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Lopez D, Tyson DR, Hong T. Intercellular signaling reinforces single-cell level phenotypic transitions and facilitates robust re-equilibrium of heterogeneous cancer cell populations. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.03.631250. [PMID: 39803530 PMCID: PMC11722408 DOI: 10.1101/2025.01.03.631250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/21/2025]
Abstract
Background Cancer cells within tumors exhibit a wide range of phenotypic states driven by non-genetic mechanisms in addition to extensively studied genetic alterations. Conversions among cancer cell states can result in intratumoral heterogeneity which contributes to metastasis and development of drug resistance. However, mechanisms underlying the initiation and/or maintenance of such phenotypic plasticity are poorly understood. In particular, the role of intercellular communications in phenotypic plasticity remains elusive. Methods In this study, we employ a multiscale inference-based approach using single-cell RNA sequencing (scRNA-seq) data to explore how intercellular interactions influence phenotypic dynamics of cancer cells, particularly cancers undergoing epithelial-mesenchymal transition. In addition, we use mathematical models based on our data-driven findings to interrogate the roles of intercellular communications at the cell populations from the viewpoint of dynamical systems. Results Our inference approach reveals that signaling interactions between cancerous cells in small cell lung cancer (SCLC) result in the reinforcement of the phenotypic transition in single cells and the maintenance of population-level intratumoral heterogeneity. Additionally, we find a recurring signaling pattern across multiple types of cancer in which the mesenchymal-like subtypes utilize signals from other subtypes to support its new phenotype, further promoting the intratumoral heterogeneity. Our models show that inter-subtype communication both accelerates the development of heterogeneous tumor populations and confers robustness to their steady state phenotypic compositions. Conclusions Our work highlights the critical role of intercellular signaling in sustaining intratumoral heterogeneity, and our approach of computational analysis of scRNA-seq data can infer inter- and intra-cellular signaling networks in a holistic manner.
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Affiliation(s)
- Daniel Lopez
- Department of Biochemistry & Cellular and Molecular Biology, The University of Tennessee, Knoxville. Knoxville, Tennessee 37916, USA
| | - Darren R Tyson
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27710, USA
| | - Tian Hong
- Department of Biological Sciences, The University of Texas at Dallas. Richardson, Texas 75080, USA
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2
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Wang A, Yan S, Liu J, Chen X, Hu M, Du X, Jiang W, Pan Z, Fan L, Sun G. Endoplasmic reticulum stress-related super enhancer promotes epithelial-mesenchymal transformation in hepatocellular carcinoma through CREB5 mediated activation of TNC. Cell Death Dis 2025; 16:73. [PMID: 39915455 PMCID: PMC11802765 DOI: 10.1038/s41419-025-07356-y] [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: 08/11/2024] [Revised: 12/19/2024] [Accepted: 01/14/2025] [Indexed: 02/09/2025]
Abstract
Super-enhancers (SEs) are associated with key genes that control cellular state and cell identity. Endoplasmic reticulum stress (ERS) regulates epithelial-mesenchymal transformation (EMT). However, whether SEs are involved in ERS-related activation of EMT in hepatocellular carcinoma (HCC) is unknown. In this study, we identified 17 ERS-related SEs by comparing ERS-HCC cells with untreated control cells using ChIP-seq and RNA-seq. CRISPR-Cas9 and RT-qPCR identified CAMP responsive element binding protein 5 (CREB5) as a key target of ERS-related SE. Analyses of TCGA datasets and tissue arrays showed that CREB5 mRNA and protein expression levels were higher in liver cancer tissues than in paired normal tissues. In addition, overexpression of CREB5 was associated with poor prognosis and an aggressive phenotype in patients with HCC. We also found that activation of ERS enhanced the expression of CREB5, and upregulation of CREB5 significantly increased cell proliferation, migration, and invasion, and promoted EMT, but inhibited apoptosis. More importantly, ERS activation increased the expression of several EMT markers by modulating the expression of CREB5. Mechanistically, CREB5 upregulates the transcription of tenascin-C (TNC) by directly binding to its promoter region, thereby promoting EMT in liver cancer cells. In summary, our findings suggest that ERS activation promotes EMT in liver cancer cells via SE-mediated upregulation of the CREB5/TNC pathway. This result provides a new direction for uncovering how ERS regulates EMT and a foundation for preventing the progression of EMT in HCC.
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Affiliation(s)
- Anqi Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Sitong Yan
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jiatao Liu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xiang Chen
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Mengyao Hu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xiao Du
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Weijia Jiang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Zhipeng Pan
- Department of Oncology, The Second Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Lulu Fan
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Guoping Sun
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
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3
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Glaviano A, Lau HSH, Carter LM, Lee EHC, Lam HY, Okina E, Tan DJJ, Tan W, Ang HL, Carbone D, Yee MYH, Shanmugam MK, Huang XZ, Sethi G, Tan TZ, Lim LHK, Huang RYJ, Ungefroren H, Giovannetti E, Tang DG, Bruno TC, Luo P, Andersen MH, Qian BZ, Ishihara J, Radisky DC, Elias S, Yadav S, Kim M, Robert C, Diana P, Schalper KA, Shi T, Merghoub T, Krebs S, Kusumbe AP, Davids MS, Brown JR, Kumar AP. Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition. J Hematol Oncol 2025; 18:6. [PMID: 39806516 PMCID: PMC11733683 DOI: 10.1186/s13045-024-01634-6] [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: 04/20/2024] [Accepted: 11/11/2024] [Indexed: 01/16/2025] Open
Abstract
The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.
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Affiliation(s)
- Antonino Glaviano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Hannah Si-Hui Lau
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Lukas M Carter
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - E Hui Clarissa Lee
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Hiu Yan Lam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Elena Okina
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Donavan Jia Jie Tan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- School of Chemical and Life Sciences, Singapore Polytechnic, Singapore, 139651, Singapore
| | - Wency Tan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- School of Chemical and Life Sciences, Singapore Polytechnic, Singapore, 139651, Singapore
| | - Hui Li Ang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Daniela Carbone
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Michelle Yi-Hui Yee
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
| | - Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Xiao Zi Huang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Lina H K Lim
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
- Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, 117456, Singapore
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Ruby Yun-Ju Huang
- School of Medicine and Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan
- Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore
| | - Hendrik Ungefroren
- First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), Campus Lübeck, 23538, Lübeck, Germany
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, UMC, Vrije Universiteit, HV Amsterdam, 1081, Amsterdam, The Netherlands
- Cancer Pharmacology Lab, Fondazione Pisana Per La Scienza, 56017, San Giuliano, Italy
| | - Dean G Tang
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
- Experimental Therapeutics (ET) Graduate Program, University at Buffalo & Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Tullia C Bruno
- Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Mads Hald Andersen
- National Center for Cancer Immune Therapy, Department of Oncology, Herlev and Gentofte Hospital, Herlev, Denmark
| | - Bin-Zhi Qian
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, The Human Phenome Institute, Zhangjiang-Fudan International Innovation Center, Fudan University, Shanghai, China
| | - Jun Ishihara
- Department of Bioengineering, Imperial College London, London, W12 0BZ, UK
| | - Derek C Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Salem Elias
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Saurabh Yadav
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Minah Kim
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Caroline Robert
- Department of Cancer Medicine, Inserm U981, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif, France
- Faculty of Medicine, University Paris-Saclay, Kremlin Bicêtre, Paris, France
| | - Patrizia Diana
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Kurt A Schalper
- Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT, USA
| | - Tao Shi
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Taha Merghoub
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Department of Medicine, Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, NY, USA
| | - Simone Krebs
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anjali P Kusumbe
- Tissue and Tumor Microenvironment Group, MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Matthew S Davids
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jennifer R Brown
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
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4
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Zhang J, Yang S, Chen X, Zhang F, Guo S, Wu C, Wang T, Wang H, Lu S, Qiao C, Sheng X, Liu S, Zhang X, Luo H, Li Q, Wu J. Aidi injection inhibits the migration and invasion of gefitinib-resistant lung adenocarcinoma cells by regulating the PLAT/FAK/AKT pathway. Chin Med 2025; 20:2. [PMID: 39754146 PMCID: PMC11699780 DOI: 10.1186/s13020-024-01054-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 12/26/2024] [Indexed: 01/06/2025] Open
Abstract
BACKGROUND With extended gefitinib treatment, the therapeutic effect in some non-small cell lung cancer (NSCLC) patients declined with the development of drug resistance. Aidi injection (ADI) is utilized in various cancers as a traditional Chinese medicine prescription. This study explores the molecular mechanism by which ADI, when combined with gefitinib, attenuates gefitinib resistance in PC9GR NSCLC cells. METHODS In vitro and in vivo pharmacological experiments were conducted in PC9GR cells and NSG mice with PC9GR cell-derived tumors, respectively. The molecular mechanism of ADI was further studied using whole-transcriptome sequencing technology. Bioinformatics and molecular biology methods were employed to validate the critical targets of ADI. RESULTS Firstly, ADI treatment alone and combined with gefitinib significantly inhibited the proliferation, migration, and invasion of PC9GR cells. Then, whole-transcriptome sequencing and bioinformatics analysis revealed that PLAT is a key target for the increased efficacy of ADI combined with gefitinib. Additionally, ADI downregulates the expression of PLAT, TNC, ITGB3, p-AKT, p-PI3K, and p-FAK. ADI inhibits the migration and invasion of PC9GR cells by regulating the PLAT/FAK/AKT pathway. CONCLUSIONS Aidi injection inhibits the migration and invasion of gefitinib-resistant lung adenocarcinoma cells by regulating the PLAT/FAK/AKT pathway. This study provides essential evidence for elucidating the mechanism of ADI in synergistic therapy for lung cancer.
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Affiliation(s)
- Jingyuan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Siyun Yang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xiaodong Chen
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Fanqin Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Siyu Guo
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Chao Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Tieshan Wang
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Haojia Wang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Shan Lu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Chuanqi Qiao
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xiaoguang Sheng
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Shuqi Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xiaomeng Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Hua Luo
- Macau Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, People's Republic of China.
| | - Qinglin Li
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
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5
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Surman M, Wilczak M, Jankowska U, Skupień-Rabian B, Przybyło M. Shotgun proteomics of thyroid carcinoma exosomes - Insight into the role of exosomal proteins in carcinogenesis and thyroid homeostasis. Biochim Biophys Acta Gen Subj 2024; 1868:130672. [PMID: 39025337 DOI: 10.1016/j.bbagen.2024.130672] [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: 02/01/2024] [Revised: 06/11/2024] [Accepted: 07/13/2024] [Indexed: 07/20/2024]
Abstract
BACKGROUND Transport of molecules via exosomes is one of the factors involved in thyroid cancer development, and transported molecules may serve as cancer biomarkers. The aim of the study was to characterize protein content of thyroid-derived exosomes and their functional effect exerted on recipient cells. METHODS LC-MS/MS proteomics of exosomes released by FTC and 8305C thyroid carcinoma cell lines, and Nthy-ori 3-1 normal thyroid follicular cells was performed, followed by bioinformatic analysis and functional tests (wound healing and Alamar Blue assays). RESULTS Exosomes from Nthy-ori 3-1 cells had the highest number of 1504 proteins, while in exosomes from thyroid carcinoma FTC and 8305C cells 730 and 1304 proteins were identified, respectively. For proteins uniquely found in FTC- and 8305C-derived exosomes, enriched cancer-related gene ontology categories included cell adhesion, positive regulation of cell migration, N-glycosylation, drug resistance, and response to NK/T cell cytotoxicity. Furthermore, through label-free quantification (that identified differentially expressed proteins) and comparison with The Human Protein Atlas database several potential diagnostic and/or prognostic biomarkers were indicated. Finally, exosomes from FTC and 8305C cells displayed ability to stimulate migratory properties of recipient Nthy-ori 3-1 cells. Additionally, 8305C-derived exosomes increased recipient cell viability. CONCLUSIONS Multiple proteins identified in thyroid cancer-derived exosomes have a direct link to thyroid cancer progression. Also, in functional tests exosomes enhanced growth and dissemination of non-transformed thyroid cells. GENERAL SIGNIFICANCE The obtained results expands the knowledge concerning the role of exosomal proteins in thyroid cancer and indicate potential biomarkers for further evaluation in clinical settings.
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Affiliation(s)
- Magdalena Surman
- Department of Glycoconjugate Biochemistry, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Krakow, Poland.
| | - Magdalena Wilczak
- Department of Glycoconjugate Biochemistry, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Krakow, Poland; Doctoral School of Exact and Natural Sciences, Jagiellonian University, 30-348 Krakow, Poland.
| | - Urszula Jankowska
- Proteomics and Mass Spectrometry Core Facility, Malopolska Centre of Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
| | - Bożena Skupień-Rabian
- Proteomics and Mass Spectrometry Core Facility, Malopolska Centre of Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
| | - Małgorzata Przybyło
- Department of Glycoconjugate Biochemistry, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Krakow, Poland.
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Haughton PD, Haakma W, Chalkiadakis T, Breimer GE, Driehuis E, Clevers H, Willems S, Prekovic S, Derksen PWB. Differential transcriptional invasion signatures from patient derived organoid models define a functional prognostic tool for head and neck cancer. Oncogene 2024; 43:2463-2474. [PMID: 38942893 PMCID: PMC11315671 DOI: 10.1038/s41388-024-03091-4] [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: 10/24/2023] [Revised: 06/07/2024] [Accepted: 06/18/2024] [Indexed: 06/30/2024]
Abstract
Clinical outcome for patients suffering from HPV-negative head and neck squamous cell carcinoma (HNSCC) remains poor. This is mostly due to highly invasive tumors that cause loco-regional relapses after initial therapeutic intervention and metastatic outgrowth. The molecular pathways governing the detrimental invasive growth modes in HNSCC remain however understudied. Here, we have established HNSCC patient derived organoid (PDO) models that recapitulate 3-dimensional invasion in vitro. Single cell mRNA sequencing was applied to study the differences between non-invasive and invasive conditions, and in a collective versus single cell invading PDO model. Differential expression analysis under invasive conditions in Collagen gels reveals an overall upregulation of a YAP-centered transcriptional program, irrespective of the invasion mode. However, we find that collectively invading HNSCC PDO cells show elevated levels of YAP transcription targets when compared to single cell invasion. Also, collectively invading cells are characterized by increased nuclear translocation of YAP within the invasive strands, which coincides with Collagen-I matrix alignment at the invasive front. Using gene set enrichment analysis, we identify immune cell-like migratory pathways in the single cell invading HNSCC PDO, while collective invasion is characterized by overt upregulation of adhesion and migratory pathways. Lastly, based on clinical head and neck cancer cohorts, we demonstrate that the identified collective invasion signature provides a candidate prognostic platform for survival in HNSCC. By uncoupling collective and single cell invasive programs, we have established invasion signatures that may guide new therapeutic options.
