahmed Abdal Dayem
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center (MCRC), Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Kwonwoo Song
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center (MCRC), Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Hye Yeon Choi
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center (MCRC), Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Yujin Choi
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center (MCRC), Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Kyoung Sik Park
- Department of Surgery, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05029, Republic of Korea
| | - Hyun Jin Shin
- Department of Ophthalmology, Research Institute of Medical Science, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05029, Republic of Korea
| | - Aram Kim
- Department of Urology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05029, Republic of Korea
| | - Minchan Gil
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center (MCRC), Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Subbroto Kumar Saha
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center (MCRC), Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Ssang-Goo Cho
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center (MCRC), Incurable Disease Animal Model & Stem Cell Institute (IDASI), Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
- Correspondence: ; Tel.: +82-2-450-4207 or +82-2-444-4207
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17
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Lv J, Zhou Y, Zhou N, Wang Z, Chen J, Chen H, Wang D, Zhou L, Wei K, Zhang H, Tang K, Ma J, Liu Y, Wan Y, Zhang Y, Zhang H, Huang B. Epigenetic modification of CSDE1 locus dictates immune recognition of nascent tumorigenic cells. Sci Transl Med 2023; 15:eabq6024. [PMID: 36724242 DOI: 10.1126/scitranslmed.abq6024] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 01/12/2023] [Indexed: 02/03/2023]
Abstract
Weak immunogenicity of tumor cells is a root cause for the ultimate failure of immunosurveillance and immunotherapy. Although tumor evolution can be shaped by immunoediting toward a less immunogenic phenotype, mechanisms governing the initial immunogenicity of primordial tumor cells or original cancer stem cells remain obscure. Here, using a single tumor-repopulating cell (TRC) to form tumors in immunodeficient or immunocompetent mice, we demonstrated that immunogenic heterogeneity is an inherent trait of tumorigenic cells defined by the activation status of signal transducer and activator of transcription 1 (STAT1) protein in the absence of immune pressure. Subsequent investigation identified that the RNA binding protein cold shock domain-containing protein E1 (CSDE1) can promote STAT1 dephosphorylation by stabilizing T cell protein tyrosine phosphatase (TCPTP). A methyltransferase SET and MYN domain-containing 3 (SMYD3) was further identified to mediate H3K4 trimethylation of CSDE1 locus, which was under the regulation of mechanotransduction by cell-matrix and cell-cell contacts. Thus, owing to the differential epigenetic modification and subsequent differential expression of CSDE1, nascent tumorigenic cells may exhibit either a high or low immunogenicity. This identified SMYD3-CSDE1 pathway represents a potential prognostic marker for cancer immunotherapy effectiveness that requires further investigation.
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Affiliation(s)
- Jiadi Lv
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing 100005, China
| | - Yabo Zhou
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing 100005, China
| | - Nannan Zhou
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing 100005, China
| | - Zhenfeng Wang
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing 100005, China
| | - Jie Chen
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing 100005, China
| | - Haoran Chen
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing 100005, China
| | - Dianheng Wang
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing 100005, China
| | - Li Zhou
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing 100005, China
| | - Keke Wei
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Huafeng Zhang
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ke Tang
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jingwei Ma
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yuying Liu
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing 100005, China
| | - Yonghong Wan
- McMaster Immunology Research Centre and Department of Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Yi Zhang
- Biotherapy Center and Cancer Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Haizeng Zhang
- Department of Medical Oncology, National Cancer Center, Cancer Hospital, CAMS and Peking Union Medical College, Beijing 100021, China
| | - Bo Huang
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing 100005, China
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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18
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Coppo R, Kondo J, Iida K, Okada M, Onuma K, Tanaka Y, Kamada M, Ohue M, Kawada K, Obama K, Inoue M. Distinct but interchangeable subpopulations of colorectal cancer cells with different growth fates and drug sensitivity. iScience 2023; 26:105962. [PMID: 36718360 PMCID: PMC9883198 DOI: 10.1016/j.isci.2023.105962] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 11/22/2022] [Accepted: 01/09/2023] [Indexed: 01/14/2023] Open
Abstract
Dynamic changes in cell properties lead to intratumor heterogeneity; however, the mechanisms of nongenetic cellular plasticity remain elusive. When the fate of each cell from colorectal cancer organoids was tracked through a clonogenic growth assay, the cells showed a wide range of growth ability even within the clonal organoids, consisting of distinct subpopulations; the cells generating large spheroids and the cells generating small spheroids. The cells from the small spheroids generated only small spheroids (S-pattern), while the cells from the large spheroids generated both small and large spheroids (D-pattern), both of which were tumorigenic. Transition from the S-pattern to the D-pattern occurred by various extrinsic triggers, in which Notch signaling and Musashi-1 played a key role. The S-pattern spheroids were resistant to chemotherapy and transited to the D-pattern upon drug treatment through Notch signaling. As the transition is linked to the drug resistance, it can be a therapeutic target.
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Affiliation(s)
- Roberto Coppo
- Department of Clinical Bio-resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Jumpei Kondo
- Department of Clinical Bio-resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Keita Iida
- Institute for Protein Research, Osaka University, Suita, Osaka, Japan
| | - Mariko Okada
- Institute for Protein Research, Osaka University, Suita, Osaka, Japan
| | - Kunishige Onuma
- Department of Clinical Bio-resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshihisa Tanaka
- Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan,RIKEN Center for Computational Science, HPC- and AI-driven Drug Development Platform Division, Biomedical Computational Intelligence Unit, Hyogo, Japan
| | - Mayumi Kamada
- Department of Biomedical Data Intelligence, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masayuki Ohue
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan
| | - Kenji Kawada
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kazutaka Obama
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masahiro Inoue
- Department of Clinical Bio-resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan,Corresponding author
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19
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Nagaraju GP, Farran B, Luong T, El-Rayes BF. Understanding the molecular mechanisms that regulate pancreatic cancer stem cell formation, stemness and chemoresistance: A brief overview. Semin Cancer Biol 2023; 88:67-80. [PMID: 36535506 DOI: 10.1016/j.semcancer.2022.12.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
Pancreatic cancer is one of the most aggressive cancers worldwide due to the resistances to conventional therapies and early metastasis. Recent research has shown that cancer stem cell populations modulate invasiveness, recurrence, and drug resistance in various cancers, including pancreatic cancer. Pancreatic cancer stem cells (PaCSCs) are characterized by their high plasticity and self-renewal capacities that endow them with unique metabolic, metastatic, and chemoresistant properties. Understanding the exact molecular and signaling mechanisms that underlay malignant processes in PaCSCs is instrumental for developing novel therapeutic modalities that overcome the limitations of current therapeutic regimens. In this paper, we provide an updated review of the latest research in the field and summarize the current knowledge of PaCSCs characteristics, cellular metabolism, stemness, and drug resistance. We explore how the crosstalk between the TME and PaCSCs influences stemness. We also highlight some of the key signalling pathways involved in PaCSCs stemness and drug evasion. The aim of this review is to explore how PaCSCs develop, maintain their properties, and drive tumor relapse in PC. The last section explores some of the latest therapeutic strategies aimed at targeting PaCSCs.
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Affiliation(s)
- Ganji Purnachandra Nagaraju
- Department of Hematology and Oncology, Heersink School of Medicine, University of Alabama, Birmingham, AL 35201, USA.
| | - Batoul Farran
- Department of Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Tha Luong
- Department of Hematology and Oncology, Heersink School of Medicine, University of Alabama, Birmingham, AL 35201, USA
| | - Bassel F El-Rayes
- Department of Hematology and Oncology, Heersink School of Medicine, University of Alabama, Birmingham, AL 35201, USA.
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20
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Niu Y, Yang W, Qian H, Sun Y. Intracellular and extracellular factors of colorectal cancer liver metastasis: a pivotal perplex to be fully elucidated. Cancer Cell Int 2022; 22:341. [DOI: 10.1186/s12935-022-02766-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 10/19/2022] [Indexed: 11/09/2022] Open
Abstract
AbstractMetastasis is the leading cause of death in colorectal cancer (CRC) patients, and the liver is the most common site of metastasis. Tumor cell metastasis can be thought of as an invasion-metastasis cascade and metastatic organotropism is thought to be a process that relies on the intrinsic properties of tumor cells and their interactions with molecules and cells in the microenvironment. Many studies have provided new insights into the molecular mechanism and contributing factors involved in CRC liver metastasis for a better understanding of the organ-specific metastasis process. The purpose of this review is to summarize the theories that explain CRC liver metastasis at multiple molecular dimensions (including genetic and non-genetic factors), as well as the main factors that cause CRC liver metastasis. Many findings suggest that metastasis may occur earlier than expected and with specific organ-anchoring property. The emergence of potential metastatic clones, the timing of dissemination, and the distinct routes of metastasis have been explained by genomic studies. The main force of CRC liver metastasis is also thought to be epigenetic alterations and dynamic phenotypic traits. Furthermore, we review key extrinsic factors that influence CRC cell metastasis and liver tropisms, such as pre-niches, tumor stromal cells, adhesion molecules, and immune/inflammatory responses in the tumor microenvironment. In addition, biomarkers associated with early diagnosis, prognosis, and recurrence of liver metastasis from CRC are summarized to enlighten potential clinical practice, including some markers that can be used as therapeutic targets to provide new perspectives for the treatment strategies of CRC liver metastasis.
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21
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De Angelis ML, Francescangeli F, Nicolazzo C, Xhelili E, La Torre F, Colace L, Bruselles A, Macchia D, Vitale S, Gazzaniga P, Baiocchi M, Zeuner A. An Orthotopic Patient-Derived Xenograft (PDX) Model Allows the Analysis of Metastasis-Associated Features in Colorectal Cancer. Front Oncol 2022; 12:869485. [PMID: 35837106 PMCID: PMC9275818 DOI: 10.3389/fonc.2022.869485] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 06/02/2022] [Indexed: 11/24/2022] Open
Abstract
Metastasis is the primary cause of death in patients with colorectal cancer (CRC), urging the need for preclinical models that recapitulate the metastatic process at the individual patient level. We used an orthotopic patient-derived xenograft (PDX) obtained through the direct implantation of freshly dissociated CRC cells in the colon of immunocompromised mice to model the metastatic process. Ortho-PDX engraftment was associated to a specific set of molecular features of the parental tumor, such as epithelial-to-mesenchymal transition (EMT), TGF-β pathway activation, increased expression of stemness-associated factors and higher numbers of circulating tumor cells (CTCs) clusters expressing the metastatic marker CD44v6. A parallel analysis of orthotopic/metastatic xenografts and organoids showed that tumor cells underwent mesenchymal-to-epithelial transition at the metastatic site and that metastasis-derived organoids had increased chemotherapy resistance. These observations support the usefulness of ortho-PDX as a preclinical model to study metastasis-related features and provide preliminary evidence that EMT/stemness properties of primary colorectal tumors may be crucial for orthotopic tumor engraftment.
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Affiliation(s)
- Maria Laura De Angelis
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | | | - Chiara Nicolazzo
- Department of Molecular Medicine, Liquid Biopsy Unit, Sapienza University, Rome, Italy
| | - Eljona Xhelili
- Surgical Sciences and Emergency Department, Policlinico Umberto I/Sapienza University of Rome, Rome, Italy
| | - Filippo La Torre
- Surgical Sciences and Emergency Department, Policlinico Umberto I/Sapienza University of Rome, Rome, Italy
| | - Lidia Colace
- Department of Surgical Sciences, Policlinico Umberto I/Sapienza University of Rome, Rome, Italy
| | - Alessandro Bruselles
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Daniele Macchia
- Center of Animal research and Welfare, Istituto Superiore di Sanità, Rome, Italy
| | - Sara Vitale
- Department of Medicine and Traslational Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Paola Gazzaniga
- Department of Molecular Medicine, Liquid Biopsy Unit, Sapienza University, Rome, Italy
| | - Marta Baiocchi
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Ann Zeuner
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
- *Correspondence: Ann Zeuner,
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22
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Shrestha S, Banstola A, Jeong JH, Seo JH, Yook S. Targeting Cancer Stem Cells: Therapeutic and diagnostic strategies by the virtue of nanoparticles. J Control Release 2022; 348:518-536. [PMID: 35709876 DOI: 10.1016/j.jconrel.2022.06.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 06/08/2022] [Accepted: 06/09/2022] [Indexed: 12/18/2022]
Abstract
Cancer stem cells (CSCs) are the subpopulation of cells present within a tumor with the properties of self-renewing, differentiating, and proliferating. Owing to the presence of ATP-binding cassette drug pumps and increased expression of anti-apoptotic proteins, the conventional chemotherapeutic agents have failed to eliminate CSCs resulting in relapse and resistance of cancer. Therefore, to obtain long-lasting clinical responses and avoid the recurrence of cancer, it is crucial to develop an efficient strategy targeting CSCs by either employing a differentiation therapy or specifically delivering drugs to CSCs. Several intracellular and extracellular cancer specific biomarkers are overexpressed by CSCs and are utilized as targets for the development of new approaches in the diagnosis and treatment of CSCs. Moreover, several nanostructured particles, alone or in combination with current treatment approaches, have been used to improve the detection, imaging, and targeting of CSCs, thus addressing the limitations of cancer therapies. Targeting CSC surface markers, stemness-related signaling pathways, and tumor microenvironmental signals has improved the detection and eradication of CSCs and, therefore, tumor diagnosis and treatment. This review summarizes a variety of promising nanoparticles targeting the surface biomarkers of CSCs for the detection and eradication of tumor-initiating stem cells, used in combination with other treatment regimens.
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Affiliation(s)
- Samjhana Shrestha
- College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Dalseo-Gu, Daegu 42601, Republic of Korea
| | - Asmita Banstola
- College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Dalseo-Gu, Daegu 42601, Republic of Korea; Wellman Center for Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School, Boston, MA 02114, USA
| | - Jee-Heon Jeong
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Ji Hae Seo
- Department of Biochemistry, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea
| | - Simmyung Yook
- College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Dalseo-Gu, Daegu 42601, Republic of Korea.
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23
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Chowdhury F, Huang B, Wang N. Forces in stem cells and cancer stem cells. Cells Dev 2022; 170:203776. [DOI: 10.1016/j.cdev.2022.203776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/26/2022] [Accepted: 03/22/2022] [Indexed: 10/18/2022]
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24
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Generation of Cancer Stem/Initiating Cells by Cell-Cell Fusion. Int J Mol Sci 2022; 23:ijms23094514. [PMID: 35562905 PMCID: PMC9101717 DOI: 10.3390/ijms23094514] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/10/2022] [Accepted: 04/17/2022] [Indexed: 02/04/2023] Open
Abstract
CS/ICs have raised great expectations in cancer research and therapy, as eradication of this key cancer cell type is expected to lead to a complete cure. Unfortunately, the biology of CS/ICs is rather complex, since no common CS/IC marker has yet been identified. Certain surface markers or ALDH1 expression can be used for detection, but some studies indicated that cancer cells exhibit a certain plasticity, so CS/ICs can also arise from non-CS/ICs. Another problem is intratumoral heterogeneity, from which it can be inferred that different CS/IC subclones must be present in the tumor. Cell–cell fusion between cancer cells and normal cells, such as macrophages and stem cells, has been associated with the generation of tumor hybrids that can exhibit novel properties, such as an enhanced metastatic capacity and even CS/IC properties. Moreover, cell–cell fusion is a complex process in which parental chromosomes are mixed and randomly distributed among daughter cells, resulting in multiple, unique tumor hybrids. These, if they have CS/IC properties, may contribute to the heterogeneity of the CS/IC pool. In this review, we will discuss whether cell–cell fusion could also lead to the origin of different CS/ICs that may expand the overall CS/IC pool in a primary tumor.
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25
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Ternes D, Tsenkova M, Pozdeev VI, Meyers M, Koncina E, Atatri S, Schmitz M, Karta J, Schmoetten M, Heinken A, Rodriguez F, Delbrouck C, Gaigneaux A, Ginolhac A, Nguyen TTD, Grandmougin L, Frachet-Bour A, Martin-Gallausiaux C, Pacheco M, Neuberger-Castillo L, Miranda P, Zuegel N, Ferrand JY, Gantenbein M, Sauter T, Slade DJ, Thiele I, Meiser J, Haan S, Wilmes P, Letellier E. The gut microbial metabolite formate exacerbates colorectal cancer progression. Nat Metab 2022; 4:458-475. [PMID: 35437333 PMCID: PMC9046088 DOI: 10.1038/s42255-022-00558-0] [Citation(s) in RCA: 172] [Impact Index Per Article: 57.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 02/25/2022] [Indexed: 02/07/2023]
Abstract
The gut microbiome is a key player in the immunomodulatory and protumorigenic microenvironment during colorectal cancer (CRC), as different gut-derived bacteria can induce tumour growth. However, the crosstalk between the gut microbiome and the host in relation to tumour cell metabolism remains largely unexplored. Here we show that formate, a metabolite produced by the CRC-associated bacterium Fusobacterium nucleatum, promotes CRC development. We describe molecular signatures linking CRC phenotypes with Fusobacterium abundance. Cocultures of F. nucleatum with patient-derived CRC cells display protumorigenic effects, along with a metabolic shift towards increased formate secretion and cancer glutamine metabolism. We further show that microbiome-derived formate drives CRC tumour invasion by triggering AhR signalling, while increasing cancer stemness. Finally, F. nucleatum or formate treatment in mice leads to increased tumour incidence or size, and Th17 cell expansion, which can favour proinflammatory profiles. Moving beyond observational studies, we identify formate as a gut-derived oncometabolite that is relevant for CRC progression.