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Affiliation(s)
- Peter D Haughton
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Wisse Haakma
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Theofilos Chalkiadakis
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Gerben E Breimer
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Else Driehuis
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, 3584, CT, Utrecht, The Netherlands
| | - Hans Clevers
- Roche Pharmaceutical Research and Early Development, Basel, Switzerland
| | - Stefan Willems
- Department Pathology and Medical biology, University Medical Center Groningen, Groningen, The Netherlands
| | - Stefan Prekovic
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
| | - Patrick W B Derksen
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
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7
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Chandran RR, Vijayaraj P, Garcia-Milian R, King J, Castillo K, Chen L, Kwon Y, William S, Rickabaugh TM, Langerman J, Choi W, Sen C, Lever JEP, Li Q, Pavelkova N, Plosa EJ, Rowe SM, Plath K, Clair G, Gomperts BN. Loss of cell junctional components and matrix alterations drive cell desquamation and fibrotic changes in Idiopathic Pulmonary Fibrosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.17.599411. [PMID: 38948715 PMCID: PMC11212876 DOI: 10.1101/2024.06.17.599411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
The distal bronchioles in Idiopathic Pulmonary Fibrosis (IPF) exhibit histopathological abnormalities such as bronchiolization, peribronchiolar fibrosis and honeycomb cysts that contribute to the overall architectural remodeling of lung tissue seen in the disease. Here we describe an additional histopathologic finding of epithelial desquamation in patients with IPF, wherein epithelial cells detach from the basement membrane of the distal bronchioles. To understand the mechanism driving this pathology, we performed spatial transcriptomics of the epithelial cells and spatial proteomics of the basement membrane of the distal bronchioles from IPF patients and patients with no prior history of lung disease. Our findings reveal a downregulation of cell junctional components, upregulation of epithelial-mesenchymal transition signatures and dysregulated basement membrane matrix in IPF distal bronchioles, facilitating epithelial desquamation. Further, functional assays identified regulation between Collagen IV in the matrix, and the junctional genes JUP and PLEC , that is crucial for maintaining distal bronchiolar homeostasis. In IPF, this balanced regulation between matrix and cell-junctions is disrupted, leading to loss of epithelial adhesion, peribronchiolar fibrosis and epithelial desquamation. Overall, our study suggests that in IPF the interplay between the loss of cell junctions and a dysregulated matrix results in desquamation of distal bronchiolar epithelium and lung remodeling, exacerbating the disease. One Sentence Summary Two-way regulation of cell junctional proteins and matrix proteins drives cellular desquamation and fibrosis in the distal bronchioles of patients with Idiopathic Pulmonary Fibrosis.
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8
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Khalil AA, Smits D, Haughton PD, Koorman T, Jansen KA, Verhagen MP, van der Net M, van Zwieten K, Enserink L, Jansen L, El-Gammal AG, Visser D, Pasolli M, Tak M, Westland D, van Diest PJ, Moelans CB, Roukens MG, Tavares S, Fortier AM, Park M, Fodde R, Gloerich M, Zwartkruis FJT, Derksen PW, de Rooij J. A YAP-centered mechanotransduction loop drives collective breast cancer cell invasion. Nat Commun 2024; 15:4866. [PMID: 38849373 PMCID: PMC11161601 DOI: 10.1038/s41467-024-49230-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: 02/16/2022] [Accepted: 05/28/2024] [Indexed: 06/09/2024] Open
Abstract
Dense and aligned Collagen I fibers are associated with collective cancer invasion led by protrusive tumor cells, leader cells. In some breast tumors, a population of cancer cells (basal-like cells) maintain several epithelial characteristics and express the myoepithelial/basal cell marker Keratin 14 (K14). Emergence of leader cells and K14 expression are regarded as interconnected events triggered by Collagen I, however the underlying mechanisms remain unknown. Using breast carcinoma organoids, we show that Collagen I drives a force-dependent loop, specifically in basal-like cancer cells. The feed-forward loop is centered around the mechanotransducer Yap and independent of K14 expression. Yap promotes a transcriptional program that enhances Collagen I alignment and tension, which further activates Yap. Active Yap is detected in invading breast cancer cells in patients and required for collective invasion in 3D Collagen I and in the mammary fat pad of mice. Our work uncovers an essential function for Yap in leader cell selection during collective cancer invasion.
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Affiliation(s)
- Antoine A Khalil
- Center for Molecular Medicine (CMM), University Medical Center Utrecht, Utrecht, The Netherlands.
| | - Daan Smits
- Center for Molecular Medicine (CMM), University Medical Center Utrecht, Utrecht, The Netherlands
| | - Peter D Haughton
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Thijs Koorman
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Karin A Jansen
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Mathijs P Verhagen
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Mirjam van der Net
- Center for Molecular Medicine (CMM), University Medical Center Utrecht, Utrecht, The Netherlands
| | - Kitty van Zwieten
- Center for Molecular Medicine (CMM), University Medical Center Utrecht, Utrecht, The Netherlands
| | - Lotte Enserink
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Lisa Jansen
- Center for Molecular Medicine (CMM), University Medical Center Utrecht, Utrecht, The Netherlands
| | - Abdelrahman G El-Gammal
- Center for Molecular Medicine (CMM), University Medical Center Utrecht, Utrecht, The Netherlands
| | - Daan Visser
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Milena Pasolli
- Center for Molecular Medicine (CMM), University Medical Center Utrecht, Utrecht, The Netherlands
| | - Max Tak
- Center for Molecular Medicine (CMM), University Medical Center Utrecht, Utrecht, The Netherlands
| | - Denise Westland
- Center for Molecular Medicine (CMM), University Medical Center Utrecht, Utrecht, The Netherlands
| | - Paul J van Diest
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Cathy B Moelans
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - M Guy Roukens
- Center for Molecular Medicine (CMM), University Medical Center Utrecht, Utrecht, The Netherlands
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Sandra Tavares
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Anne-Marie Fortier
- Goodman Cancer Institute McGill University, Depts Biochemistry and Oncology, McGill University, Goodman Cancer Institute, Montréal, Canada
| | - Morag Park
- Goodman Cancer Institute McGill University, Depts Biochemistry and Oncology, McGill University, Goodman Cancer Institute, Montréal, Canada
| | - Riccardo Fodde
- Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Martijn Gloerich
- Center for Molecular Medicine (CMM), University Medical Center Utrecht, Utrecht, The Netherlands
| | - Fried J T Zwartkruis
- Center for Molecular Medicine (CMM), University Medical Center Utrecht, Utrecht, The Netherlands
| | - Patrick Wb Derksen
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
| | - Johan de Rooij
- Center for Molecular Medicine (CMM), University Medical Center Utrecht, Utrecht, The Netherlands.
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9
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Guerrero-Barberà G, Burday N, Costell M. Shaping Oncogenic Microenvironments: Contribution of Fibronectin. Front Cell Dev Biol 2024; 12:1363004. [PMID: 38660622 PMCID: PMC11039881 DOI: 10.3389/fcell.2024.1363004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 03/25/2024] [Indexed: 04/26/2024] Open
Abstract
The extracellular matrix (ECM) is a complex network of proteins and glycans, dynamically remodeled and specifically tailored to the structure/function of each organ. The malignant transformation of cancer cells is determined by both cell intrinsic properties, such as mutations, and extrinsic variables, such as the mixture of surrounding cells in the tumor microenvironment and the biophysics of the ECM. During cancer progression, the ECM undergoes extensive remodeling, characterized by disruption of the basal lamina, vascular endothelial cell invasion, and development of fibrosis in and around the tumor cells resulting in increased tissue stiffness. This enhanced rigidity leads to aberrant mechanotransduction and further malignant transformation potentiating the de-differentiation, proliferation and invasion of tumor cells. Interestingly, this fibrotic microenvironment is primarily secreted and assembled by non-cancerous cells. Among them, the cancer-associated fibroblasts (CAFs) play a central role. CAFs massively produce fibronectin together with type I collagen. This review delves into the primary interactions and signaling pathways through which fibronectin can support tumorigenesis and metastasis, aiming to provide critical molecular insights for better therapy response prediction.
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Affiliation(s)
| | | | - Mercedes Costell
- Departament of Biochemistry and Molecular Biology, Institut Universitari de Biotecnologia i Biomedicina, Universitat de València, Valencia, Spain
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10
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Liu Y, Yang LY, Chen DX, Chang C, Yuan Q, Zhang Y, Cai Y, Wei WQ, Hao JJ, Wang MR. Tenascin-C as a potential biomarker and therapeutic target for esophageal squamous cell carcinoma. Transl Oncol 2024; 42:101888. [PMID: 38354632 PMCID: PMC10877408 DOI: 10.1016/j.tranon.2024.101888] [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: 09/03/2023] [Revised: 01/01/2024] [Accepted: 01/22/2024] [Indexed: 02/16/2024] Open
Abstract
PURPOSE To establish a prognostic model of esophageal squamous cell carcinoma (ESCC) patients based on tenascin-C (TNC) expression level and clinicopathological characteristics, and to explore the therapeutic potential of TNC inhibition. METHODS The expression of TNC was detected using immunohistochemistry (IHC) in 326 ESCC specimens and 50 normal esophageal tissues. Prognostic factors were determined by Cox regression analyses and were incorporated to establish the nomogram. The effects of TNC knockdown on ESCC cells were assessed in vitro and in vivo. Transcriptome sequencing (RNA-seq) and gene set enrichment analysis (GSEA) were performed to reveal signaling pathways regulated by TNC knockdown. The therapeutic significance of TNC knockdown combined with small-molecule inhibitors on cell proliferation was examined. RESULTS TNC protein was highly expressed in 48.77 % of ESCC tissues compared to only 2 % in normal esophageal epithelia (p < 0.001). The established nomogram model, based on TNC expression, pT stage, and lymph node metastasis, showed good performance on prognosis evaluation. More importantly, the reduction of TNC expression inhibited tumor cell proliferation and xenograft growth, and mainly down-regulated signaling pathways involved in tumor growth, hypoxia signaling transduction, metabolism, infection, etc. Knockdown of TNC enhanced the inhibitory effect of inhibitors targeting ErbB, PI3K-Akt, Ras and MAPK signaling pathways. CONCLUSION The established nomogram may be a promising model for survival prediction in ESCC. Reducing TNC expression enhanced the sensitivity of ESCC cells to inhibitors of Epidermal Growth Factor Receptor (EGFR) and downstream signaling pathways, providing a novel combination therapy strategy.
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Affiliation(s)
- Yang Liu
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Li-Yan Yang
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ding-Xiong Chen
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Chen Chang
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Qing Yuan
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yu Zhang
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yan Cai
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wen-Qiang Wei
- Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jia-Jie Hao
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
| | - Ming-Rong Wang
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
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11
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Wang Z, Yan N, Sheng H, Xiao Y, Sun J, Cao C. Single-cell Transcriptomic Analysis Reveals an Immunosuppressive Network Between POSTN CAFs and ACKR1 ECs in TKI-resistant Lung Cancer. Cancer Genomics Proteomics 2024; 21:65-78. [PMID: 38151287 PMCID: PMC10756349 DOI: 10.21873/cgp.20430] [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: 08/21/2023] [Revised: 11/21/2023] [Accepted: 11/23/2023] [Indexed: 12/29/2023] Open
Abstract
BACKGROUND/AIM Tyrosine kinase inhibitor (TKI) therapy, a principal treatment for advanced non-small cell lung cancer (NSCLC), frequently encounters the development of drug resistance. The tumor microenvironment (TME) plays a critical role in the progression of NSCLC, yet the relationship between endothelial cells (ECs) and cancer-associated fibroblasts (CAFs) subpopulations in TKI treatment resistance remains largely unexplored. MATERIALS AND METHODS The BioProject database PRJNA591860 project was used to analyze scRNA-seq data including 49 advanced-stage NSCLC samples across three different time points: pre-targeted therapy (naïve), post-partial response (PR) to targeted therapy, and post-progressive disease (PD) stage. The data involved clustering stromal cells into multiple CAFs and ECs subpopulations. The abundance changes and functions of each cluster during TKI treatment were investigated by KEGG and GO analysis. Additionally, we identified specific transcription factors and metabolic pathways via DoRothEA and scMetabolism. Moreover, cell-cell communications between PD and PR stages were compared by CellChat. RESULTS ECs and CAFs were clustered and annotated using 49 scRNA-seq samples. We identified seven ECs subpopulations, with OIT3 ECs showing enrichment in the PR phase with a drug-resistance phenotype, and ACKR1 ECs being prevalent in the PD phase with enhanced cell adhesion. Similarly, CAFs were clustered into 7 subpopulations. PLA2G2A CAFs were predominant in PR, whereas POSTN CAFs were prevalent in PD, characterized by an immunomodulatory phenotype and increased collagen secretion. CellChat analysis showed that ACKR1 ECs strongly interacted with macrophage through the CD39 pathway and POSTN CAFs secreted Tenascin-C (TNC) to promote the progression of epithelial cells, primarily malignant ones, in PD. CONCLUSION This study reveals that POSTN CAFs and ACKR1 ECs are associated with resistance to TKI treatment, based on single-cell sequencing.
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Affiliation(s)
- Zhiyi Wang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Ning Yan
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Hailong Sheng
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Yazhi Xiao
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Jingyuan Sun
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Chuanhui Cao
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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12
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Elkady N, Aldesoky AI, Allam DM. Can β-catenin, Tenascin and Fascin be potential biomarkers for personalized therapy in Gastric carcinoma? J Immunoassay Immunochem 2023; 44:396-417. [PMID: 37694977 DOI: 10.1080/15321819.2023.2251564] [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: 09/12/2023]
Abstract
Gastric carcinoma (GC) is one of the most prevalent cancers worldwide and the fourth leading cause of cancer-related death. Studying the molecular profile of GC is essential for developing targeted therapies. β-catenin, Tenascin, and Fascin expression are among the molecular abnormalities that are claimed to cause GC progression and chemoresistance. Therefore, they could be used as potential therapeutic targets. This study aimed to evaluate β-catenin, Tenascin, and Fascin expression and their possible roles as prognostic and predictive biomarkers in GC using immunohistochemistry. This retrospective study included 84 GC cases. Tissue microarrays were constructed, followed by β-catenin, Tenascin, and Fascin immunostaining. Their expression was assessed and compared with clinicopathological parameters and survival data. The study results revealed that β-catenin nucleocytoplasmic expression, positive Tenascin, and Fascin expressions were detected in 86.9%, 70%, and 59.5% of cases, respectively. Their expression was significantly associated with poor prognostic parameters, such as deeper tumor invasion, lymph node metastasis, advanced pathological stage, vascular invasion, positive omental nodules, poor response to chemotherapy, and short overall survival. Hence, nucleocytoplasmic β-catenin expression together with Tenascin and Fascin positivity can be potential prognostic and predictive markers, and they can be used as therapeutic targets for GC.
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Affiliation(s)
- Noha Elkady
- Pathology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Amira I Aldesoky
- Clinical oncology and nuclear medicine department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Dina Mohamed Allam
- Pathology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
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13
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Wandrey M, Jablonska J, Stauber RH, Gül D. Exosomes in Cancer Progression and Therapy Resistance: Molecular Insights and Therapeutic Opportunities. Life (Basel) 2023; 13:2033. [PMID: 37895415 PMCID: PMC10608050 DOI: 10.3390/life13102033] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 10/04/2023] [Accepted: 10/05/2023] [Indexed: 10/29/2023] Open
Abstract
The development of therapy resistance still represents a major hurdle in treating cancers, leading to impaired treatment success and increased patient morbidity. The establishment of minimally invasive liquid biopsies is a promising approach to improving the early diagnosis, as well as therapy monitoring, of solid tumors. Because of their manifold functions in the tumor microenvironment, tumor-associated small extracellular vesicles, referred to as exosomes, have become a subject of intense research. Besides their important roles in cancer progression, metastasis, and the immune response, it has been proposed that exosomes also contribute to the acquisition and transfer of therapy resistance, mainly by delivering functional proteins and RNAs, as well as facilitating the export of active drugs or functioning as extracellular decoys. Extensive research has focused on understanding the molecular mechanisms underlying the occurrence of resistance and translating these into strategies for early detection. With this review, we want to provide an overview of the current knowledge about the (patho-)biology of exosomes, as well as state-of-the-art methods of isolation and analysis. Furthermore, we highlight the role of exosomes in tumorigenesis and cancer treatment, where they can function as therapeutic agents, biomarkers, and/or targets. By focusing on their roles in therapy resistance, we will reveal new paths of exploiting exosomes for cancer diagnosis and treatment.
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Affiliation(s)
- Madita Wandrey
- Nanobiomedicine/ENT Department, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.W.); (R.H.S.)
| | - Jadwiga Jablonska
- Translational Oncology/ENT Department, University Hospital Essen, Hufelandstraße 55, 45147 Essen, Germany;
- German Cancer Consortium (DKTK) Partner Site Düsseldorf/Essen, 45147 Essen, Germany
| | - Roland H. Stauber
- Nanobiomedicine/ENT Department, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.W.); (R.H.S.)
| | - Désirée Gül
- Nanobiomedicine/ENT Department, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany; (M.W.); (R.H.S.)
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Campos A, Burgos-Ravanal R, Lobos-González L, Huilcamán R, González MF, Díaz J, Verschae AC, Acevedo JP, Carrasco M, Sepúlveda F, Jeldes E, Varas-Godoy M, Leyton L, Quest AF. Caveolin-1-dependent tenascin C inclusion in extracellular vesicles is required to promote breast cancer cell malignancy. Nanomedicine (Lond) 2023; 18:1651-1668. [PMID: 37929694 DOI: 10.2217/nnm-2023-0143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2023] Open
Abstract
Background: Elevated expression of CAV1 in breast cancer increases tumor progression. Extracellular vesicles (EVs) from CAV1-expressing MDA-MB-231 breast cancer cells contain Tenascin C (TNC), but the relevance of TNC remained to be defined. Methods: EVs were characterized by nanotracking analysis, microscopy and western blotting. The uptake of EVs by cells was studied using flow cytometry. The effects of EVs on breast cancer cells were tested in migration, invasion, colony formation and in vivo assays. Results: EVs were taken up by cells; however, only those containing TNC promoted invasiveness. In vivo, EVs lacking TNC ceased to promote tumor growth. Conclusion: CAV1 and TNC contained in breast cancer cell-derived EVs were identified as proteins that favor progression of breast cancer.
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Affiliation(s)
- America Campos
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, 8380492, Universidad de Chile
- Centro Científico y Tecnológico de Excelencia Ciencia y Vida, Santiago, 8340148, Chile
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, Scotland
| | - Renato Burgos-Ravanal
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, 8380492, Universidad de Chile
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
| | - Lorena Lobos-González
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
- Centro de Medicina Regenerativa, Facultad de Medicina-Clínica Alemana, Universidad del Desarrollo, Santiago, 7610615, Chile
| | - Ricardo Huilcamán
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, 8380492, Universidad de Chile
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
| | - María Fernanda González
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, 8380492, Universidad de Chile
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
| | - Jorge Díaz
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, 8380492, Universidad de Chile
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
| | - Albano Cáceres Verschae
- Laboratorio de Biología Celular del Cáncer, CEBICEM, Universidad San Sebastián, Santiago, 7510157, Chile
- Department of Oncology/Pathology, Karolinska Institutet, Stockholm, 17177, Sweden
| | - Juan Pablo Acevedo
- Center of Interventional Medicine for Precision & Advanced Cellular Therapy (IMPACT), Santiago, 8331150, Chile
| | - Macarena Carrasco
- Centro Científico y Tecnológico de Excelencia Ciencia y Vida, Santiago, 8340148, Chile
| | - Francisca Sepúlveda
- Centro Científico y Tecnológico de Excelencia Ciencia y Vida, Santiago, 8340148, Chile
- Centro de Medicina Regenerativa, Facultad de Medicina-Clínica Alemana, Universidad del Desarrollo, Santiago, 7610615, Chile
| | - Emanuel Jeldes
- Centro Científico y Tecnológico de Excelencia Ciencia y Vida, Santiago, 8340148, Chile
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, Scotland
| | - Manuel Varas-Godoy
- Centro Científico y Tecnológico de Excelencia Ciencia y Vida, Santiago, 8340148, Chile
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
- Laboratorio de Biología Celular del Cáncer, CEBICEM, Universidad San Sebastián, Santiago, 7510157, Chile
| | - Lisette Leyton
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, 8380492, Universidad de Chile
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
| | - Andrew Fg Quest
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, 8380492, Universidad de Chile
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago, 8380492, Chile
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Huber LT, Kraus JM, Ezić J, Wanli A, Groth M, Laban S, Hoffmann TK, Wollenberg B, Kestler HA, Brunner C. Liquid biopsy: an examination of platelet RNA obtained from head and neck squamous cell carcinoma patients for predictive molecular tumor markers. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2023; 4:422-446. [PMID: 37455825 PMCID: PMC10344902 DOI: 10.37349/etat.2023.00143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 03/01/2023] [Indexed: 07/18/2023] Open
Abstract
Aim Recently, a tumor cell-platelet interaction was identified in different tumor entities, resulting in a transfer of tumor-derived RNA into platelets, named further "tumor-educated platelets (TEP)". The present pilot study aims to investigate whether such a tumor-platelet transfer of RNA occurs also in patients suffering from head and neck squamous cell carcinoma (HNSCC). Methods Sequencing analysis of RNA derived from platelets of tumor patients (TPs) and healthy donors (HDs) were performed. Subsequently, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used for verification of differentially expressed genes in platelets from TPs and HDs in a second cohort of patients and HDs. Data were analyzed by applying bioinformatic tools. Results Sequencing of RNA derived from the tumor as well as from platelets of TPs and HDs revealed 426 significantly differentially existing RNA, at which 406 RNA were more and 20 RNA less abundant in platelets from TPs in comparison to that of HDs. In TPs' platelets, abundantly existing RNA coding for 49 genes were detected, characteristically expressed in epithelial cells and RNA, the products of which are involved in tumor progression. Applying bioinformatic tools and verification on a second TP/HD cohort, collagen type I alpha 1 chain (COL1A1) and zinc finger protein 750 (ZNF750) were identified as the strongest potentially platelet-RNA-sequencing (RNA-seq)-based biomarkers for HNSCC. Conclusions These results indicate a transfer of tumor-derived messenger RNA (mRNA) into platelets of HNSCC patients. Therefore, analyses of a patient's platelet RNA could be an efficient option for liquid biopsy in order to diagnose HNSCC or to monitor tumorigenesis as well as therapeutic responses at any time and in real time.
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Affiliation(s)
- Lisa T. Huber
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Ulm University Medical Center, 89075 Ulm, Germany
| | - Johann M. Kraus
- Institute of Medical Systems Biology, Ulm University, 89081 Ulm, Germany
| | - Jasmin Ezić
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Ulm University Medical Center, 89075 Ulm, Germany
| | - Amin Wanli
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Ulm University Medical Center, 89075 Ulm, Germany
| | - Marco Groth
- Leibniz Institute of Aging – Fritz Lipmann Institute, CF DNA sequencing, 07745 Jena, Germany
| | - Simon Laban
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Ulm University Medical Center, 89075 Ulm, Germany
| | - Thomas K. Hoffmann
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Ulm University Medical Center, 89075 Ulm, Germany
| | - Barbara Wollenberg
- Clinic for Otorhinolaryngology, Head and Neck Surgery, Technical University of Munich, 80333 Munich, Germany
| | - Hans A. Kestler
- Institute of Medical Systems Biology, Ulm University, 89081 Ulm, Germany
| | - Cornelia Brunner
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Ulm University Medical Center, 89075 Ulm, Germany
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Shinkai T, Kuriyama N, Usui M, Hayasaki A, Fujii T, Iizawa Y, Tanemura A, Murata Y, Kishiwada M, Katoh D, Matsumoto T, Wada H, Yoshida T, Isaji S, Mizuno S. Clinical Significance of Plasma Tenascin-C Levels in Recipients With Prolonged Jaundice After Living Donor Liver Transplantation. Transplant Proc 2023; 55:913-923. [PMID: 36973145 DOI: 10.1016/j.transproceed.2023.01.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 01/26/2023] [Indexed: 03/29/2023]
Abstract
BACKGROUND Focusing on tenascin-C (TNC), whose expression is enhanced during the tissue remodeling process, the present study aimed to clarify whether plasma TNC levels after living donor liver transplantation (LDLT) could be a predictor of irreversible liver damage in the recipients with prolonged jaundice (PJ). METHODS Among 123 adult recipients who underwent LDLT between March 2002 and December 2016, the subjects were 79 recipients in whom we could measure plasma TNC levels preoperatively (pre-) and on postoperative days 1 to 14 (POD1 to POD14). Prolonged jaundice was defined as serum total bilirubin level >10 mg/dL on POD14, and 79 recipients were divided into 2 groups: 56 in the non-PJ (NJ) group and 23 in the PJ group. RESULTS The PJ group had significantly increased pre-TNC; smaller grafts; decreased platelet counts POD14; increased TB-POD1, -POD7, and -POD14; increased prothrombin time-international normalized ratio on POD7 and POD14; and higher 90-day mortality than the NJ group. As for the risk factors for 90-day mortality, multivariate analysis identified TNC-POD14 as a single significant independent prognostic factor (P = .015). The best cut-off value of TNC-POD14 for 90-day survival was determined to be 193.7 ng/mL. In the PJ group, the patients with low TNC-POD14 (<193.7 ng/mL) had satisfactory survival, with 100.0 % at 90 days, while the patients with high TNC-POD14 (≥193.7 ng/mL) had significantly poor survival, with 38.5 % at 90 days (P = .004). CONCLUSIONS In PJ after LDLT, plasma TNC-POD14 is very useful for diagnosing postoperative irreversible liver damage early.
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Affiliation(s)
- Toru Shinkai
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan; Department of Disaster and Emergency Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Naohisa Kuriyama
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
| | - Masanobu Usui
- Department of Palliative Medicine, Fujita Health University Faculty of Medicine, Toyoake, Aichi, Japan
| | - Aoi Hayasaki
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Takehiro Fujii
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Yusuke Iizawa
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Akihiro Tanemura
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Yasuhiro Murata
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Masashi Kishiwada
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Daisuke Katoh
- Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Takeshi Matsumoto
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Hideo Wada
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Toshimichi Yoshida
- Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Shuji Isaji
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Shugo Mizuno
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
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Schlensog M, Ruehlmann AC, Haeberle L, Opitz F, Becher AK, Goering W, Buth J, Knoefel WT, Ladage D, Meyer A, Esposito I. Tenascin-C affects invasiveness of EGFR-mutated lung adenocarcinoma through a putative paracrine loop. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166684. [PMID: 36878305 DOI: 10.1016/j.bbadis.2023.166684] [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: 09/12/2022] [Revised: 01/26/2023] [Accepted: 02/28/2023] [Indexed: 03/07/2023]
Abstract
Tenascin C (TNC) is an extracellular matrix (ECM) protein and a potential biomarker affecting progression of different tumor types, such as pancreatic and lung cancer. Alternative splicing variants of TNC are known to have an impact on interaction partners like other ECM proteins or cell surface receptors, including epidermal growth factor receptor (EGFR), leading to numerous and sometimes opposite roles of TNC in tumor cell dissemination and proliferation. Only little is known about the impact of TNC on biologic characteristics of lung cancer, such as invasion and metastatic potential. In the present study, we could link an increased expression of TNC in lung adenocarcinoma (LUAD) tissues with an unfavorable clinical outcome of patients. Furthermore, we investigated the functional role of TNC in LUAD. Immunohistochemical staining of TNC revealed a significant increase of TNC levels in primary tumours and metastases compared to normal lung tissue. Additionally, a significant correlation between TNC mRNA expression and EGFR copy number and protein expression levels has been determined. Moreover, inhibition of TNC in lung fibroblasts led to reduced invasiveness of LUAD cells harboring EGFR-activating mutations and to a shorter lamellipodia perimeter and a reduced lamellipodia area on the surface of LUAD cells. This study provides the evidence that TNC expression might be a biological relevant factor in LUAD progression in an EGFR-dependent manner and that it regulates tumor cell invasion by rearrangement of the actin cytoskeleton, especially affecting lamellipodia formation.
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Affiliation(s)
- Martin Schlensog
- Institute of Pathology, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany
| | - Ann-Cathrin Ruehlmann
- Institute of Pathology, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany
| | - Lena Haeberle
- Institute of Pathology, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany
| | - Friederike Opitz
- Institute of Pathology, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany
| | - Ann-Kathrin Becher
- Institute of Pathology, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany
| | - Wolfgang Goering
- Institute of Pathology, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany
| | - Juliane Buth
- Institute of Pathology, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany
| | - Wolfram Trudo Knoefel
- Department of General, Visceral and Pediatric Surgery, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany
| | - Dennis Ladage
- Department of Pneumology, Kliniken Maria Hilf GmbH, Moenchengladbach, Germany
| | - Andreas Meyer
- Department of Pneumology, Kliniken Maria Hilf GmbH, Moenchengladbach, Germany
| | - Irene Esposito
- Institute of Pathology, Medical Faculty of the Heinrich Heine University, Duesseldorf, Germany.