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Affiliation(s)
- Dominik Ternes
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Mina Tsenkova
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Vitaly Igorevich Pozdeev
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Marianne Meyers
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Eric Koncina
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Sura Atatri
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Martine Schmitz
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Jessica Karta
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Maryse Schmoetten
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Almut Heinken
- School of Medicine, National University of Ireland, Galway, Ireland
- Ryan Institute, National University of Galway, Galway, Ireland
| | - Fabien Rodriguez
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Catherine Delbrouck
- Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Anthoula Gaigneaux
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Aurelien Ginolhac
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Tam Thuy Dan Nguyen
- Department of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Lea Grandmougin
- Systems Ecology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Audrey Frachet-Bour
- Systems Ecology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Camille Martin-Gallausiaux
- Systems Ecology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Maria Pacheco
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | | | - Paulo Miranda
- National Center of Pathology, Laboratoire National de Santé, Dudelange, Luxembourg
| | - Nikolaus Zuegel
- Department of Surgery, Centre Hospitalier Emile Mayrisch, Esch-sur-Alzette, Luxembourg
| | - Jean-Yves Ferrand
- Clinical and Epidemiological Investigation Center, Department of Population Health, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Manon Gantenbein
- Clinical and Epidemiological Investigation Center, Department of Population Health, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Thomas Sauter
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Daniel Joseph Slade
- Department of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Ines Thiele
- School of Medicine, National University of Ireland, Galway, Ireland
- Ryan Institute, National University of Galway, Galway, Ireland
- Discipline of Microbiology, School of Natural Sciences, National University of Ireland, Galway, Ireland
- APC Microbiome, Cork, Ireland
| | - Johannes Meiser
- Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Serge Haan
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
| | - Paul Wilmes
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg
- Systems Ecology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Elisabeth Letellier
- Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg.
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26
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Hashemi M, abbasiazam A, Oraee-Yazdani S, Lenzer J. Response of human glioblastoma cells to hyperthermia: Cellular apoptosis and molecular events. Tissue Cell 2022; 75:101751. [DOI: 10.1016/j.tice.2022.101751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/03/2022] [Indexed: 10/19/2022]
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27
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Fan B, Zhang Q, Wang N, Wang G. LncRNAs, the Molecules Involved in Communications With Colorectal Cancer Stem Cells. Front Oncol 2022; 12:811374. [PMID: 35155247 PMCID: PMC8829571 DOI: 10.3389/fonc.2022.811374] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/07/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer stem cells (CRCSCs) can actively self-renew, as well as having multidirectional differentiation and tumor regeneration abilities. Because the high functional activities of CRCSCs are associated with low cure rates in patients with colorectal cancer, efforts have sought to determine the function and regulatory mechanisms of CRCSCs. To date, however, the potential regulatory mechanisms of CRCSCs remain incompletely understood. Many non-coding genes are involved in tumor invasion and spread through their regulation of CRCSCs, with long non-coding RNAs (lncRNAs) being important non-coding RNAs. LncRNAs may be involved in the colorectal cancer development and drug resistance through their regulation of CRCSCs. This review systematically evaluates the latest research on the ability of lncRNAs to regulate CRCSC signaling pathways and the involvement of these lncRNAs in colorectal cancer promotion and suppression. The regulatory network of lncRNAs in the CRCSC signaling pathway has been determined. Further analysis of the potential clinical applications of lncRNAs as novel clinical diagnostic and prognostic biomarkers and therapeutic targets for colorectal cancer may provide new ideas and protocols for the prevention and treatment of colorectal cancer.
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Affiliation(s)
- Boyang Fan
- Department of Colorectal Cancer Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qian Zhang
- Department of Colorectal Surgery, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | - Ning Wang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Guiyu Wang
- Department of Colorectal Cancer Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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28
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Ding L, Yang Y, Lu Q, Cao Z, Weygant N. Emerging Prospects for the Study of Colorectal Cancer Stem Cells using Patient-Derived Organoids. Curr Cancer Drug Targets 2022; 22:195-208. [DOI: 10.2174/1568009622666220117124546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/29/2021] [Accepted: 11/24/2021] [Indexed: 11/22/2022]
Abstract
Abstract:
Human colorectal cancer (CRC) patient-derived organoids (PDOs) are a powerful ex vivo platform to directly assess the impact of molecular alterations and therapies on tumor cell proliferation, differentiation, response to chemotherapy, tumor-microenvironment interactions, and other facets of CRC biology. Next-generation sequencing studies have demonstrated that CRC is a highly heterogeneous disease with multiple distinct subtypes. PDOs are a promising new tool to study CRC due to their ability to accurately recapitulate their source tumor and thus reproduce this heterogeneity. This review summarizes the state-of-the-art for CRC PDOs in the study of cancer stem cells (CSCs) and the cancer stem cell niche. Areas of focus include the relevance of PDOs to understanding CSC-related paracrine signaling, identifying interactions between CSCs and the tumor microenvironment, and modeling CSC-driven resistance to chemotherapies and targeted therapies. Finally, we summarize current findings regarding the identification and verification of CSC targets using PDOs and their potential use in personalized medicine.
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Affiliation(s)
- Ling Ding
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, CN 350122
| | - Yuning Yang
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, CN 350122
| | - Qin Lu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, CN 350122
| | - Zhiyun Cao
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, CN 350122
| | - Nathaniel Weygant
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, CN 350122
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29
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Puig I, Palmer HG. A Label Retaining System to Capture Slow-Cycling Cancer Cells. Methods Mol Biol 2022; 2535:85-92. [PMID: 35867224 DOI: 10.1007/978-1-0716-2513-2_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Dormant or slow-cycling tumor cells can form a residual chemoresistant reservoir responsible for relapse in patients, years after curative surgery and adjuvant therapy. Slow-cycling cancer cells (SCCC) represent a cellular status rather than a cell population present in a minor proportion, even in growing tumors. We have adapted the pulse-chase expression of histone H2B fused to enhanced GFP (H2BeGFP) for labelling and isolating SCCC. SCCC show cancer-initiation potential and enhanced chemoresistance, and present a distinctive nongenetic and cell-autonomous gene expression profile shared across different tumor types. The use of our H2BeGFP pulse-chase method opens the possibility to study live SCCC in any growing tissue either cancerous or normal.
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Affiliation(s)
- Isabel Puig
- Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology (VHIO), CIBERONC, Barcelona, Spain
| | - Héctor G Palmer
- Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology (VHIO), CIBERONC, Barcelona, Spain.
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30
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Colorectal Cancer Stem Cells: An Overview of Evolving Methods and Concepts. Cancers (Basel) 2021; 13:cancers13235910. [PMID: 34885020 PMCID: PMC8657142 DOI: 10.3390/cancers13235910] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary In recent years, colorectal cancer stem cells (cCSCs) have been the object of intense investigation for their promise to disclose new aspects of colorectal cancer cell biology, as well as to devise new treatment strategies for colorectal cancer (CRC). However, accumulating studies on cCSCs by complementary technologies have progressively disclosed their plastic nature, i.e., their capability to acquire different phenotypes and/or functions under different circumstances in response to both intrinsic and extrinsic signals. In this review, we aim to recapitulate how a progressive methodological development has contributed to deepening and remodeling the concept of cCSCs over time, up to the present. Abstract Colorectal cancer (CRC) represents one of the most deadly cancers worldwide. Colorectal cancer stem cells (cCSCs) are the driving units of CRC initiation and development. After the concept of cCSC was first formulated in 2007, a huge bulk of research has contributed to expanding its definition, from a cell subpopulation defined by a fixed phenotype in a plastic entity modulated by complex interactions with the tumor microenvironment, in which cell position and niche-driven signals hold a prominent role. The wide development of cellular and molecular technologies recent years has been a main driver of advancements in cCSCs research. Here, we will give an overview of the parallel role of technological progress and of theoretical evolution in shaping the concept of cCSCs.