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18
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Critical Review on the Different Roles of Exosomes in TNBC and Exosomal-Mediated Delivery of microRNA/siRNA/lncRNA and Drug Targeting Signalling Pathways in Triple-Negative Breast Cancer. Molecules 2023; 28:molecules28041802. [PMID: 36838790 PMCID: PMC9967195 DOI: 10.3390/molecules28041802] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 12/23/2022] [Accepted: 01/12/2023] [Indexed: 02/17/2023] Open
Abstract
Triple-negative breast cancer is the most potent metastatic type of breast cancer that can spread to other body parts. Chemotherapy and surgical intervention are the sole treatments for TNBC, owing to the scarcity of therapeutic targets. Manipulation of the membranes as per the desired targets of exosomes has recently gained much attention as a drug delivery method. Despite their known roles in different diseases, very few studies have focused on signalling that triggers the metastasis of triple-negative breast cancer to other body parts by exosomes. This article highlights the significant roles of exosomes associated with TNBC, the involvement of exosomes in breast cancer diagnosis, progression, and the treatment of triple-negative breast cancer by the exosomes as a drug delivery system. This review paper also illustrates the role of exosomes in initiating EMT in breast cancer, including novel signalling.
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19
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Tedja R, Alvero AB, Fox A, Cardenas C, Pitruzzello M, Chehade H, Bawa T, Adzibolosu N, Gogoi R, Mor G. Generation of Stable Epithelial-Mesenchymal Hybrid Cancer Cells with Tumorigenic Potential. Cancers (Basel) 2023; 15:cancers15030684. [PMID: 36765641 PMCID: PMC9913490 DOI: 10.3390/cancers15030684] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/11/2023] [Accepted: 01/16/2023] [Indexed: 01/25/2023] Open
Abstract
PURPOSE Cancer progression, invasiveness, and metastatic potential have been associated with the activation of the cellular development program known as epithelial-to-mesenchymal transition (EMT). This process is known to yield not only mesenchymal cells, but instead an array of cells with different degrees of epithelial and mesenchymal phenotypes with high plasticity, usually referred to as E/M hybrid cells. The characteristics of E/M hybrid cells, their importance in tumor progression, and the key regulators in the tumor microenvironment that support this phenotype are still poorly understood. METHODS In this study, we established an in vitro model of EMT and characterized the different stages of differentiation, allowing us to identify the main genomic signature associated with the E/M hybrid state. RESULTS We report that once the cells enter the E/M hybrid state, they acquire stable anoikis resistance, invasive capacity, and tumorigenic potential. We identified the hepatocyte growth factor (HGF)/c-MET pathway as a major driver that pushes cells in the E/M hybrid state. CONCLUSIONS Herein, we provide a detailed characterization of the signaling pathway(s) promoting and the genes associated with the E/M hybrid state.
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Affiliation(s)
- Roslyn Tedja
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
- Correspondence: (R.T.); (G.M.)
| | - Ayesha B. Alvero
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
| | - Alexandra Fox
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
| | - Carlos Cardenas
- Department of Obstetrics and Gynecology, Family HealthCare Network, Porterville, CA 93257, USA
| | - Mary Pitruzzello
- Department of Dermatology, Yale Medical School, New Haven, CT 06510, USA
| | - Hussein Chehade
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA
| | - Tejeshwhar Bawa
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
| | - Nicholas Adzibolosu
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
- Department of Physiology, Wayne State University, Detroit, MI 48201, USA
| | - Radhika Gogoi
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
- Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
| | - Gil Mor
- Department of Obstetrics and Gynecology, Family HealthCare Network, Porterville, CA 93257, USA
- Correspondence: (R.T.); (G.M.)
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20
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Low-Dose X-Ray Increases Paracellular Permeability of Human Renal Glomerular Endothelial Cells. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:5382420. [PMID: 36267304 PMCID: PMC9578893 DOI: 10.1155/2022/5382420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/13/2022] [Accepted: 09/20/2022] [Indexed: 11/28/2022]
Abstract
Objective Glomerular endothelium functions as a filtration barrier of metabolites in the kidney. Although X-ray irradiation modulated the permeability of the vascular endothelium, the response of human renal glomerular endothelial cells (HRGECs) to low-dose X-ray irradiation has not been investigated. We evaluated the impacts of low-dose X-ray irradiation on HRGECs and revealed the underlying mechanism. Methods HRGECs were exposed to X-ray with doses of 0, 0.1, 0.5, 1.0, and 2.0 Gy. The proliferation, viability, and apoptosis of HRGECs were examined by MTT assay, trypan blue staining assay, and TUNEL staining, respectively. The paracellular permeability was assessed by paracellular permeability assay. The expression of VE-cadherin was investigated via immunofluorescence assay. Western blot and qRT-PCR detected the expression levels of VE-cadherin and CLDN5. Besides, the expression levels of pVE-cadherin (pY658), TGF-β, TGF-βRI, Src, p-Src, Smad2, p-Smad2, Smad3, p-Smad3, SNAIL, SLUG, and apoptosis-related proteins were tested by Western blot. Results The proliferation, viability, and apoptosis of HRGECs were not affected by low-dose (<2.0 Gy) X-ray irradiation. X-ray irradiation dose-dependently reduced the level of VE-cadherin, and VE-cadherin and CLDN5 levels were reduced with X-ray irradiation. The levels of pY658, p-Src, p-Smad2, and p-Smad3 were upregulated with the increase in X-ray dose. Besides, the paracellular permeability of HRGECs was increased by even low-dose (<2.0 Gy) X-ray irradiation. Therefore, low-dose X-ray irradiation reduced the cumulative content of VE-cadherin and increased the level of pY658 via activation of the TGF-β signaling pathway. Conclusion Even though low-dose X-ray exposure had no impact on proliferation, viability, and apoptosis of HRGECs, it increased the paracellular permeability by deterioration and downregulation of VE-cadherin through stimulating the TGF-β signaling pathway. This study built the framework for kidney response to low-dose irradiation exposure.
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21
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Identification of AGR2 Gene-Specific Expression Patterns Associated with Epithelial-Mesenchymal Transition. Int J Mol Sci 2022; 23:ijms231810845. [PMID: 36142758 PMCID: PMC9504245 DOI: 10.3390/ijms231810845] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 09/01/2022] [Accepted: 09/13/2022] [Indexed: 11/28/2022] Open
Abstract
The TGF-β signaling pathway is involved in numerous cellular processes, and its deregulation may result in cancer development. One of the key processes in tumor progression and metastasis is epithelial to mesenchymal transition (EMT), in which TGF-β signaling plays important roles. Recently, AGR2 was identified as a crucial component of the cellular machinery responsible for maintaining the epithelial phenotype, thereby interfering with the induction of mesenchymal phenotype cells by TGF-β effects in cancer. Here, we performed transcriptomic profiling of A549 lung cancer cells with CRISPR-Cas9 mediated AGR2 knockout with and without TGF-β treatment. We identified significant changes in transcripts associated with focal adhesion and eicosanoid production, in particular arachidonic acid metabolism. Changes in transcripts associated with the focal adhesion pathway were validated by RT-qPCR of COL4A1, COL4A2, FLNA, VAV3, VEGFA, and VINC mRNAs. In addition, immunofluorescence showed the formation of stress fibers and vinculin foci in cells without AGR2 and in response to TGF-β treatment, with synergistic effects observed. These findings imply that both AGR2 downregulation and TGF-β have a role in focal adhesion formation and cancer cell migration and invasion. Transcripts associated with arachidonic acid metabolism were downregulated after both AGR2 knockout and TGF-β treatment and were validated by RT-qPCR of GPX2, PTGS2, and PLA2G4A. Since PGE2 is a product of arachidonic acid metabolism, its lowered concentration in media from AGR2-knockout cells was confirmed by ELISA. Together, our results demonstrate that AGR2 downregulation and TGF-β have an essential role in focal adhesion formation; moreover, we have identified AGR2 as an important component of the arachidonic acid metabolic pathway.
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22
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Yilmaz A, Loustau T, Salomé N, Poilil Surendran S, Li C, Tucker RP, Izzi V, Lamba R, Koch M, Orend G. Advances on the roles of tenascin-C in cancer. J Cell Sci 2022; 135:276631. [PMID: 36102918 PMCID: PMC9584351 DOI: 10.1242/jcs.260244] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The roles of the extracellular matrix molecule tenascin-C (TNC) in health and disease have been extensively reviewed since its discovery over 40 years ago. Here, we will describe recent insights into the roles of TNC in tumorigenesis, angiogenesis, immunity and metastasis. In addition to high levels of expression in tumors, and during chronic inflammation, and bacterial and viral infection, TNC is also expressed in lymphoid organs. This supports potential roles for TNC in immunity control. Advances using murine models with engineered TNC levels were instrumental in the discovery of important functions of TNC as a danger-associated molecular pattern (DAMP) molecule in tissue repair and revealed multiple TNC actions in tumor progression. TNC acts through distinct mechanisms on many different cell types with immune cells coming into focus as important targets of TNC in cancer. We will describe how this knowledge could be exploited for cancer disease management, in particular for immune (checkpoint) therapies.
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Affiliation(s)
- Alev Yilmaz
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d'Hématologie et d'Immunologie 1 , 1 Place de l'Hôpital, 67091 Strasbourg , France
- Université Strasbourg 2 , 67000 Strasbourg , France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS) 3 , 67000 Strasbourg , France
| | - Thomas Loustau
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d'Hématologie et d'Immunologie 1 , 1 Place de l'Hôpital, 67091 Strasbourg , France
- Université Strasbourg 2 , 67000 Strasbourg , France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS) 3 , 67000 Strasbourg , France
| | - Nathalie Salomé
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d'Hématologie et d'Immunologie 1 , 1 Place de l'Hôpital, 67091 Strasbourg , France
- Université Strasbourg 2 , 67000 Strasbourg , France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS) 3 , 67000 Strasbourg , France
| | - Suchithra Poilil Surendran
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d'Hématologie et d'Immunologie 1 , 1 Place de l'Hôpital, 67091 Strasbourg , France
- Université Strasbourg 2 , 67000 Strasbourg , France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS) 3 , 67000 Strasbourg , France
| | - Chengbei Li
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d'Hématologie et d'Immunologie 1 , 1 Place de l'Hôpital, 67091 Strasbourg , France
- Université Strasbourg 2 , 67000 Strasbourg , France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS) 3 , 67000 Strasbourg , France
| | - Richard P. Tucker
- University of California at Davis 4 Department of Cell Biology and Human Anatomy , , 95616 Davis, CA , USA
| | - Valerio Izzi
- University of Oulu 5 Faculty of Biochemistry and Molecular Medicine , , FI-90014 Oulu , Finland
- University of Oulu 6 Faculty of Medicine , , FI-90014 Oulu , Finland
| | - Rijuta Lamba
- University of Oulu 5 Faculty of Biochemistry and Molecular Medicine , , FI-90014 Oulu , Finland
- University of Oulu 6 Faculty of Medicine , , FI-90014 Oulu , Finland
| | - Manuel Koch
- Institute for Dental Research and Oral Musculoskeletal Research, Center for Biochemistry, Center for Molecular Medicine Cologne (CMMC) 7 , Faculty of Medicine and , Joseph-Stelzmann-Str. 52, 50931 Cologne , Germany
- University Hospital Cologne, University of Cologne 7 , Faculty of Medicine and , Joseph-Stelzmann-Str. 52, 50931 Cologne , Germany
| | - Gertraud Orend
- The Tumor Microenvironment Laboratory, INSERM U1109, Hôpital Civil, Institut d'Hématologie et d'Immunologie 1 , 1 Place de l'Hôpital, 67091 Strasbourg , France
- Université Strasbourg 2 , 67000 Strasbourg , France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS) 3 , 67000 Strasbourg , France
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23
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Pulford CS, Uppalapati CK, Montgomery MR, Averitte RL, Hull EE, Leyva KJ. A Hybrid Epithelial to Mesenchymal Transition in Ex Vivo Cutaneous Squamous Cell Carcinoma Tissues. Int J Mol Sci 2022; 23:ijms23169183. [PMID: 36012449 PMCID: PMC9408944 DOI: 10.3390/ijms23169183] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/09/2022] [Accepted: 08/14/2022] [Indexed: 11/16/2022] Open
Abstract
While most cases of cutaneous squamous cell carcinoma (cSCC) are benign, invasive cSCC is associated with higher mortality and is often more difficult to treat. As such, understanding the factors that influence the progression of cSCC are important. Aggressive cancers metastasize through a series of evolutionary changes, collectively called the epithelial-to-mesenchymal transition (EMT). During EMT, epithelial cells transition to a highly mobile mesenchymal cell type with metastatic capacities. While changes in expression of TGF-β, ZEB1, SNAI1, MMPs, vimentin, and E-cadherin are hallmarks of an EMT process occurring within cancer cells, including cSCC cells, EMT within tissues is not an “all or none” process. Using patient-derived cSCC and adjacent normal tissues, we show that cells within individual cSCC tumors are undergoing a hybrid EMT process, where there is variation in expression of EMT markers by cells within a tumor mass that may be facilitating invasion. Interestingly, cells along the outer edges of a tumor mass exhibit a more mesenchymal phenotype, with reduced E-cadherin, β-catenin, and cytokeratin expression and increased vimentin expression. Conversely, cells in the center of a tumor mass retain a higher expression of the epithelial markers E-cadherin and cytokeratin and little to no expression of vimentin, a mesenchymal marker. We also detected inverse expression changes in the miR-200 family and the EMT-associated transcription factors ZEB1 and SNAI1, suggesting that cSCC EMT dynamics are regulated in a miRNA-dependent manner. These novel findings in cSCC tumors provide evidence of phenotypic plasticity of the EMT process occurring within patient tissues, and extend the characterization of a hybrid EMT program occurring within a tumor mass. This hybrid EMT program may be promoting both survival and invasiveness of the tumors. A better understanding of this hybrid EMT process may influence therapeutic strategies in more invasive disease.