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31
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Wursthorn A, Schwager C, Kurth I, Peitzsch C, Herold-Mende C, Debus J, Abdollahi A, Nowrouzi A. High-Complexity cellular barcoding and clonal tracing reveals stochastic and deterministic parameters of radiation resistance. Int J Cancer 2021; 150:663-677. [PMID: 34706068 DOI: 10.1002/ijc.33855] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 07/16/2021] [Accepted: 08/26/2021] [Indexed: 11/10/2022]
Abstract
It is elusive whether clonal selection of tumor cells in response to ionizing radiation (IR) is a deterministic or stochastic process. With high resolution clonal barcoding and tracking of over 400 000 HNSCC patient-derived tumor cells the clonal dynamics of tumor cells in response to IR was analyzed. Fractionated IR induced a strong selective pressure for clonal reduction which significantly exceeded uniform clonal survival probabilities indicative for a strong clone-to-clone difference within tumor cell lines. IR induced clonal reduction affected the majority of tumor cells ranging between 96% and 75% and correlated to the degree of radiation sensitivity. Survival to IR is driven by a deterministic clonal selection of a smaller population which commonly survives radiation, while increased clonogenic capacity is a result of clonal competition of cells which have been selected stochastically. A 2-fold increase in radiation resistance results in a 4-fold (P < .05) higher deterministic clonal selection showing that the ratio of these parameters is amenable to radiation sensitivity which correlates to prognostic biomarkers of HNSCC. Evidence for the existence of a rare subpopulation with an intrinsically radiation resistant phenotype commonly surviving IR was found at a frequency of 0.6% to 3.3% (P < .001, FDR 3%). With cellular barcoding we introduce a novel functional heterogeneity associated qualitative readout for tracking dynamics of clonogenic survival in response to radiation. This enables the quantification of intrinsically radiation resistant tumor cells from patient samples and reveals the contribution of stochastic and deterministic clonal selection processes in response to IR.
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Affiliation(s)
- Anne Wursthorn
- Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Radiation Oncology, Heidelberg University Hospital (UKHD), National Center for Tumor Diseases (NCT), Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.,German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany
| | - Christian Schwager
- Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Radiation Oncology, Heidelberg University Hospital (UKHD), National Center for Tumor Diseases (NCT), Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.,German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany
| | - Ina Kurth
- German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany.,Department of Radiooncology and Radiobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Claudia Peitzsch
- OncoRay-National Center for Radiation Research in Oncology (NCRO), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,National Center for Tumor Diseases (NCT), Dresden, Germany.,German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany
| | - Christel Herold-Mende
- German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany.,Department of Neurosurgery, Division of Experimental Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Jürgen Debus
- Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Radiation Oncology, Heidelberg University Hospital (UKHD), National Center for Tumor Diseases (NCT), Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.,German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany
| | - Amir Abdollahi
- Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Radiation Oncology, Heidelberg University Hospital (UKHD), National Center for Tumor Diseases (NCT), Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.,German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany
| | - Ali Nowrouzi
- Clinical Cooperation Unit Translational Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Radiation Oncology, Heidelberg University Hospital (UKHD), National Center for Tumor Diseases (NCT), Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany.,Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany.,German Cancer Consortium (DKTK), Core Center, Heidelberg, Germany
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32
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Jiang X, Liang L, Chen G, Liu C. Modulation of Immune Components on Stem Cell and Dormancy in Cancer. Cells 2021; 10:2826. [PMID: 34831048 PMCID: PMC8616319 DOI: 10.3390/cells10112826] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 10/10/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) refer to a certain subpopulation within the tumor entity that is characterized by restricted cellular proliferation and multipotent differentiation potency. The existence of CSCs has been proven to contribute to the heterogeneity of malignancies, accounting for intensified tumorigenesis, treatment resistance, and metastatic spread. Dormancy was proposed as a reversible state of cancer cells that are temporarily arrested in the cell cycle, possessing several hallmarks that facilitate their survival within a devastating niche. This transient period is evoked to enter an actively proliferating state by multiple regulatory alterations, and one of the most significant and complex factors comes from local and systemic inflammatory reactions and immune components. Although CSCs and dormant cancer cells share several similarities, the clear relationship between these two concepts remains unclear. Thus, the detailed mechanism of immune cells interacting with CSCs and dormant cancer cells also warrants elucidation for prevention of cancer relapse and metastasis. In this review, we summarize recent findings and prospective studies on CSCs and cancer dormancy to conclude the relationship between these two concepts. Furthermore, we aim to outline the mechanism of immune components in interfering with CSCs and dormant cancer cells to provide a theoretical basis for the prevention of relapse and metastasis.
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Affiliation(s)
| | | | | | - Caigang Liu
- Department of Oncology, Shengjing Hospital, China Medical University, Shenyang 110004, China; (X.J.); (L.L.); (G.C.)
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33
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The Ultrastructural Analysis of Human Colorectal Cancer Stem Cell-Derived Spheroids and Their Mouse Xenograft Shows That the Same Cells Types Have Different Ratios. BIOLOGY 2021; 10:biology10090929. [PMID: 34571806 PMCID: PMC8465655 DOI: 10.3390/biology10090929] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/08/2021] [Accepted: 09/16/2021] [Indexed: 12/21/2022]
Abstract
Spheroids from primary colorectal cancer cells and their mice xenografts have emerged as useful preclinical models for cancer research as they replicate tumor features more faithfully as compared to cell lines. While 3D models provide a reliable system for drug discovery and testing, their structural complexity represents a challenge and their structure-function relationships are only partly understood. Here, we present a comparative ultrastructural and flow citometric analysis of patient colorectal cancer-derived spheroids and their mice xenografts. Ultrastructural observations highlighted that multicellular spheroids and their xenografts contain the same cancer cell types but with different ratios, specifically multicellular spheroids were enriched in cells with a stem-like phenotype, while xenografts had an increased amount of lipid droplets-containing cells. The flow cytometric analysis for stem cell marker and activity showed enrichment of stem-like cells presence and activity in spheroids while xenografts had the inverse response. Our results evidence the effects on cancer cells of different in vitro and in vivo microenvironments. Those differences have to be paid into account in designing innovative experimental models for personalized drug testing.
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34
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Yin H, Gao T, Xie J, Huang Z, Zhang X, Yang F, Qi W, Yang Z, Zhou T, Gao G, Yang X. FUBP1 promotes colorectal cancer stemness and metastasis via DVL1-mediated activation of Wnt/β-catenin signaling. Mol Oncol 2021; 15:3490-3512. [PMID: 34288405 PMCID: PMC8637553 DOI: 10.1002/1878-0261.13064] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 05/02/2021] [Accepted: 07/19/2021] [Indexed: 11/17/2022] Open
Abstract
Distant metastasis is, unfortunately, the leading cause of death in colorectal cancer (CRC). Approximately 50% of CRC patients develop liver metastases, while 10–30% of patients develop pulmonary metastases. The occurrence of metastasis is considered to be almost exclusively driven by cancer stem cells (CSCs) formation. However, the key molecules that confer the transformation to stem cells in CRC, and subsequent metastasis, remain unclear. Far upstream element‐binding protein 1 (FUBP1), a transcriptional regulator of c‐Myc, was screened in CSCs of CRC by mass spectrometry and was examined by immunohistochemistry in a cohort of CRC tissues. FUBP1 was upregulated in 85% of KRAS‐mutant and 25% of wild‐type CRC patients. Further, whether in KRAS‐mutant or wild‐type patients, elevated FUBP1 was positively correlated with CRC lymph node metastasis and clinical stage, and negatively associated with overall survival. Overexpression of FUBP1 significantly enhanced CRC cell migration, invasion, tumor sphere formation, and CD133 and ALDH1 expression in vitro, and tumorigenicity in vivo. Mechanistically, FUBP1 promoted the initiation of CSCs by activating Wnt/β‐catenin signaling via directly binding to the promoter of DVL1, a potent activator of β‐catenin. Knockdown of DVL1 significantly inhibited the transformation to stem cells in, as well as the tumorigenicity of, CRC. Activation of Wnt/β‐catenin signaling by DVL1 increased pluripotent transcription factors, including c‐Myc, NANOG, and SOX2. Moreover, FUBP1 was upregulated at the post‐transcriptional level. Elevated FUBP1 levels in KRAS wild‐type CRC patients is due to the decrease in Smurf2, which promotes ubiquitin‐mediated degradation of FUBP1. In contrast, FUBP1 was upregulated in KRAS‐mutant patients through both inhibition of caspase 3‐dependent cleavage and decreased Smurf2. Our results demonstrate, for the first time, that FUBP1 is an oncogene, initiating the development of CSCs, as well as a new powerful endogenous Wnt‐signaling agonist that could provide an important prognostic factor and therapeutic target for metastasis in both KRAS‐mutant and wild‐type CRC.