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Affiliation(s)
- Christopher S. Pulford
- Arizona College of Osteopathic Medicine, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA
- Biomedical Sciences Program, College of Graduate Studies, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA
| | - Chandana K. Uppalapati
- Department of Microbiology & Immunology, College of Graduate Studies, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA
| | | | - Richard L. Averitte
- Affiliated Dermatology & Affiliated Laboratories, 20401 N. 73rd Street #230, Scottsdale, AZ 85255, USA
| | - Elizabeth E. Hull
- Biomedical Sciences Program, College of Graduate Studies, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA
| | - Kathryn J. Leyva
- Department of Microbiology & Immunology, College of Graduate Studies, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA
- Correspondence: ; Tel.: 1-623-572-3294
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24
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Fu Z, Zhu G, Luo C, Chen Z, Dou Z, Chen Y, Zhong C, Su S, Liu F. Matricellular protein tenascin C: Implications in glioma progression, gliomagenesis, and treatment. Front Oncol 2022; 12:971462. [PMID: 36033448 PMCID: PMC9413079 DOI: 10.3389/fonc.2022.971462] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 07/25/2022] [Indexed: 11/24/2022] Open
Abstract
Matricellular proteins are nonstructural extracellular matrix components that are expressed at low levels in normal adult tissues and are upregulated during development or under pathological conditions. Tenascin C (TNC), a matricellular protein, is a hexameric and multimodular glycoprotein with different molecular forms that is produced by alternative splicing and post-translational modifications. Malignant gliomas are the most common and aggressive primary brain cancer of the central nervous system. Despite continued advances in multimodal therapy, the prognosis of gliomas remains poor. The main reasons for such poor outcomes are the heterogeneity and adaptability caused by the tumor microenvironment and glioma stem cells. It has been shown that TNC is present in the glioma microenvironment and glioma stem cell niches, and that it promotes malignant properties, such as neovascularization, proliferation, invasiveness, and immunomodulation. TNC is abundantly expressed in neural stem cell niches and plays a role in neurogenesis. Notably, there is increasing evidence showing that neural stem cells in the subventricular zone may be the cells of origin of gliomas. Here, we review the evidence regarding the role of TNC in glioma progression, propose a potential association between TNC and gliomagenesis, and summarize its clinical applications. Collectively, TNC is an appealing focus for advancing our understanding of gliomas.
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Affiliation(s)
- Zaixiang Fu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ganggui Zhu
- Department of Neurosurgery, Hangzhou First People’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chao Luo
- Department of Neurosurgery, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Zihang Chen
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhangqi Dou
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yike Chen
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chen Zhong
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Sheng Su
- Department of Neurosurgery, The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China
| | - Fuyi Liu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Fuyi Liu,
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Thomas R, Jerome JM, Dang TD, Souto EP, Mallam JN, Rowley DR. Androgen receptor variant-7 regulation by tenascin-c induced src activation. Cell Commun Signal 2022; 20:119. [PMID: 35948987 PMCID: PMC9364530 DOI: 10.1186/s12964-022-00925-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 06/23/2022] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Bone metastatic prostate cancer does not completely respond to androgen-targeted therapy and generally evolves into lethal castration resistant prostate cancer (CRPC). Expression of AR-V7- a constitutively active, ligand independent splice variant of AR is one of the critical resistant mechanisms regulating metastatic CRPC. TNC is an extracellular matrix glycoprotein, crucial for prostate cancer progression, and associated with prostate cancer bone metastases. In this study, we investigated the mechanisms that regulate AR-V7 expression in prostate cancer cells interacting with osteogenic microenvironment including TNC. METHODS Prostate cancer/preosteoblast heterotypical organoids were evaluated via immunofluorescence imaging and gene expression analysis using RT-qPCR to assess cellular compartmentalization, TNC localization, and to investigate regulation of AR-V7 in prostate cancer cells by preosteoblasts and hormone or antiandrogen action. Prostate cancer cells cultured on TNC were assessed using RT-qPCR, Western blotting, cycloheximide chase assay, and immunofluorescence imaging to evaluate (1) regulation of AR-V7, and (2) signaling pathways activated by TNC. Identified signaling pathway induced by TNC was targeted using siRNA and a small molecular inhibitor to investigate the role of TNC-induced signaling activation in regulation of AR-V7. Both AR-V7- and TNC-induced signaling effectors were targeted using siRNA, and TNC expression assessed to evaluate potential feedback regulation. RESULTS Utilizing heterotypical organoids, we show that TNC is an integral component of prostate cancer interaction with preosteoblasts. Interaction with preosteoblasts upregulated both TNC and AR-V7 expression in prostate cancer cells which was suppressed by testosterone but elevated by antiandrogen enzalutamide. Interestingly, the results demonstrate that TNC-induced Src activation regulated AR-V7 expression, post-translational stability, and nuclear localization in prostate cancer cells. Treatment with TNC neutralizing antibody, Src knockdown, and inhibition of Src kinase activity repressed AR-V7 transcript and protein. Reciprocally, both activated Src and AR-V7 were observed to upregulate autocrine TNC gene expression in prostate cancer cells. CONCLUSION Overall, the findings reveal that prostate cancer cell interactions with the cellular and ECM components in the osteogenic microenvironment plays critical role in regulating AR-V7 associated with metastatic CRPC. Video Abstract.
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Affiliation(s)
- Rintu Thomas
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX USA
| | - John Michael Jerome
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX USA
| | - Truong D. Dang
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX USA
| | - Eric P. Souto
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX USA
| | - Joshua N. Mallam
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX USA
| | - David R. Rowley
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX USA
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Tucker RP, Degen M. Revisiting the Tenascins: Exploitable as Cancer Targets? Front Oncol 2022; 12:908247. [PMID: 35785162 PMCID: PMC9248440 DOI: 10.3389/fonc.2022.908247] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 05/16/2022] [Indexed: 12/12/2022] Open
Abstract
For their full manifestation, tumors require support from the surrounding tumor microenvironment (TME), which includes a specific extracellular matrix (ECM), vasculature, and a variety of non-malignant host cells. Together, these components form a tumor-permissive niche that significantly differs from physiological conditions. While the TME helps to promote tumor progression, its special composition also provides potential targets for anti-cancer therapy. Targeting tumor-specific ECM molecules and stromal cells or disrupting aberrant mesenchyme-cancer communications might normalize the TME and improve cancer treatment outcome. The tenascins are a family of large, multifunctional extracellular glycoproteins consisting of four members. Although each have been described to be expressed in the ECM surrounding cancer cells, tenascin-C and tenascin-W are currently the most promising candidates for exploitability and clinical use as they are highly expressed in various tumor stroma with relatively low abundance in healthy tissues. Here, we review what is known about expression of all four tenascin family members in tumors, followed by a more thorough discussion on tenascin-C and tenascin-W focusing on their oncogenic functions and their potential as diagnostic and/or targetable molecules for anti-cancer treatment purposes.
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Affiliation(s)
- Richard P. Tucker
- Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, CA, United States
| | - Martin Degen
- Laboratory for Oral Molecular Biology, Department of Orthodontics and Dentofacial Orthopedics, University of Bern, Bern, Switzerland
- *Correspondence: Martin Degen,
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Tumor suppressive role of microRNA-4731-5p in breast cancer through reduction of PAICS-induced FAK phosphorylation. Cell Death Dis 2022; 8:154. [PMID: 35379785 PMCID: PMC8980087 DOI: 10.1038/s41420-022-00938-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 02/21/2022] [Accepted: 03/08/2022] [Indexed: 12/25/2022]
Abstract
A wide array of microRNAs (miRNAs) is differentially expressed in breast tumors and also functions as tumor suppressors. Herein, the current study sought to unravel the function of miR-4731-5p in breast cancer progression. First, breast cancer-related miRNA and mRNA microarray data sets were retrieved for differential analyses. Subsequently, the expression patterns of miR-4731-5p, PAICS, and FAK in breast cancer tissues and cells were determined, in addition to analyses of their roles in glycometabolism, migration, invasion, epithelial–mesenchymal transition (EMT) analyzed through functional assays. Next, the targeting relation between miR-4731-5p and PAICS was validated. Xenograft tumors in nude mice were further established to reproduce and verify the in vitro findings. miR-4731-5p was poorly expressed and PAICS was highly expressed in breast cancer tissues and cells. PAICS was confirmed as a target of miR-4731-5p. Moreover, miR-4731-5p exerted an inhibitory effect on glycolysis, EMT, migration, and invasion in breast cancer cells via regulation of PAICS-dependent phosphorylation of FAK. In vivo assay further validated the significance of the miR-4731-5p/PAICS/FAK axis in vivo tumorigenesis and lung metastasis in breast cancer. Collectively, our findings indicated that miR-4731-5p inhibited breast cancer cell glycolysis and EMT through the reduction of PAICS-induced phosphorylation of FAK.
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Rahimmanesh I, Fatehi R, Khanahmad H. Identification of Significant Genes and Pathways Associated with Tenascin-C in Cancer Progression by Bioinformatics Analysis. Adv Biomed Res 2022; 11:17. [PMID: 35386538 PMCID: PMC8977614 DOI: 10.4103/abr.abr_201_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 09/02/2020] [Accepted: 09/07/2020] [Indexed: 11/16/2022] Open
Abstract
Background Tenascin-C (TNC) is a large glycoprotein of the extracellular matrix which associated with poor clinical outcomes in several malignancies. TNC over-expression is repeatedly observed in several cancer tissues and promotes several processes in tumor progression. Until quite recently, more needs to be known about the potential mechanisms of TNC as a key player in cancer progression and metastasis. Materials and Methods In the present study, we performed a bioinformatics analysis of breast and colorectal cancer expression microarray data to survey TNC role and function with holistic view. Gene expression profiles were analyzed to identify differentially expressed genes (DEGs) between normal samples and cancer biopsy samples. The protein-protein interaction (PPI) networks of the DEGs with CluePedia plugin of Cytoscape software were constructed. Furthermore, after PPI network construction, gene-regulatory networks analysis was performed to predict long noncoding RNAs and microRNAs associated with TNC and cluster analysis was performed. Using the Clue gene ontology (GO) plugin of Cytoscape software, the GO and pathway enrichment analysis were performed. Results PPI and DEGs-miRNA-lncRNA regulatory networks showed TNC is a significant node in a huge network, and one of the main gene with high centrality parameters. Furthermore, from the regulatory level perspective, TNC could be significantly impressed by miR-335-5p. GO analysis results showed that TNC was significantly enriched in cancer-related biological processes. Conclusions It is important to identify the TNC underlying molecular mechanisms in cancer progression, which may be clinically useful for tumor-targeting strategies. Bioinformatics analysis provides an insight into the significant roles that TNC plays in cancer progression scenarios.
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Affiliation(s)
- Ilnaz Rahimmanesh
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran,Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Razieh Fatehi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hossein Khanahmad
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran,Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non- Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran,Address for correspondence: Dr. Hossein Khanahmad, Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. E-mail:
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Lee YC, Lin SC, Yu G, Zhu M, Song JH, Rivera K, Pappin DJ, Logothetis CJ, Panaretakis T, Wang G, Yu-Lee LY, Lin SH. Prostate tumor-induced stromal reprogramming generates Tenascin C that promotes prostate cancer metastasis through YAP/TAZ inhibition. Oncogene 2022; 41:757-769. [PMID: 34845375 PMCID: PMC8818031 DOI: 10.1038/s41388-021-02131-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 11/11/2021] [Accepted: 11/19/2021] [Indexed: 11/09/2022]
Abstract
Metastatic prostate cancer (PCa) in bone induces bone-forming lesions that enhance PCa progression. How tumor-induced bone formation enhances PCa progression is not known. We have previously shown that PCa-induced bone originates from endothelial cells (ECs) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition by tumor-secreted bone morphogenetic protein 4 (BMP4). Here, we show that EC-to-OSB transition leads to changes in the tumor microenvironment that increases the metastatic potential of PCa cells. We found that conditioned medium (CM) from EC-OSB hybrid cells increases the migration, invasion, and survival of PC3-mm2 and C4-2B4 PCa cells. Quantitative mass spectrometry (Isobaric Tags for Relative and Absolute Quantitation) identified Tenascin C (TNC) as one of the major proteins secreted from EC-OSB hybrid cells. TNC expression in tumor-induced OSBs was confirmed by immunohistochemistry of MDA PCa-118b xenograft and human bone metastasis specimens. Mechanistically, BMP4 increases TNC expression in EC-OSB cells through the Smad1-Notch/Hey1 pathway. How TNC promotes PCa metastasis was next interrogated by in vitro and in vivo studies. In vitro studies showed that a TNC-neutralizing antibody inhibits EC-OSB-CM-mediated PCa cell migration and survival. TNC knockdown decreased, while the addition of recombinant TNC or TNC overexpression increased migration and anchorage-independent growth of PC3 or C4-2b cells. When injected orthotopically, PC3-mm2-shTNC clones decreased metastasis to bone, while C4-2b-TNC-overexpressing cells increased metastasis to lymph nodes. TNC enhances PCa cell migration through α5β1 integrin-mediated YAP/TAZ inhibition. These studies elucidate that tumor-induced stromal reprogramming generates TNC that enhances PCa metastasis and suggest that TNC may be a target for PCa therapy.
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Affiliation(s)
- Yu-Chen Lee
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Song-Chang Lin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Guoyu Yu
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Ming Zhu
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jian H Song
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Keith Rivera
- Cold Spring Harbor Laboratory, Cold Spring Harbor, 11724, NY, USA
| | - Darryl J Pappin
- Cold Spring Harbor Laboratory, Cold Spring Harbor, 11724, NY, USA
| | - Christopher J Logothetis
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Theocharis Panaretakis
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Guocan Wang
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Li-Yuan Yu-Lee
- Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Sue-Hwa Lin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
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Loustau T, Abou-Faycal C, Erne W, zur Wiesch PA, Ksouri A, Imhof T, Mörgelin M, Li C, Mathieu M, Salomé N, Crémel G, Dhaouadi S, Bouhaouala-Zahar B, Koch M, Orend G. Modulating tenascin-C functions by targeting the MAtrix REgulating MOtif, “MAREMO”. Matrix Biol 2022; 108:20-38. [DOI: 10.1016/j.matbio.2022.02.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/31/2022] [Accepted: 02/23/2022] [Indexed: 12/11/2022]
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Structural Biology of the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1350:91-100. [PMID: 34888845 DOI: 10.1007/978-3-030-83282-7_4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cancers can be described as "rogue organs" (Balkwill FR, Capasso M, Hagemann T, J Cell Sci 125:5591-5596, 2012) because they are composed of multiple cell types and tissues. The transformed cells can recruit and alter healthy cells from surrounding tissues for their own benefit. It is these interactions that create the tumor microenvironment (TME). The TME describes the cells, factors, and extracellular matrix proteins that make up the tumor and the area around it; the biology of the TME influences tumor progression. Changes in the TME can lead to the growth and development of the tumor, the death of the tumor, or tumor metastasis. Metastasis is the process by which cancer spreads from its initial site to a different part of the body. Metastasis occurs when cancer cells enter the circulatory system or lymphatic system after they break away from a tumor. Once the cells leave, they can travel to a different part of the body and form new tumors. Therefore, understanding the TME is critical to fully understand cancer and find a way to successfully combat it. Knowledge of the TME can better inform researchers of the ability of potential therapies to reach tumor cells. It can also give researchers potential targets to kill the tumor. Instead of directly killing the cancer cells, therapies can target an aspect of the TME which could then halt tumor development or lead to tumor death. In other cases, targeting another aspect of the TME could make it easier for another therapy to kill the cancer cells, for example, using nanoparticles with collagenases to target the collagen in the surrounding environment to expose the cancer cells to drugs (Zinger A, et al, ACS Nano 13(10):11008-11021, 2019).The TME can be split simply into cells and the structural matrix. Within these groups are fibroblasts, structural proteins, immune cells, lymphocytes, bone marrow-derived inflammatory cells, blood vessels, and signaling molecules (Spill F, et al, Curr Opin Biotechnol 40:41-48, 2016; Del Prete A, et al, Curr Opin Pharmacol 35:40-47, 2017; Arneth B, Medicina (Kaunas) 56(1), 2019). From structure to providing nutrients for growth, each of these components plays a critical role in tumor maintenance. Together these components impact cancer growth, development, and resistance to therapies (Hanahan D, Coussens LM, Cancer Cell 21:309-322, 2012). In this chapter, we will describe the TME and express the importance of the cellular and structural elements of the TME.