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Affiliation(s)
- Haofan Yin
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.,Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Tianxiao Gao
- Department of Biochemistry, Zhongshan School of Medicine, SunYat-sen University, Guangzhou, China
| | - Jinye Xie
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.,Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zhijian Huang
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.,Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xiaoyan Zhang
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.,Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Fengyu Yang
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.,Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Weiwei Qi
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.,Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zhonghan Yang
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.,Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Ti Zhou
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.,Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Guoquan Gao
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.,Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Guangdong Engineering & Technology Research Center for Gene Manipulation and Biomacromolecular Products, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Brain Function and Disease, Sun Yat-sen University, Guangzhou, China
| | - Xia Yang
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.,Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China
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35
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Dieter SM, Siegl C, Codó PL, Huerta M, Ostermann-Parucha AL, Schulz E, Zowada MK, Martin S, Laaber K, Nowrouzi A, Blatter M, Kreth S, Westermann F, Benner A, Uhrig U, Putzker K, Lewis J, Haegebarth A, Mumberg D, Holton SJ, Weiske J, Toepper LM, Scheib U, Siemeister G, Ball CR, Kuster B, Stoehr G, Hahne H, Johannes S, Lange M, Herbst F, Glimm H. Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer. Cell Rep 2021; 36:109394. [PMID: 34289372 DOI: 10.1016/j.celrep.2021.109394] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 04/08/2021] [Accepted: 06/23/2021] [Indexed: 02/07/2023] Open
Abstract
Novel treatment options for metastatic colorectal cancer (CRC) are urgently needed to improve patient outcome. Here, we screen a library of non-characterized small molecules against a heterogeneous collection of patient-derived CRC spheroids. By prioritizing compounds with inhibitory activity in a subset of-but not all-spheroid cultures, NCT02 is identified as a candidate with minimal risk of non-specific toxicity. Mechanistically, we show that NCT02 acts as molecular glue that induces ubiquitination of cyclin K (CCNK) and proteasomal degradation of CCNK and its complex partner CDK12. Knockout of CCNK or CDK12 decreases proliferation of CRC cells in vitro and tumor growth in vivo. Interestingly, sensitivity to pharmacological CCNK/CDK12 degradation is associated with TP53 deficiency and consensus molecular subtype 4 in vitro and in patient-derived xenografts. We thus demonstrate the efficacy of targeted CCNK/CDK12 degradation for a CRC subset, highlighting the potential of drug-induced proteolysis for difficult-to-treat types of cancer.
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Affiliation(s)
- Sebastian M Dieter
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany.
| | | | - Paula L Codó
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany; CureVac AG, 60325 Frankfurt am Main, Germany
| | - Mario Huerta
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany
| | - Anna L Ostermann-Parucha
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany
| | - Erik Schulz
- Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Martina K Zowada
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
| | - Sylvia Martin
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany
| | - Karin Laaber
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
| | - Ali Nowrouzi
- Division of Molecular and Translational Radiation Oncology, Heidelberg Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany
| | - Mona Blatter
- Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Neuroblastoma Genomics, DKFZ Heidelberg, 69120 Heidelberg, Germany
| | - Sina Kreth
- Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Neuroblastoma Genomics, DKFZ Heidelberg, 69120 Heidelberg, Germany
| | - Frank Westermann
- Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Neuroblastoma Genomics, DKFZ Heidelberg, 69120 Heidelberg, Germany
| | - Axel Benner
- Division of Biostatistics, DKFZ Heidelberg, 69120 Heidelberg, Germany
| | - Ulrike Uhrig
- European Molecular Biology Laboratory (EMBL), Chemical Biology Core Facility, 69117 Heidelberg, Germany
| | - Kerstin Putzker
- European Molecular Biology Laboratory (EMBL), Chemical Biology Core Facility, 69117 Heidelberg, Germany
| | - Joe Lewis
- European Molecular Biology Laboratory (EMBL), Chemical Biology Core Facility, 69117 Heidelberg, Germany
| | - Andrea Haegebarth
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany
| | - Dominik Mumberg
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany
| | - Simon J Holton
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany; Nuvisan Innovation Campus Berlin GmbH, 13353 Berlin, Germany
| | - Joerg Weiske
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany; Nuvisan Innovation Campus Berlin GmbH, 13353 Berlin, Germany
| | - Lena-Marit Toepper
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany; Nuvisan Innovation Campus Berlin GmbH, 13353 Berlin, Germany
| | - Ulrike Scheib
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany; Nuvisan Innovation Campus Berlin GmbH, 13353 Berlin, Germany
| | - Gerhard Siemeister
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany; Nuvisan Innovation Campus Berlin GmbH, 13353 Berlin, Germany
| | - Claudia R Ball
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 01307 Dresden, Germany; Center for Personalized Oncology, University Hospital Carl Gustav Carus Dresden at TU Dresden, 01307 Dresden, Germany
| | - Bernhard Kuster
- Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354 Freising, Germany
| | | | | | - Sarah Johannes
- Bayer AG, Research & Development, Pharmaceuticals, 42117 Wuppertal, Germany
| | - Martin Lange
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany; Nuvisan Innovation Campus Berlin GmbH, 13353 Berlin, Germany
| | - Friederike Herbst
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany
| | - Hanno Glimm
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 01307 Dresden, Germany; Center for Personalized Oncology, University Hospital Carl Gustav Carus Dresden at TU Dresden, 01307 Dresden, Germany.
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36
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Chowdhury F, Huang B, Wang N. Cytoskeletal prestress: The cellular hallmark in mechanobiology and mechanomedicine. Cytoskeleton (Hoboken) 2021; 78:249-276. [PMID: 33754478 PMCID: PMC8518377 DOI: 10.1002/cm.21658] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 03/16/2021] [Accepted: 03/17/2021] [Indexed: 12/13/2022]
Abstract
Increasing evidence demonstrates that mechanical forces, in addition to soluble molecules, impact cell and tissue functions in physiology and diseases. How living cells integrate mechanical signals to perform appropriate biological functions is an area of intense investigation. Here, we review the evidence of the central role of cytoskeletal prestress in mechanotransduction and mechanobiology. Elevating cytoskeletal prestress increases cell stiffness and reinforces cell stiffening, facilitates long-range cytoplasmic mechanotransduction via integrins, enables direct chromatin stretching and rapid gene expression, spurs embryonic development and stem cell differentiation, and boosts immune cell activation and killing of tumor cells whereas lowering cytoskeletal prestress maintains embryonic stem cell pluripotency, promotes tumorigenesis and metastasis of stem cell-like malignant tumor-repopulating cells, and elevates drug delivery efficiency of soft-tumor-cell-derived microparticles. The overwhelming evidence suggests that the cytoskeletal prestress is the governing principle and the cellular hallmark in mechanobiology. The application of mechanobiology to medicine (mechanomedicine) is rapidly emerging and may help advance human health and improve diagnostics, treatment, and therapeutics of diseases.
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Affiliation(s)
- Farhan Chowdhury
- Department of Mechanical Engineering and Energy ProcessesSouthern Illinois University CarbondaleCarbondaleIllinoisUSA
| | - Bo Huang
- Department of Immunology, Institute of Basic Medical Sciences & State Key Laboratory of Medical Molecular BiologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Ning Wang
- Department of Mechanical Science and EngineeringUniversity of Illinois at Urbana‐ChampaignUrbanaIllinoisUSA
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37
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Wang H, Gong P, Chen T, Gao S, Wu Z, Wang X, Li J, Marjani SL, Costa J, Weissman SM, Qi F, Pan X, Liu L. Colorectal Cancer Stem Cell States Uncovered by Simultaneous Single-Cell Analysis of Transcriptome and Telomeres. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2004320. [PMID: 33898197 PMCID: PMC8061397 DOI: 10.1002/advs.202004320] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 12/15/2020] [Indexed: 05/02/2023]
Abstract
Cancer stem cells (CSCs) presumably contribute to tumor progression and drug resistance, yet their definitive features have remained elusive. Here, simultaneous measurement of telomere length and transcriptome in the same cells enables systematic assessment of CSCs in primary colorectal cancer (CRC). The in-depth transcriptome profiled by SMART-seq2 is independently validated by high-throughput scRNA-seq using 10 × Genomics. It is found that rare CSCs exist in dormant state and display plasticity toward cancer epithelial cells (EPCs) that essentially are presumptive tumor-initiating cells (TICs), while both retaining the prominent signaling pathways including WNT, TGF-β, and HIPPO/YAP. Moreover, CSCs exhibit chromosome copy number variation (CNV) pattern resembling cancer EPCs but distinct from normal stem cells, suggesting the phylogenetic relationship between CSCs and cancer EPCs. Notably, CSCs maintain shorter telomeres and possess minimal telomerase activity consistent with their nonproliferative nature, unlike cancer EPCs. Additionally, the specific signature of CSCs particularly NOTUM, SMOC2, BAMBI, PHLDA1, and TNFRSF19 correlates with the prognosis of CRC. These findings characterize the heterogeneity of CSCs and their linkage to cancer EPCs/TICs, some of which are conventionally regarded as CSCs.
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Affiliation(s)
- Hua Wang
- State Key Laboratory of Medicinal Chemical BiologyNankai UniversityTianjin300350China
- Department of Cell Biology and GeneticsCollege of Life SciencesThe Key Laboratory of Bioactive Materials, Ministry of EducationNankai UniversityTianjin300071China
| | - Peng Gong
- State Key Laboratory of Medicinal Chemical BiologyNankai UniversityTianjin300350China
- Department of Cell Biology and GeneticsCollege of Life SciencesThe Key Laboratory of Bioactive Materials, Ministry of EducationNankai UniversityTianjin300071China
- Department of GeneticsYale School of MedicineNew HavenCT06520USA
| | - Tong Chen
- EHBIO Gene Technology co., LTDBeijing100029China
| | - Shan Gao
- Department of Cell Biology and GeneticsCollege of Life SciencesThe Key Laboratory of Bioactive Materials, Ministry of EducationNankai UniversityTianjin300071China
| | - Zhenfeng Wu
- School of Mathematical SciencesNankai UniversityTianjin300071China
| | - Xiaodong Wang
- Department of General SurgeryTianjin Medical University General HospitalTianjin300052China
| | - Jie Li
- State Key Laboratory of Medicinal Chemical BiologyNankai UniversityTianjin300350China
- Department of Cell Biology and GeneticsCollege of Life SciencesThe Key Laboratory of Bioactive Materials, Ministry of EducationNankai UniversityTianjin300071China
| | - Sadie L. Marjani
- Department of BiologyCentral Connecticut State UniversityNew BritainCT06050USA
| | - José Costa
- Department of Pathology, Yale School of MedicineNew HavenCT06520USA
| | | | - Feng Qi
- Department of General SurgeryTianjin Medical University General HospitalTianjin300052China
| | - Xinghua Pan
- Department of GeneticsYale School of MedicineNew HavenCT06520USA
- Department of Biochemistry and Molecular BiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouGuangdong Province510515China
- Guangdong Provincial Key Laboratory for Single Cell Technology and ApplicationGuangzhouGuangdong Province510515China
| | - Lin Liu
- State Key Laboratory of Medicinal Chemical BiologyNankai UniversityTianjin300350China
- Department of Cell Biology and GeneticsCollege of Life SciencesThe Key Laboratory of Bioactive Materials, Ministry of EducationNankai UniversityTianjin300071China
- Institute of Translational MedicineTianjin Union Medical CenterNankai UniversityTianjin300000China
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38
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Identification of a subpopulation of long-term tumor-initiating cells in colon cancer. Biosci Rep 2021; 40:225947. [PMID: 32729895 PMCID: PMC7447854 DOI: 10.1042/bsr20200437] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 06/30/2020] [Accepted: 07/22/2020] [Indexed: 12/27/2022] Open
Abstract
Long-term tumor-initiating cells (LT-TICs) are viewed as a quantifiable target for colon cancer therapy owing to their extensive self-renewal and tumorigenic and metastatic capacities. However, it is unknown which subpopulation of colon cancer cells contains LT-TICs. Here, based on the methods for isolating and identifying cancer stem cells (CSCs) and the functional features of LT-TICs, we aimed to identify a subpopulation of LT-TICs. Among the six cell lines assessed, our results showed that CD133 and CD44 coexpression was only detected in HCT116 and HT29 cell lines. In HCT116 and HT29 cells, CD133+CD44+ cells not only shared the extensive tumorigenic potential of LT-TICs but also functionally reproduced the behaviors of LT-TICs that drive tumor metastasis (TM) formation, suggesting that CD133+CD44+ cells are a typical representation of LT-TICs in colon cancer. Mechanistically, the enhanced capacity of CD133+CD44+ cells to drive metastasis involves the up-regulated expression of Wnt-, epithelial–mesenchymal transition (EMT)-, and metastasis-related genes in these cells. Additionally, CD133+CD44+ cells presented significant chemoresistance compared with corresponding nontumorigenic CD133−CD44− cells following exposure to oxaliplatin (OXLP) or 5-fluorouracil (5-FU). Accordingly, CD133+CD44+ cells contained lower reactive oxygen species (ROS) levels than CD1133−CD44− cells, and the low ROS levels in CD133+CD44+ cells were related to the enhancement of antioxidant defense systems. More importantly, CD133+CD44+ cells developed less DNA damage after exposure to chemotherapeutics than CD133−CD44− cells. In conclusion, we identified a subpopulation of LT-TICs in colon cancer.
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39
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Lei X, He Q, Li Z, Zou Q, Xu P, Yu H, Ding Y, Zhu W. Cancer stem cells in colorectal cancer and the association with chemotherapy resistance. Med Oncol 2021; 38:43. [PMID: 33738588 DOI: 10.1007/s12032-021-01488-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/01/2021] [Indexed: 12/13/2022]
Abstract
The incidence and mortality of colorectal cancer (CRC) have always been among the highest in the world, although the diagnosis and treatment are becoming more and more advanced. At present, the main reason is that patients have acquired drug resistance after long-term conventional drug treatment. An increasing number of evidences confirm the existence of cancer stem cells (CSCs), which are a group of special cells in cancer, only a small part of cancer cells. These special cell populations are not eliminated by chemotherapeutic drugs and result in tumor recurrence and metastasis after drug treatment. CSCs have the ability of self-renewal and multidirectional differentiation, which is associated with the occurrence and development of cancer. CSCs can be screened and identified by related surface markers. In this paper, the characteristic surface markers of CSCs in CRC and the related mechanism of drug resistance will be discussed in detail. A better understanding of the mechanism of CSCs resistance to chemotherapy may lead to better targeted therapy.
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Affiliation(s)
- Xue Lei
- Department of Pathology, Guangdong Medical University, No.1 Xincheng Road, Dongguan, 523808, Guangdong Province, China
| | - Qinglian He
- Department of Pathology, Guangdong Medical University, No.1 Xincheng Road, Dongguan, 523808, Guangdong Province, China
| | - Ziqi Li
- Department of Pathology, Guangdong Medical University, No.1 Xincheng Road, Dongguan, 523808, Guangdong Province, China
| | - Qian Zou
- Department of Pathology, Guangdong Medical University, No.1 Xincheng Road, Dongguan, 523808, Guangdong Province, China
| | - Pingrong Xu
- Department of Pathology, Guangdong Medical University, No.1 Xincheng Road, Dongguan, 523808, Guangdong Province, China
| | - Haibing Yu
- School of Public Health, Guangdong Medical University, Dongguan, 523808, Guangdong Province, China
| | - Yuanlin Ding
- School of Public Health, Guangdong Medical University, Dongguan, 523808, Guangdong Province, China
| | - Wei Zhu
- Department of Pathology, Guangdong Medical University, No.1 Xincheng Road, Dongguan, 523808, Guangdong Province, China.