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32
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Espejo C, Wilson R, Willms E, Ruiz-Aravena M, Pye RJ, Jones ME, Hill AF, Woods GM, Lyons AB. Extracellular vesicle proteomes of two transmissible cancers of Tasmanian devils reveal tenascin-C as a serum-based differential diagnostic biomarker. Cell Mol Life Sci 2021; 78:7537-7555. [PMID: 34655299 PMCID: PMC11073120 DOI: 10.1007/s00018-021-03955-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/26/2021] [Accepted: 09/28/2021] [Indexed: 12/15/2022]
Abstract
The iconic Tasmanian devil (Sarcophilus harrisii) is endangered due to the transmissible cancer Devil Facial Tumour Disease (DFTD), of which there are two genetically independent subtypes (DFT1 and DFT2). While DFT1 and DFT2 can be differentially diagnosed using tumour biopsies, there is an urgent need to develop less-invasive biomarkers that can detect DFTD and distinguish between subtypes. Extracellular vesicles (EVs), the nano-sized membrane-enclosed vesicles present in most biofluids, represent a valuable resource for biomarker discovery. Here, we characterized the proteome of EVs from cultured DFTD cells using data-independent acquisition-mass spectrometry and an in-house spectral library of > 1500 proteins. EVs from both DFT1 and DFT2 cell lines expressed higher levels of proteins associated with focal adhesion functions. Furthermore, hallmark proteins of epithelial-mesenchymal transition were enriched in DFT2 EVs relative to DFT1 EVs. These findings were validated in EVs derived from serum samples, revealing that the mesenchymal marker tenascin-C was also enriched in EVs derived from the serum of devils infected with DFT2 relative to those infected with DFT1 and healthy controls. This first EV-based investigation of DFTD increases our understanding of the cancers' EVs and their possible involvement in DFTD progression, such as metastasis. Finally, we demonstrated the potential of EVs to differentiate between DFT1 and DFT2, highlighting their potential use as less-invasive liquid biopsies for the Tasmanian devil.
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Affiliation(s)
- Camila Espejo
- Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, TAS, 7000, Australia.
| | - Richard Wilson
- Central Science Laboratory, University of Tasmania, Hobart, TAS, 7005, Australia
| | - Eduard Willms
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, 3083, Australia
| | - Manuel Ruiz-Aravena
- Department of Microbiology and Immunology, Montana State University, Bozeman, MT, 59717, USA
- School of Natural Sciences, University of Tasmania, Hobart, TAS, 7001, Australia
| | - Ruth J Pye
- Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania, Hobart, TAS, 7000, Australia
| | - Menna E Jones
- School of Natural Sciences, University of Tasmania, Hobart, TAS, 7001, Australia
| | - Andrew F Hill
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, 3083, Australia
| | - Gregory M Woods
- Menzies Institute for Medical Research, College of Health and Medicine, University of Tasmania, Hobart, TAS, 7000, Australia
| | - A Bruce Lyons
- Tasmanian School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, TAS, 7000, Australia
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Saxena M, Hisano M, Neutzner M, Diepenbruck M, Ivanek R, Sharma K, Kalathur RKR, Bürglin TR, Risoli S, Christofori G. The long non-coding RNA ET-20 mediates EMT by impairing desmosomes in breast cancer cells. J Cell Sci 2021; 134:272428. [PMID: 34633031 DOI: 10.1242/jcs.258418] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 09/24/2021] [Indexed: 01/06/2023] Open
Abstract
The vast majority of breast cancer-associated deaths are due to metastatic spread of cancer cells, a process aided by epithelial-to-mesenchymal transition (EMT). Mounting evidence has indicated that long non-coding RNAs (lncRNAs) also contribute to tumor progression. We report the identification of 114 novel lncRNAs that change their expression during TGFβ-induced EMT in murine breast cancer cells (referred to as EMT-associated transcripts; ETs). Of these, the ET-20 gene localizes in antisense orientation within the tenascin C (Tnc) gene locus. TNC is an extracellular matrix protein that is critical for EMT and metastasis formation. Both ET-20 and Tnc are regulated by the EMT master transcription factor Sox4. Notably, ablation of ET-20 lncRNA effectively blocks Tnc expression and with it EMT. Mechanistically, ET-20 interacts with desmosomal proteins, thereby impairing epithelial desmosomes and promoting EMT. A short transcript variant of ET-20 is shown to be upregulated in invasive human breast cancer cell lines, where it also promotes EMT. Targeting ET-20 appears to be a therapeutically attractive lead to restrain EMT and breast cancer metastasis in addition to its potential utility as a biomarker for invasive breast cancer.
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Affiliation(s)
- Meera Saxena
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
| | - Mizue Hisano
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
| | - Melanie Neutzner
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
| | - Maren Diepenbruck
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
| | - Robert Ivanek
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.,Swiss Institute of Bioinformatics, 4058 Basel, Switzerland
| | - Kirti Sharma
- Proteomics Kymera Therapeutics Basel Cambridge, MA 02472, USA
| | - Ravi K R Kalathur
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.,Murdoch Children's Research Institute, Royal Children's Hospital, 3052 Parkville, Australia
| | - Thomas R Bürglin
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
| | - Salvatore Risoli
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
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Xu K, Shao Y, Xia Y, Qian Y, Jiang N, Liu X, Yang L, Wang C. Tenascin-C regulates migration of SOX10 tendon stem cells via integrin-α9 for promoting patellar tendon remodeling. Biofactors 2021; 47:768-777. [PMID: 34058037 DOI: 10.1002/biof.1759] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 05/14/2021] [Indexed: 12/24/2022]
Abstract
Insufficient attention has been focused on the directional migration of SOX10+ tendon stem cells (STSCs) during tendon remodeling. Here, we investigate whether tenascin-C (TNC) promotes STSC motility and migration. Based on the hypothesis that TNCs induce STSC migration, RNA-sequencing (RNA-seq) was conducted, identifying 2107 differentially expressed genes (DEGs), of which 1272 were up-regulated and 835 down-regulated following treatment with TNC versus the control. The DEGs were principally involved in cell adhesion and cell membrane signal transduction. Highly enriched-related signaling included the PI3K-Akt, focal adhesion, and ECM-receptor interaction pathways. Protein interaction analysis established that TNC was positively correlated with ITGA9 (integrin-α9). Furthermore, TNC activated the phosphorylation levels of FAK and Akt, and knockdown of ITGA9 with siRNA revealed that TNC contributes to STSC migration via the targeting of ITGA9. In addition, in vivo administration of TNC promoted tissue regeneration of injured tendons. In conclusion, TNC regulated the migration of STSCs via ITGA9, thereby promoting the regeneration of tendon injuries.
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Affiliation(s)
- Kang Xu
- Hubei Engineering Technology Research Center of Chinese Materia Medica Processing, College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
- Engineering Research Center of Clinical Functional Materials and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, China
| | - Yibo Shao
- National Innovation and Attracting Talents "111" base, Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Yi Xia
- Hubei University of Chinese Medicine, Huangjiahu Hospital, Wuhan, China
| | - Yuna Qian
- Engineering Research Center of Clinical Functional Materials and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, China
| | - Nan Jiang
- Hubei Engineering Technology Research Center of Chinese Materia Medica Processing, College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Xianqiong Liu
- Hubei Engineering Technology Research Center of Chinese Materia Medica Processing, College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Li Yang
- National Innovation and Attracting Talents "111" base, Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Chunli Wang
- National Innovation and Attracting Talents "111" base, Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
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Cheng X, Li F, Tao Z. Tenascin-C promotes epithelial-to-mesenchymal transition and the mTOR signaling pathway in nasopharyngeal carcinoma. Oncol Lett 2021; 22:570. [PMID: 34113398 PMCID: PMC8185706 DOI: 10.3892/ol.2021.12831] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 04/22/2021] [Indexed: 12/24/2022] Open
Abstract
Tenascin-C (TNC) is a large extracellular matrix glycoprotein that promotes cell adhesion and tissue remodeling, and is involved in the transduction of cellular signaling pathways. The present study aimed to investigate the role of TNC and determine its effect in nasopharyngeal carcinoma (NPC). TNC gene transcription and expression were analyzed using the NPC dataset and immunohistochemistry analysis of NPC tissues. Weighted gene co-expression network and gene enrichment analyses were performed to determine the potential molecular mechanisms underlying the effects of TNC in NPC. TNC expression was suppressed in NPC cells, and the effects were determined both in vitro and in vivo. The results demonstrated that TNC gene transcription and expression were high in NPC tissues compared with normal tissues. Notably, TNC knockdown inhibited NPC cell proliferation, migration and invasion. In addition, TNC knockdown inhibited tumor growth in mice. In vitro, TNC knockdown inhibited epithelial-to-mesenchymal transition (EMT) and decreased activity of the PI3K/AKT/mTOR signaling pathway in NPC cells. Taken together, these results suggest that TNC promotes cell proliferation, EMT and activity of the PI3K/AKT/mTOR signaling pathway in NPC cells, and thus functions as an oncogene.
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Affiliation(s)
- Xiang Cheng
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Fen Li
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Zezhang Tao
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Albacete-Albacete L, Sánchez-Álvarez M, Del Pozo MA. Extracellular Vesicles: An Emerging Mechanism Governing the Secretion and Biological Roles of Tenascin-C. Front Immunol 2021; 12:671485. [PMID: 33981316 PMCID: PMC8107694 DOI: 10.3389/fimmu.2021.671485] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/08/2021] [Indexed: 12/12/2022] Open
Abstract
ECM composition and architecture are tightly regulated for tissue homeostasis. Different disorders have been associated to alterations in the levels of proteins such as collagens, fibronectin (FN) or tenascin-C (TnC). TnC emerges as a key regulator of multiple inflammatory processes, both during physiological tissue repair as well as pathological conditions ranging from tumor progression to cardiovascular disease. Importantly, our current understanding as to how TnC and other non-collagen ECM components are secreted has remained elusive. Extracellular vesicles (EVs) are small membrane-bound particles released to the extracellular space by most cell types, playing a key role in cell-cell communication. A broad range of cellular components can be transported by EVs (e.g. nucleic acids, lipids, signalling molecules and proteins). These cargoes can be transferred to target cells, potentially modulating their function. Recently, several extracellular matrix (ECM) proteins have been characterized as bona fide EV cargoes, exosomal secretion being particularly critical for TnC. EV-dependent ECM secretion might underpin diseases where ECM integrity is altered, establishing novel concepts in the field such as ECM nucleation over long distances, and highlighting novel opportunities for diagnostics and therapeutic intervention. Here, we review recent findings and standing questions on the molecular mechanisms governing EV–dependent ECM secretion and its potential relevance for disease, with a focus on TnC.
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Affiliation(s)
- Lucas Albacete-Albacete
- Mechanoadaptation and Caveolae Biology Lab, Area of Cell and Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Miguel Sánchez-Álvarez
- Mechanoadaptation and Caveolae Biology Lab, Area of Cell and Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Miguel Angel Del Pozo
- Mechanoadaptation and Caveolae Biology Lab, Area of Cell and Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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Bartlett AQ, Pennock ND, Klug A, Schedin P. Immune Milieu Established by Postpartum Liver Involution Promotes Breast Cancer Liver Metastasis. Cancers (Basel) 2021; 13:1698. [PMID: 33916683 PMCID: PMC8038410 DOI: 10.3390/cancers13071698] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/30/2021] [Accepted: 04/02/2021] [Indexed: 12/12/2022] Open
Abstract
In rodents, we identified a physiologic process within the normal liver that creates a pre-metastatic niche. This physiology is weaning-induced liver involution, characterized by hepatocyte cell death, immune influx, and extracellular matrix remodeling. Here, using weaning-induced liver involution as a model of a physiologically regulated pro-metastatic niche, we investigate how liver involution supports breast cancer metastasis. Liver metastases were induced in BALB/c immune competent hosts by portal vein injection of D2OR (low metastatic) or D2A1 (high metastatic) mouse mammary tumor cells. Tumor incidence and multiplicity increased in involution hosts with no evidence of a proliferation advantage. D2OR tumor cell extravasation, seeding, and early survival were not enhanced in the involuting group compared to the nulliparous group. Rather, the involution metastatic advantage was observed at 14 days post tumor cell injection. This metastatic advantage associated with induction of immune tolerance in the involution host liver, reproductive state dependent intra-tumoral immune composition, and CD8-dependent suppression of metastases in nulliparous hosts. Our findings suggest that the normal postpartum liver is in an immune suppressed state, which can provide a pro-metastatic advantage to circulating breast cancer cells. Potential relevance to women is suggested as a postpartum diagnosis of breast cancer is an independent predictor of liver metastasis.
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Affiliation(s)
- Alexandra Q. Bartlett
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA; (A.Q.B.); (N.D.P.); (A.K.)
| | - Nathan D. Pennock
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA; (A.Q.B.); (N.D.P.); (A.K.)
| | - Alex Klug
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA; (A.Q.B.); (N.D.P.); (A.K.)
| | - Pepper Schedin
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA; (A.Q.B.); (N.D.P.); (A.K.)
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
- Young Women’s Breast Cancer Translational Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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Albacete-Albacete L, Navarro-Lérida I, López JA, Martín-Padura I, Astudillo AM, Ferrarini A, Van-Der-Heyden M, Balsinde J, Orend G, Vázquez J, Del Pozo MÁ. ECM deposition is driven by caveolin-1-dependent regulation of exosomal biogenesis and cargo sorting. J Cell Biol 2021; 219:211453. [PMID: 33053168 PMCID: PMC7551399 DOI: 10.1083/jcb.202006178] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/31/2020] [Accepted: 08/03/2020] [Indexed: 12/16/2022] Open
Abstract
The composition and physical properties of the extracellular matrix (ECM) critically influence tumor progression, but the molecular mechanisms underlying ECM layering are poorly understood. Tumor–stroma interaction critically depends on cell communication mediated by exosomes, small vesicles generated within multivesicular bodies (MVBs). We show that caveolin-1 (Cav1) centrally regulates exosome biogenesis and exosomal protein cargo sorting through the control of cholesterol content at the endosomal compartment/MVBs. Quantitative proteomics profiling revealed that Cav1 is required for exosomal sorting of ECM protein cargo subsets, including Tenascin-C (TnC), and for fibroblast-derived exosomes to efficiently deposit ECM and promote tumor invasion. Cav1-driven exosomal ECM deposition not only promotes local stromal remodeling but also the generation of distant ECM-enriched stromal niches in vivo. Cav1 acts as a cholesterol rheostat in MVBs, determining sorting of ECM components into specific exosome pools and thus ECM deposition. This supports a model by which Cav1 is a central regulatory hub for tumor–stroma interactions through a novel exosome-dependent ECM deposition mechanism.