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40
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Functional States in Tumor-Initiating Cell Differentiation in Human Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13051097. [PMID: 33806447 PMCID: PMC7961698 DOI: 10.3390/cancers13051097] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 02/28/2021] [Indexed: 12/19/2022] Open
Abstract
Simple Summary Different types of cells with tumor-initiating cell (TIC) activity contribute to colorectal cancer (CRC) progression and resistance to anti-cancer treatment. In this study, we aimed to understand whether different cell types exist within a patient-derived tumor culture, distinguishable by different patterns of their gene expression. By mRNA sequencing of patient-derived CRC cultures at the single-cell level, we defined expression programs that closely resemble differentiated cell populations of the normal intestine. Here, cell type-associated subpopulations showed differences in functional properties such as cell growth and energy metabolism. Subsequent functional analyses in vitro and in vivo demonstrated that metabolic states are linked to TIC activity in primary CRC cultures. We also show that TIC activity is dependent on oxidative phosphorylation, which may therefore represent a target for novel therapies. Abstract Intra-tumor heterogeneity of tumor-initiating cell (TIC) activity drives colorectal cancer (CRC) progression and therapy resistance. Here, we used single-cell RNA-sequencing of patient-derived CRC models to decipher distinct cell subpopulations based on their transcriptional profiles. Cell type-specific expression modules of stem-like, transit amplifying-like, and differentiated CRC cells resemble differentiation states of normal intestinal epithelial cells. Strikingly, identified subpopulations differ in proliferative activity and metabolic state. In summary, we here show at single-cell resolution that transcriptional heterogeneity identifies functional states during TIC differentiation. Furthermore, identified expression signatures are linked to patient prognosis. Targeting transcriptional states associated to cancer cell differentiation might unravel novel vulnerabilities in human CRC.
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41
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Sphyris N, Hodder MC, Sansom OJ. Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell. Cancers (Basel) 2021; 13:1000. [PMID: 33673710 PMCID: PMC7957493 DOI: 10.3390/cancers13051000] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/15/2021] [Accepted: 02/17/2021] [Indexed: 12/12/2022] Open
Abstract
The intestinal epithelium fulfils pleiotropic functions in nutrient uptake, waste elimination, and immune surveillance while also forming a barrier against luminal toxins and gut-resident microbiota. Incessantly barraged by extraneous stresses, the intestine must continuously replenish its epithelial lining and regenerate the full gamut of specialized cell types that underpin its functions. Homeostatic remodelling is orchestrated by the intestinal stem cell (ISC) niche: a convergence of epithelial- and stromal-derived cues, which maintains ISCs in a multipotent state. Following demise of homeostatic ISCs post injury, plasticity is pervasive among multiple populations of reserve stem-like cells, lineage-committed progenitors, and/or fully differentiated cell types, all of which can contribute to regeneration and repair. Failure to restore the epithelial barrier risks seepage of toxic luminal contents, resulting in inflammation and likely predisposing to tumour formation. Here, we explore how homeostatic niche-signalling pathways are subverted in tumorigenesis, enabling ISCs to gain autonomy from niche restraints ("ISC emancipation") and transform into cancer stem cells capable of driving tumour initiation, progression, and therapy resistance. We further consider the implications of the pervasive plasticity of the intestinal epithelium for the trajectory of colorectal cancer, the emergence of distinct molecular subtypes, the propensity to metastasize, and the development of effective therapeutic strategies.
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Affiliation(s)
- Nathalie Sphyris
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; (N.S.); (M.C.H.)
| | - Michael C. Hodder
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; (N.S.); (M.C.H.)
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK
| | - Owen J. Sansom
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; (N.S.); (M.C.H.)
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK
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42
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Plasticity in Colorectal Cancer: Why Cancer Cells Differentiate. Cancers (Basel) 2021; 13:cancers13040918. [PMID: 33671641 PMCID: PMC7926445 DOI: 10.3390/cancers13040918] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/09/2021] [Accepted: 02/17/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary The cancer stem cell hypothesis postulates that tumors arise from a few cells with self-renewal capabilities. The identification of stem cell markers, the development of mouse and human tumor organoids and their application in mouse models, allowing lineage tracing, helped to better understand the cancer stem cell model as well as the role of differentiation. This review aims at providing insights on the interplay between cancer stem cells and differentiated cells, as well as the importance of plasticity between the two states. Abstract The cancer stem cell hypothesis poses that the bulk of differentiated cells are non-tumorigenic and only a subset of cells with self-renewal capabilities drive tumor initiation and progression. This means that differentiation could have a tumor-suppressive effect. Accumulating evidence shows, however, that in some solid tumors, like colorectal cancer, such a hierarchical organization is necessary. The identification of Lgr5 as a reliable marker of normal intestinal epithelial stem cells, together with strategies to trace cell lineages within tumors and the possibility to selectively ablate these cells, have proven the relevance of Lgr5+ cells for cancer progression. On the contrary, the role of Lgr5− cells during this process remains largely unknown. In this review, we explore available evidence pointing towards possible selective advantages of cancer cells organized hierarchically and its resulting cell heterogeneity. Clear evidence of plasticity between cell states, in which loss of Lgr5+ cells can be replenished by dedifferentiation of Lgr5− cells, shows that cell hierarchies could grant adaptive traits to tumors upon changing selective pressures, including those derived from anticancer therapy, as well as during tumor progression to metastasis.
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Zhou HM, Zhang JG, Zhang X, Li Q. Targeting cancer stem cells for reversing therapy resistance: mechanism, signaling, and prospective agents. Signal Transduct Target Ther 2021; 6:62. [PMID: 33589595 PMCID: PMC7884707 DOI: 10.1038/s41392-020-00430-1] [Citation(s) in RCA: 250] [Impact Index Per Article: 62.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/26/2020] [Accepted: 10/08/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) show a self-renewal capacity and differentiation potential that contribute to tumor progression and therapy resistance. However, the underlying processes are still unclear. Elucidation of the key hallmarks and resistance mechanisms of CSCs may help improve patient outcomes and reduce relapse by altering therapeutic regimens. Here, we reviewed the identification of CSCs, the intrinsic and extrinsic mechanisms of therapy resistance in CSCs, the signaling pathways of CSCs that mediate treatment failure, and potential CSC-targeting agents in various tumors from the clinical perspective. Targeting the mechanisms and pathways described here might contribute to further drug discovery and therapy.
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Affiliation(s)
- He-Ming Zhou
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of medicine, No.100 Haining Road, 200080, Shanghai, People's Republic of China
| | - Ji-Gang Zhang
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of medicine, No.100 Haining Road, 200080, Shanghai, People's Republic of China
| | - Xue Zhang
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of medicine, No.100 Haining Road, 200080, Shanghai, People's Republic of China
| | - Qin Li
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of medicine, No.100 Haining Road, 200080, Shanghai, People's Republic of China.
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Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51. Cell Death Differ 2021; 28:2060-2082. [PMID: 33531658 PMCID: PMC8257675 DOI: 10.1038/s41418-020-00733-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 12/20/2020] [Accepted: 12/30/2020] [Indexed: 12/31/2022] Open
Abstract
Cancer stem cells (CSCs) are tumor subpopulations driving disease development, progression, relapse and therapy resistance, and their targeting ensures tumor eradication. CSCs display heterogeneous replication stress (RS), but the functionality/relevance of the RS response (RSR) centered on the ATR-CHK1 axis is debated. Here, we show that the RSR is efficient in primary CSCs from colorectal cancer (CRC-SCs), and describe unique roles for PARP1 and MRE11/RAD51. First, we demonstrated that PARP1 is upregulated in CRC-SCs resistant to several replication poisons and RSR inhibitors (RSRi). In these cells, PARP1 modulates replication fork speed resulting in low constitutive RS. Second, we showed that MRE11 and RAD51 cooperate in the genoprotection and mitosis execution of PARP1-upregulated CRC-SCs. These roles represent therapeutic vulnerabilities for CSCs. Indeed, PARP1i sensitized CRC-SCs to ATRi/CHK1i, inducing replication catastrophe, and prevented the development of resistance to CHK1i. Also, MRE11i + RAD51i selectively killed PARP1-upregulated CRC-SCs via mitotic catastrophe. These results provide the rationale for biomarker-driven clinical trials in CRC using distinct RSRi combinations.
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Lv J, Liu Y, Cheng F, Li J, Zhou Y, Zhang T, Zhou N, Li C, Wang Z, Ma L, Liu M, Zhu Q, Liu X, Tang K, Ma J, Zhang H, Xie J, Fang Y, Zhang H, Wang N, Liu Y, Huang B. Cell softness regulates tumorigenicity and stemness of cancer cells. EMBO J 2021; 40:e106123. [PMID: 33274785 PMCID: PMC7809788 DOI: 10.15252/embj.2020106123] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 10/07/2020] [Accepted: 10/23/2020] [Indexed: 12/26/2022] Open
Abstract
Identifying and sorting highly tumorigenic and metastatic tumor cells from a heterogeneous cell population is a daunting challenge. Here, we show that microfluidic devices can be used to sort marker-based heterogeneous cancer stem cells (CSC) into mechanically stiff and soft subpopulations. The isolated soft tumor cells (< 400 Pa) but not the stiff ones (> 700 Pa) can form a tumor in immunocompetent mice with 100 cells per inoculation. Notably, only the soft, but not the stiff cells, isolated from CD133+ , ALDH+ , or side population CSCs, are able to form a tumor with only 100 cells in NOD-SCID or immunocompetent mice. The Wnt signaling protein BCL9L is upregulated in soft tumor cells and regulates their stemness and tumorigenicity. Clinically, BCL9L expression is correlated with a worse prognosis. Our findings suggest that the intrinsic softness is a unique marker of highly tumorigenic and metastatic tumor cells.