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Affiliation(s)
- Lucas Albacete-Albacete
- Mechanoadaptation and Caveolae Biology Laboratory, Cell and Developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Inmaculada Navarro-Lérida
- Mechanoadaptation and Caveolae Biology Laboratory, Cell and Developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Juan Antonio López
- Cardiovascular Proteomics Lab, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain
| | - Inés Martín-Padura
- Mechanoadaptation and Caveolae Biology Laboratory, Cell and Developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Alma M Astudillo
- Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, Valladolid, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
| | - Alessia Ferrarini
- Cardiovascular Proteomics Lab, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Michael Van-Der-Heyden
- Institut National de la Santé et de la Recherche Médicale U1109-MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, Université de Strasbourg, LabEx Medalis, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France
| | - Jesús Balsinde
- Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, Valladolid, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
| | - Gertraud Orend
- Institut National de la Santé et de la Recherche Médicale U1109-MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, Université de Strasbourg, LabEx Medalis, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France
| | - Jesús Vázquez
- Cardiovascular Proteomics Lab, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain
| | - Miguel Ángel Del Pozo
- Mechanoadaptation and Caveolae Biology Laboratory, Cell and Developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
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Rigiracciolo DC, Cirillo F, Talia M, Muglia L, Gutkind JS, Maggiolini M, Lappano R. Focal Adhesion Kinase Fine Tunes Multifaced Signals toward Breast Cancer Progression. Cancers (Basel) 2021; 13:645. [PMID: 33562737 PMCID: PMC7915897 DOI: 10.3390/cancers13040645] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 02/07/2023] Open
Abstract
Breast cancer represents the most common diagnosed malignancy and the main leading cause of tumor-related death among women worldwide. Therefore, several efforts have been made in order to identify valuable molecular biomarkers for the prognosis and prediction of therapeutic responses in breast tumor patients. In this context, emerging discoveries have indicated that focal adhesion kinase (FAK), a non-receptor tyrosine kinase, might represent a promising target involved in breast tumorigenesis. Of note, high FAK expression and activity have been tightly correlated with a poor clinical outcome and metastatic features in several tumors, including breast cancer. Recently, a role for the integrin-FAK signaling in mechanotransduction has been suggested and the function of FAK within the breast tumor microenvironment has been ascertained toward tumor angiogenesis and vascular permeability. FAK has been also involved in cancer stem cells (CSCs)-mediated initiation, maintenance and therapeutic responses of breast tumors. In addition, the potential of FAK to elicit breast tumor-promoting effects has been even associated with the capability to modulate immune responses. On the basis of these findings, several agents targeting FAK have been exploited in diverse preclinical tumor models. Here, we recapitulate the multifaceted action exerted by FAK and its prognostic significance in breast cancer. Moreover, we highlight the recent clinical evidence regarding the usefulness of FAK inhibitors in the treatment of breast tumors.
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Affiliation(s)
- Damiano Cosimo Rigiracciolo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (F.C.); (M.T.); (L.M.); (R.L.)
| | - Francesca Cirillo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (F.C.); (M.T.); (L.M.); (R.L.)
| | - Marianna Talia
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (F.C.); (M.T.); (L.M.); (R.L.)
| | - Lucia Muglia
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (F.C.); (M.T.); (L.M.); (R.L.)
| | - Jorge Silvio Gutkind
- Department of Pharmacology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA;
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (F.C.); (M.T.); (L.M.); (R.L.)
| | - Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (F.C.); (M.T.); (L.M.); (R.L.)
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Iyoda T, Fujita M, Fukai F. Biologically Active TNIIIA2 Region in Tenascin-C Molecule: A Major Contributor to Elicit Aggressive Malignant Phenotypes From Tumors/Tumor Stroma. Front Immunol 2020; 11:610096. [PMID: 33362799 PMCID: PMC7755593 DOI: 10.3389/fimmu.2020.610096] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 11/06/2020] [Indexed: 02/06/2023] Open
Abstract
Tenascin (TN)-C is highly expressed specifically in the lesions of inflammation-related diseases, including tumors. The expression level of TN-C in tumors and the tumor stroma is positively correlated with poor prognosis. However, no drugs targeting TN-C are currently clinically available, partly because the role of TN-C in tumor progression remains controversial. TN-C harbors an alternative splicing site in its fibronectin type III repeat domain, and its splicing variants including the type III-A2 domain are frequently detected in malignant tumors. We previously identified a biologically active region termed TNIIIA2 in the fibronectin type III-A2 domain of TN-C molecule and showed that this region is involved in promoting firm and persistent cell adhesion to fibronectin. In the past decade, through the exposure of various cell lines to peptides containing the TNIIIA2 region, we have published reports demonstrating the ability of the TNIIIA2 region to modulate distinct cellular activities, including survival/growth, migration, and invasion. Recently, we reported that the signals derived from TNIIIA2-mediated β1 integrin activation might play a crucial role for inducing malignant behavior of glioblastoma (GBM). GBM cells exposed to the TNIIIA2 region showed not only exacerbation of PDGF-dependent proliferation, but also acceleration of disseminative migration. On the other hand, we also found that the pro-inflammatory phenotypic changes were promoted when macrophages are stimulated with TNIIIA2 region in relatively low concentration and resulting MMP-9 upregulation is needed to release of the TNIIIA2 region from TN-C molecule. With the contribution of TNIIIA2-stimulated macrophages, the positive feedback spiral loop, which consists of the expression of TN-C, PDGF, and β1 integrin, and TNIIIA2 release, seemed to be activated in GBM with aggressive malignancy. Actually, the growth of transplanted GBM grafts in mice was significantly suppressed via the attenuation of β1 integrin activation. In this review, we thus introduce that the TNIIIA2 region has a significant impact on malignant progression of tumors by regulating cell adhesion. Importantly, it has been demonstrated that the TNIIIA2 region exerts unique biological functions through the extremely strong activation of β1-integrins and their long-lasting duration. These findings prompt us to develop new therapeutic agents targeting the TNIIIA2 region.
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Affiliation(s)
- Takuya Iyoda
- Department of Pharmacy, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-Onoda, Japan
| | - Motomichi Fujita
- Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Fumio Fukai
- Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
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Wawrzyniak D, Grabowska M, Głodowicz P, Kuczyński K, Kuczyńska B, Fedoruk-Wyszomirska A, Rolle K. Down-regulation of tenascin-C inhibits breast cancer cells development by cell growth, migration, and adhesion impairment. PLoS One 2020; 15:e0237889. [PMID: 32817625 PMCID: PMC7440653 DOI: 10.1371/journal.pone.0237889] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 08/04/2020] [Indexed: 12/14/2022] Open
Abstract
Tenascin-C (TNC) is an extracellular matrix (ECM) glycoprotein that plays an important role in cell proliferation, migration, and tumour invasion in various cancers. TNC is one of the main protein overexpressed in breast cancer, indicating a role for this ECM molecule in cancer pathology. In this study we have evaluated the TNC loss-off-function in breast cancer cells. In our approach, we used dsRNA sharing sequence homology with TNC mRNA, called ATN-RNA. We present the data showing the effects of ATN-RNA in MDA-MB-231 cells both in monolayer and three-dimensional culture. Cells treated with ATN-RNA were analyzed for phenotypic alterations in proliferation, migration, adhesion, cell cycle, multi-caspase activation and the involvement in epithelial to mesenchymal transition (EMT) processes. As complementary analysis the oncogenomic portals were used to assess the clinical implication of TNC expression on breast cancer patient's survival, showing the TNC overexpression associated with a poor survival outcome. Our approach applied first in brain tumors and then in breast cancer cell lines reveals that ATN-RNA significantly diminishes the cell proliferation, migration and additionally, reverses the mesenchymal cells phenotype to the epithelial one. Thus, TNC could be considered as the universal target in different types of tumors, where TNC overexpression is associated with poor prognosis.
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Affiliation(s)
- Dariusz Wawrzyniak
- Department of Molecular Neurooncology, Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Poznan, Poland
| | - Małgorzata Grabowska
- Department of Molecular Neurooncology, Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Poznan, Poland
| | - Paweł Głodowicz
- Department of Molecular Neurooncology, Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Poznan, Poland
| | - Konrad Kuczyński
- Department of Molecular Neurooncology, Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Poznan, Poland
- NanoBioMedical Centre, Adam Mickiewicz University, Poznan, Poland
| | - Bogna Kuczyńska
- Department of Molecular Neurooncology, Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Poznan, Poland
| | - Agnieszka Fedoruk-Wyszomirska
- Laboratory of Subcellular Structures Analysis, Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Poznan, Poland
| | - Katarzyna Rolle
- Department of Molecular Neurooncology, Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Poznan, Poland
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Katoh D, Kozuka Y, Noro A, Ogawa T, Imanaka-Yoshida K, Yoshida T. Tenascin-C Induces Phenotypic Changes in Fibroblasts to Myofibroblasts with High Contractility through the Integrin αvβ1/Transforming Growth Factor β/SMAD Signaling Axis in Human Breast Cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:2123-2135. [PMID: 32650003 DOI: 10.1016/j.ajpath.2020.06.008] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 05/25/2020] [Accepted: 06/15/2020] [Indexed: 12/12/2022]
Abstract
Tenascin-C (TNC) is strongly expressed by fibroblasts and cancer cells in breast cancer. To assess the effects of TNC on stromal formation, we examined phenotypic changes in human mammary fibroblasts treated with TNC. The addition of TNC significantly up-regulated α-smooth muscle actin (α-SMA) and calponin. TNC increased the number of α-SMA- and/or calponin-positive cells with well-developed stress fibers in immunofluorescence, which enhanced contractile ability in collagen gel contraction. The treatment with TNC also significantly up-regulated its own synthesis. Double immunofluorescence of human breast cancer tissues showed α-SMA- and/or calponin-positive myofibroblasts in the TNC-deposited stroma. Among several receptors for TNC, the protein levels of the αv and β1 integrin subunits were significantly increased after the treatment. Immunofluorescence showed the augmented colocalization of αv and β1 at focal adhesions. Immunoprecipitation using an anti-αv antibody revealed a significant increase in coprecipitated β1 with TNC in lysates. The knockdown of αv and β1 suppressed the up-regulation of α-SMA and calponin. The addition of TNC induced the phosphorylation of SMAD2/3, whereas SB-505124 and SIS3 blocked myofibroblast differentiation. Therefore, TNC enhances its own synthesis by forming a positive feedback loop and increases integrin αvβ1 heterodimer levels to activate transforming growth factor-β signaling, which is followed by a change to highly contractile myofibroblasts. TNC may essentially contribute to the stiffer stromal formation characteristic of breast cancer tissues.
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Affiliation(s)
- Daisuke Katoh
- Department of Pathology and Matrix Biology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Yuji Kozuka
- Department of Pathologic Oncology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Aya Noro
- Department of Breast Surgery, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Tomoko Ogawa
- Department of Breast Surgery, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Kyoko Imanaka-Yoshida
- Department of Pathology and Matrix Biology, Graduate School of Medicine, Mie University, Tsu, Japan; Research Center for Matrix Biology, Mie University, Tsu, Japan
| | - Toshimichi Yoshida
- Department of Pathology and Matrix Biology, Graduate School of Medicine, Mie University, Tsu, Japan; Research Center for Matrix Biology, Mie University, Tsu, Japan.
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Baj J, Korona-Głowniak I, Forma A, Maani A, Sitarz E, Rahnama-Hezavah M, Radzikowska E, Portincasa P. Mechanisms of the Epithelial-Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer. Cells 2020; 9:1055. [PMID: 32340207 PMCID: PMC7225971 DOI: 10.3390/cells9041055] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/16/2020] [Accepted: 04/17/2020] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori (H. pylori) is one of the most common human pathogens, affecting half of the world's population. Approximately 20% of the infected patients develop gastric ulcers or neoplastic changes in the gastric stroma. An infection also leads to the progression of epithelial-mesenchymal transition within gastric tissue, increasing the probability of gastric cancer development. This paper aims to review the role of H. pylori and its virulence factors in epithelial-mesenchymal transition associated with malignant transformation within the gastric stroma. The reviewed factors included: CagA (cytotoxin-associated gene A) along with induction of cancer stem-cell properties and interaction with YAP (Yes-associated protein pathway), tumor necrosis factor α-inducing protein, Lpp20 lipoprotein, Afadin protein, penicillin-binding protein 1A, microRNA-29a-3p, programmed cell death protein 4, lysosomal-associated protein transmembrane 4β, cancer-associated fibroblasts, heparin-binding epidermal growth factor (HB-EGF), matrix metalloproteinase-7 (MMP-7), and cancer stem cells (CSCs). The review summarizes the most recent findings, providing insight into potential molecular targets and new treatment strategies for gastric cancer.
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Affiliation(s)
- Jacek Baj
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Izabela Korona-Głowniak
- Department of Pharmaceutical Microbiology with Laboratory for Microbiological Diagnostics, Medical University of Lublin, Chodzki 1 Street, 20-093 Lublin, Poland;
| | - Alicja Forma
- Chair and Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Amr Maani
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Elżbieta Sitarz
- Chair and 1st Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin, Gluska Street 1, 20-439 Lublin, Poland;
| | - Mansur Rahnama-Hezavah
- Chair and Department of Oral Surgery, Medical University of Lublin, 20-081 Lublin, Poland;
| | - Elżbieta Radzikowska
- Department of Plastic Surgery, Central Clinical Hospital of the MSWiA in Warsaw, 01-211 Warsaw, Poland;
| | - Piero Portincasa
- Clinica Medica A. Murri, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro Medical School, 70126 Bari, Italy;
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Machado Brandão-Costa R, Helal-Neto E, Maia Vieira A, Barcellos-de-Souza P, Morgado-Diaz J, Barja-Fidalgo C. Extracellular Matrix Derived from High Metastatic Human Breast Cancer Triggers Epithelial-Mesenchymal Transition in Epithelial Breast Cancer Cells through αvβ3 Integrin. Int J Mol Sci 2020; 21:ijms21082995. [PMID: 32340328 PMCID: PMC7216035 DOI: 10.3390/ijms21082995] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 04/11/2020] [Indexed: 12/19/2022] Open
Abstract
Alterations in the composition and architecture of the extracellular matrix (ECM) can influence cancer growth and dissemination. During epithelial-mesenchymal transition (EMT), epithelial cells assume a mesenchymal cell phenotype, changing their adhesion profiles from cell-cell contacts to cell-matrix interactions, contributing to metastasis. Breast cancer cells present at different stages of differentiation, producing distinct ECMs in the same tumor mass. However, the contribution of ECM derived from metastatic tumor cells to EMT is unclear. Here, we showed the mechanisms involved in the interaction of MCF-7, a low-metastatic, epithelial breast cancer cell line, with the ECM produced by a high metastatic breast tumor cell, MDA-MB-231 (MDA-ECM). MDA-ECM induced morphological changes in MCF-7 cells, decreased the levels of E-cadherin, up-regulated mesenchymal markers, and augmented cell migration. These changes were accompanied by the activation of integrin-associated signaling, with increased phosphorylation of FAK, ERK, and AKT and activation canonical TGF-β receptor signaling, enhancing phosphorylation of SMAD2 and SMAD4 nuclear translocation in MCF-7 cells. Treatment with Kistrin (Kr), a specific ligand of integrin αvβ3 EMT induced by MDA-ECM, inhibited TGF-β receptor signaling in treated MCF-7 cells. Our results revealed that after interaction with the ECM produced by a high metastatic breast cancer cell, MCF-7 cells lost their characteristic epithelial phenotype undergoing EMT, an effect modulated by integrin signaling in crosstalk with TGF-β receptor signaling pathway. The data evidenced novel potential targets for antimetastatic breast cancer therapies.
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Affiliation(s)
- Renata Machado Brandão-Costa
- Laboratory of Cellular and Molecular Pharmacology, Department of Cell Biology, IBRAG, Rio de Janeiro State University, 20551-030 Rio de Janeiro (RJ), Brazil; (R.M.B.-C.); (E.H.-N.)
| | - Edward Helal-Neto
- Laboratory of Cellular and Molecular Pharmacology, Department of Cell Biology, IBRAG, Rio de Janeiro State University, 20551-030 Rio de Janeiro (RJ), Brazil; (R.M.B.-C.); (E.H.-N.)
| | - Andreza Maia Vieira
- Laboratory of Endothelial Cell and Angiogenesis, IBRAG, Rio de Janeiro State University, 20550-900 Rio de Janeiro (RJ), Brazil;
| | - Pedro Barcellos-de-Souza
- Cellular and Molecular Oncobiology Program, Instituto Nacional de Câncer, 20231-050 Rio de Janeiro (RJ), Brazil; (P.B.-d.-S.); (J.M.-D.)
| | - Jose Morgado-Diaz
- Cellular and Molecular Oncobiology Program, Instituto Nacional de Câncer, 20231-050 Rio de Janeiro (RJ), Brazil; (P.B.-d.-S.); (J.M.-D.)
| | - Christina Barja-Fidalgo
- Laboratory of Cellular and Molecular Pharmacology, Department of Cell Biology, IBRAG, Rio de Janeiro State University, 20551-030 Rio de Janeiro (RJ), Brazil; (R.M.B.-C.); (E.H.-N.)
- Correspondence: ; Tel.: +55-21-2868-8298; Fax: +55-21-2868-8629
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Kim H, Lee S, Shin E, Seong KM, Jin YW, Youn H, Youn B. The Emerging Roles of Exosomes as EMT Regulators in Cancer. Cells 2020; 9:cells9040861. [PMID: 32252322 PMCID: PMC7226841 DOI: 10.3390/cells9040861] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 03/28/2020] [Accepted: 03/31/2020] [Indexed: 02/06/2023] Open
Abstract
Epithelial–mesenchymal transition (EMT) causes epithelial cells to lose their polarity and adhesion property, and endows them with migratory and invasive properties to enable them to become mesenchymal stem cells. EMT occurs throughout embryonic development, during wound healing, and in various pathological processes, including tumor progression. Considerable research in the last few decades has revealed that EMT is invariably related to tumor aggressiveness and metastasis. Apart from the interactions between numerous intracellular signaling pathways known to regulate EMT, extracellular modulators in the tumor microenvironment also influence tumor cells to undergo EMT, with extracellular vesicles (EVs) receiving increasing attention as EMT inducers. EVs comprise exosomes and microvesicles that carry proteins, nucleic acids, lipids, and other small molecules to stimulate EMT in cells. Among EVs, exosomes have been investigated in many studies, and their role has been found to be significant with respect to regulating intercellular communications. In this review, we summarize recent studies on exosomes and their cargoes that induce cancer-associated EMT. Furthermore, we describe the possible applications of exosomes as promising therapeutic strategies.
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Affiliation(s)
- Hyunwoo Kim
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea; (H.K.); (S.L.); (E.S.)
| | - Sungmin Lee
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea; (H.K.); (S.L.); (E.S.)
| | - Eunguk Shin
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea; (H.K.); (S.L.); (E.S.)
| | - Ki Moon Seong
- Laboratory of Low Dose Risk Assessment, National Radiation Emergency Medical Center, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea; (K.M.S.); (Y.W.J.)
| | - Young Woo Jin
- Laboratory of Low Dose Risk Assessment, National Radiation Emergency Medical Center, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea; (K.M.S.); (Y.W.J.)
| | - HyeSook Youn
- Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul 05006, Korea
- Correspondence: (H.Y.); (B.Y.); Tel.: +82-2-6935-2438 (H.Y.); +82-51-510-2264 (B.Y.); Fax: +82-2-3408-4334 (H.Y.); +82-51-581-2962 (B.Y.)
| | - BuHyun Youn
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea; (H.K.); (S.L.); (E.S.)
- Department of Biological Sciences, Pusan National University, Busan 46241, Korea
- Correspondence: (H.Y.); (B.Y.); Tel.: +82-2-6935-2438 (H.Y.); +82-51-510-2264 (B.Y.); Fax: +82-2-3408-4334 (H.Y.); +82-51-581-2962 (B.Y.)
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Tenascin C in the Tumor-Nerve Microenvironment Enhances Perineural Invasion and Correlates With Locoregional Recurrence in Pancreatic Ductal Adenocarcinoma. Pancreas 2020; 49:442-454. [PMID: 32132519 DOI: 10.1097/mpa.0000000000001506] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Perineural invasion is common in pancreatic ductal adenocarcinoma (PDAC) and worsens the postoperative prognosis. Tenascin C (TNC), an extracellular matrix glycoprotein, modulates tumor progression. We evaluated the functional roles of TNC, especially in perineural invasion of PDAC. METHODS We examined immunohistochemical TNC expression in 78 resected PDAC specimens. The relationships between TNC expression and clinicopathological features were retrospectively analyzed. Interactions between cancer cells and nerves with TNC supplementation were investigated using an in vitro coculture model with PDAC cell line and mouse dorsal root ganglion (DRG). RESULTS Tenascin C expression was predominant in perineural sites at the invasive tumor front. High perineural TNC expression in 30 patients (38%) was associated with perineural invasion, pathological T stage ≥3, and postoperative locoregional recurrence. High TNC expression was independently associated with postoperative, poor recurrence-free survival by multivariate analysis. In the in vitro coculture model, a TNC-rich matrix enhanced both PDAC cell colony extensions toward nerves and DRG axonal outgrowth toward cancer cell colonies, whereas TNC did not affect axonal outgrowth or cancer cell proliferation in separately cultured DRG and PDAC cells. CONCLUSIONS Strong perineural TNC expression indicated poor prognosis with locoregional recurrence. The neurotropism of TNC-induced PDAC suggests that TNC is a potential PDAC therapeutic target.
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47
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Brechbuhl HM, Barrett AS, Kopin E, Hagen JC, Han AL, Gillen AE, Finlay-Schultz J, Cittelly DM, Owens P, Horwitz KB, Sartorius CA, Hansen K, Kabos P. Fibroblast subtypes define a metastatic matrisome in breast cancer. JCI Insight 2020; 5:130751. [PMID: 32045383 DOI: 10.1172/jci.insight.130751] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 01/29/2020] [Indexed: 02/06/2023] Open
Abstract
Small primary breast cancers can show surprisingly high potential for metastasis. Clinical decision-making for tumor aggressiveness, including molecular profiling, relies primarily on analysis of the cancer cells. Here we show that this analysis is insufficient - that the stromal microenvironment of the primary tumor plays a key role in tumor cell dissemination and implantation at distant sites. We previously described 2 cancer-associated fibroblasts (CAFs) that either express (CD146+) or lack (CD146-) CD146 (official symbol MCAM, alias MUC18). We now find that when mixed with human breast cancer cells, each fibroblast subtype determines the fate of cancer cells: CD146- fibroblasts promoted increased metastasis compared with CD146+ fibroblasts. Potentially novel quantitative and qualitative proteomic analyses showed that CD146+ CAFs produced an environment rich in basement membrane proteins, while CD146- CAFs exhibited increases in fibronectin 1, lysyl oxidase, and tenascin C, all overexpressed in aggressive disease. We also show clinically that CD146- CAFs predicted for likelihood of lymph node involvement even in small primary tumors (<5 cm). Clearly small tumors enriched for CD146- CAFs require aggressive treatments.
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Affiliation(s)
| | | | - Etana Kopin
- Division of Medical Oncology, Department of Medicine
| | - Jaime C Hagen
- Division of Medical Oncology, Department of Medicine
| | - Amy L Han
- Division of Medical Oncology, Department of Medicine
| | | | - Jessica Finlay-Schultz
- Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado USA
| | - Diana M Cittelly
- Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado USA
| | - Philip Owens
- Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado USA.,Research Service, Department of Veterans Affairs, Eastern Colorado Health Care System, Aurora, Colorado, USA
| | - Kathryn B Horwitz
- Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado USA.,Division of Endocrinology, Department of Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA
| | | | - Kirk Hansen
- Department of Biochemistry and Molecular Genetics
| | - Peter Kabos
- Division of Medical Oncology, Department of Medicine
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48
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Elgundi Z, Papanicolaou M, Major G, Cox TR, Melrose J, Whitelock JM, Farrugia BL. Cancer Metastasis: The Role of the Extracellular Matrix and the Heparan Sulfate Proteoglycan Perlecan. Front Oncol 2020; 9:1482. [PMID: 32010611 PMCID: PMC6978720 DOI: 10.3389/fonc.2019.01482] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 12/10/2019] [Indexed: 12/12/2022] Open
Abstract
Cancer metastasis is the dissemination of tumor cells to new sites, resulting in the formation of secondary tumors. This process is complex and is spatially and temporally regulated by intrinsic and extrinsic factors. One important extrinsic factor is the extracellular matrix, the non-cellular component of tissues. Heparan sulfate proteoglycans (HSPGs) are constituents of the extracellular matrix, and through their heparan sulfate chains and protein core, modulate multiple events that occur during the metastatic cascade. This review will provide an overview of the role of the extracellular matrix in the events that occur during cancer metastasis, primarily focusing on perlecan. Perlecan, a basement membrane HSPG is a key component of the vascular extracellular matrix and is commonly associated with events that occur during the metastatic cascade. Its contradictory role in these events will be discussed and we will highlight the recent advances in cancer therapies that target HSPGs and their modifying enzymes.
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Affiliation(s)
- Zehra Elgundi
- Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, Australia
| | - Michael Papanicolaou
- The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, UNSW Sydney, Darlinghurst, NSW, Australia.,School of Life Sciences, University of Technology Sydney, Sydney, NSW, Australia
| | - Gretel Major
- The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, UNSW Sydney, Darlinghurst, NSW, Australia
| | - Thomas R Cox
- The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, UNSW Sydney, Darlinghurst, NSW, Australia.,St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
| | - James Melrose
- Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, Australia.,Raymond Purves Bone and Joint Research Laboratories, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St Leonards, NSW, Australia
| | - John M Whitelock
- Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, Australia
| | - Brooke L Farrugia
- Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, Australia.,Department of Biomedical Engineering, Melbourne School of Engineering, The University of Melbourne, Melbourne, VIC, Australia
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49
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Rigoglio NN, Rabelo ACS, Borghesi J, de Sá Schiavo Matias G, Fratini P, Prazeres PHDM, Pimentel CMMM, Birbrair A, Miglino MA. The Tumor Microenvironment: Focus on Extracellular Matrix. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1245:1-38. [PMID: 32266651 DOI: 10.1007/978-3-030-40146-7_1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The extracellular matrix (ECM) regulates the development and maintains tissue homeostasis. The ECM is composed of a complex network of molecules presenting distinct biochemical properties to regulate cell growth, survival, motility, and differentiation. Among their components, proteoglycans (PGs) are considered one of the main components of ECM. Its composition, biomechanics, and anisotropy are exquisitely tuned to reflect the physiological state of the tissue. The loss of ECM's homeostasis is seen as one of the hallmarks of cancer and, typically, defines transitional events in tumor progression and metastasis. In this chapter, we discuss the types of proteoglycans and their roles in cancer. It has been observed that the amount of some ECM components is increased, while others are decreased, depending on the type of tumor. However, both conditions corroborate with tumor progression and malignancy. Therefore, ECM components have an increasingly important role in carcinogenesis and this leads us to believe that their understanding may be a key in the discovery of new anti-tumor therapies. In this book, the main ECM components will be discussed in more detail in each chapter.
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Affiliation(s)
- Nathia Nathaly Rigoglio
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Ana Carolina Silveira Rabelo
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Jessica Borghesi
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Gustavo de Sá Schiavo Matias
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Paula Fratini
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | | | | | - Alexander Birbrair
- Department of Radiology, Columbia University Medical Center, New York, NY, USA
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Maria Angelica Miglino
- Department of Surgery, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil.
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50
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Slocum E, Germain D. Collagen and PAPP-A in the Etiology of Postpartum Breast Cancer. Discov Oncol 2019; 10:137-144. [PMID: 31631239 DOI: 10.1007/s12672-019-00368-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 09/29/2019] [Indexed: 01/14/2023] Open
Abstract
Pregnancy has a dual effect on the risk of breast cancer. On one hand, pregnancy at a young age is known to be protective. However, pregnancy is also associated with a transient increased risk of breast cancer. For women that have children after the age of 30, the risk remains higher than women who never had children for decades. Involution of the breast has been identified as a window of mammary development associated with the adverse effect of pregnancy. In this review, we summarize the current understanding of the role of involution and describe the role of collagen in this setting. We also discuss the role of a collagen-dependent protease, pappalysin-1, in postpartum breast cancer and its role in activating both insulin-like growth factor signaling and discoidin domain collagen receptor 2, DDR2. Together, these novel advances in our understanding of postpartum breast cancer open the way to targeted therapies against this aggressive breast cancer sub-type.
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Affiliation(s)
- Elizabeth Slocum
- Department of Medicine, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, 10029, USA
| | - Doris Germain
- Department of Medicine, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, 10029, USA.
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