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Affiliation(s)
- Jiadi Lv
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Yaoping Liu
- Institute of MicroelectronicsPeking UniversityBeijingChina
| | - Feiran Cheng
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Jiping Li
- Beijing Smartchip Microelectronics Technology Company LimitedBeijingChina
| | - Yabo Zhou
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Tianzhen Zhang
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Nannan Zhou
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Cong Li
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Zhenfeng Wang
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Longfei Ma
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Mengyu Liu
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Qiang Zhu
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Xiaohan Liu
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Ke Tang
- Department of Biochemistry & Molecular BiologyTongji Medical CollegeHuazhong University of Science & TechnologyWuhanChina
| | - Jingwei Ma
- Department of Biochemistry & Molecular BiologyTongji Medical CollegeHuazhong University of Science & TechnologyWuhanChina
| | - Huafeng Zhang
- Department of Biochemistry & Molecular BiologyTongji Medical CollegeHuazhong University of Science & TechnologyWuhanChina
| | - Jing Xie
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
| | - Yi Fang
- National Cancer Center/Cancer HospitalCAMSBeijingChina
| | - Haizeng Zhang
- National Cancer Center/Cancer HospitalCAMSBeijingChina
| | - Ning Wang
- Deaprtment of Mechanical Science and TechnologyThe Grainger College of EngineeringUniversity of Illinois at Urbana‐ChampaignUrbanaILUSA
| | - Yuying Liu
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
- Clinical Immunology CenterCAMSBeijingChina
| | - Bo Huang
- Department of Immunology & National Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences (CAMS) & Peking Union Medical CollegeBeijingChina
- Department of Biochemistry & Molecular BiologyTongji Medical CollegeHuazhong University of Science & TechnologyWuhanChina
- Clinical Immunology CenterCAMSBeijingChina
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Daunys S, Janonienė A, Januškevičienė I, Paškevičiūtė M, Petrikaitė V. 3D Tumor Spheroid Models for In Vitro Therapeutic Screening of Nanoparticles. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1295:243-270. [PMID: 33543463 DOI: 10.1007/978-3-030-58174-9_11] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The anticancer activity of compounds and nanoparticles is most often determined in the cell monolayer. However, three-dimensional (3D) systems, such as tumor spheroids, are more representing the natural tumor microenvironment. They have been shown to have higher invasiveness and resistance to cytotoxic agents and radiotherapy compared to cells growing in 2D monolayer. Furthermore, to improve the prediction of clinical efficacy of drugs, in the past decades, even more sophisticated systems, such as multicellular 3D cultures, closely representing natural tumor microenvironment have been developed. Those cultures are formed from either cell lines or patient-derived tumor cells. Such models are very attractive and could improve the selection of tested materials for clinical trials avoiding unnecessary expensive tests in vivo. The microenvironment in tumor spheroids is different, and those differences or the interaction between several cell populations may contribute to different tumor response to the treatment. Also, different types of nanoparticles may have different behavior in 3D models, depending on their nature, physicochemical properties, the presence of targeting ligands on the surface, etc. Therefore, it is very important to understand in which cases which type of tumor spheroid is more suitable for testing specific types of nanoparticles, which conditions should be used, and which analytical method should be applied.
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Affiliation(s)
- Simonas Daunys
- Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Agnė Janonienė
- Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Indrė Januškevičienė
- Laboratory of Drug Targets Histopathology, Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Miglė Paškevičiūtė
- Laboratory of Drug Targets Histopathology, Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Vilma Petrikaitė
- Life Sciences Center, Vilnius University, Vilnius, Lithuania.
- Laboratory of Drug Targets Histopathology, Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
- Institute of Physiology and Pharmacology, Academy of Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania.
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Coban B, Bergonzini C, Zweemer AJM, Danen EHJ. Metastasis: crosstalk between tissue mechanics and tumour cell plasticity. Br J Cancer 2021; 124:49-57. [PMID: 33204023 PMCID: PMC7782541 DOI: 10.1038/s41416-020-01150-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 10/06/2020] [Accepted: 10/20/2020] [Indexed: 12/12/2022] Open
Abstract
Despite the fact that different genetic programmes drive metastasis of solid tumours, the ultimate outcome is the same: tumour cells are empowered to pass a series of physical hurdles to escape the primary tumour and disseminate to other organs. Epithelial-to-mesenchymal transition (EMT) has been proposed to drive the detachment of individual cells from primary tumour masses and facilitate the subsequent establishment of metastases in distant organs. However, this concept has been challenged by observations from pathologists and from studies in animal models, in which partial and transient acquisition of mesenchymal traits is seen but tumour cells travel collectively rather than as individuals. In this review, we discuss how crosstalk between a hybrid E/M state and variations in the mechanical aspects of the tumour microenvironment can provide tumour cells with the plasticity required for strategies to navigate surrounding tissues en route to dissemination. Targeting such plasticity provides therapeutic opportunities to combat metastasis.
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Affiliation(s)
- Bircan Coban
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Cecilia Bergonzini
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Annelien J M Zweemer
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Erik H J Danen
- Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
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Reddy KB. Stem Cells: Current Status and Therapeutic Implications. Genes (Basel) 2020; 11:E1372. [PMID: 33233552 PMCID: PMC7699792 DOI: 10.3390/genes11111372] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/11/2020] [Accepted: 11/18/2020] [Indexed: 12/14/2022] Open
Abstract
Cancer stem cells (CSCs) are a class of pluripotent cells that have been observed in most types of cancers. Evolving evidence suggests that CSCs, has the ability to self-renew and initiate tumors, may be responsible for promoting therapeutic resistance, tumor recurrence and metastasis. Tumor heterogeneity is originating from CSCs and its progenitors are recognized as major difficulty in efficaciously treating cancer patients. Therefore, understanding the biological mechanisms by which CSCs survive chemo- and-radiation therapy has the potential to identify new therapeutic strategies in the future. In this review, we summarized recent advances in CSC biology and their environment, and discuss about the potential therapies to prevent therapeutic resistance.
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Affiliation(s)
- Kaladhar B. Reddy
- Department of Pathology, Wayne State University, Detroit, MI 48201, USA;
- Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
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A Marine Collagen-Based Biomimetic Hydrogel Recapitulates Cancer Stem Cell Niche and Enhances Progression and Chemoresistance in Human Ovarian Cancer. Mar Drugs 2020; 18:md18100498. [PMID: 33003514 PMCID: PMC7599646 DOI: 10.3390/md18100498] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/25/2020] [Accepted: 09/28/2020] [Indexed: 12/12/2022] Open
Abstract
Recent attention has focused on the development of an effective three-dimensional (3D) cell culture system enabling the rapid enrichment of cancer stem cells (CSCs) that are resistant to therapies and serving as a useful in vitro tumor model that accurately reflects in vivo behaviors of cancer cells. Presently, an effective 3D in vitro model of ovarian cancer (OC) was developed using a marine collagen-based hydrogel. Advantages of the model include simplicity, efficiency, bioactivity, and low cost. Remarkably, OC cells grown in this hydrogel exhibited biochemical and physiological features, including (1) enhanced cell proliferation, migration and invasion, colony formation, and chemoresistance; (2) suppressed apoptosis with altered expression levels of apoptosis-regulating molecules; (3) upregulated expression of crucial multidrug resistance-related genes; (4) accentuated expression of key molecules associated with malignant progression, such as epithelial–mesenchymal transition transcription factors, Notch, and pluripotency biomarkers; and (5) robust enrichment of ovarian CSCs. The findings indicate the potential of our 3D in vitro OC model as an in vitro research platform to study OC and ovarian CSC biology and to screen novel therapies targeting OC and ovarian CSCs.
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50
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Lee SH, Reed-Newman T, Anant S, Ramasamy TS. Regulatory Role of Quiescence in the Biological Function of Cancer Stem Cells. Stem Cell Rev Rep 2020; 16:1185-1207. [DOI: 10.1007/s12015-020-10031-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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