1
|
Tang X, Khan H, Niewola-Staszkowska K, Wuest F, Brindley DN. Inhibition of autotaxin activity with IOA-289 decreases fibrosis in mouse E0771 breast tumors. Int J Cancer 2025. [PMID: 40345856 DOI: 10.1002/ijc.35471] [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: 11/28/2024] [Revised: 04/23/2025] [Accepted: 04/24/2025] [Indexed: 05/11/2025]
Abstract
Tumor-associated fibrosis contributes to an immunosuppressive microenvironment that hinders effective anti-tumor immune responses. This study investigates the potential of IOA-289, a novel autotaxin (ATX) inhibitor, which blocks lysophosphatidate (LPA) production and signaling, in modulating fibrosis in breast tumors. Bioinformatic analysis of human breast tumors revealed a strong correlation between levels of LPA1,-4 receptors and extracellular matrix (ECM) genes. Interaction of ECM molecules and integrin β1/CD44 between myofibroblasts and other cell types had the highest contribution to cell-cell communication. We showed that LPA induced α-smooth muscle actin mRNA in mouse mammary fibroblasts and increased expressions of collagen type-I α1 chain (COL1A1) and lamininγ1. IOA-289 decreased the expressions of COL1A1, fibronectin-1, and transforming growth factor β1 (TGFβ1) in E0771 breast tumors in mice. Masson's trichrome staining revealed a marked decrease in collagen deposition within breast tumors of IOA-289-treated mice. Decreased tumor fibrosis aligns with previous findings that IOA-289 enhanced the infiltration of CD8+ cytotoxic T cells and decreased fibrotic factors including leukemia inhibitory factor and transforming growth factor-beta1 in tumors. We also demonstrated that E0771 cells express negligible ATX and LPA receptors. Therefore, ATX inhibition did not affect cancer cells directly in our model. These results underscore the potential of ATX inhibitors in reprogramming the tumor microenvironment to favor anti-tumor immunity and attenuate fibrosis. ATX inhibitors are in clinical trials for treating idiopathic pulmonary fibrosis and pancreatic cancer. Our results support the development of ATX inhibitors as a strategy for improving the treatment of breast cancer and other diseases involving fibrosis.
Collapse
Affiliation(s)
- Xiaoyun Tang
- Cancer Research Institute of Northern Alberta, Edmonton, Alberta, Canada
- Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
| | - Humayara Khan
- Cancer Research Institute of Northern Alberta, Edmonton, Alberta, Canada
- Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
| | | | - Frank Wuest
- Cancer Research Institute of Northern Alberta, Edmonton, Alberta, Canada
- Department of Oncology, Division of Oncologic Imaging, University of Alberta, Edmonton, Alberta, Canada
| | - David N Brindley
- Cancer Research Institute of Northern Alberta, Edmonton, Alberta, Canada
- Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
| |
Collapse
|
2
|
Ye J, Qin SS, Hughson AL, Hannon G, Salama NA, Vrooman TG, Lesch ML, Lesser S, Eckl SL, Jewell R, Benoodt L, Mills BN, Johnston CJ, Lord E, Belt BA, Calvi LM, Linehan D, Luheshi N, Eyles J, Gerber SA. Blocking LIF and PD-L1 enhances the antitumor efficacy of SBRT in murine PDAC models. J Immunother Cancer 2025; 13:e010820. [PMID: 40341024 PMCID: PMC12067785 DOI: 10.1136/jitc-2024-010820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Accepted: 04/21/2025] [Indexed: 05/10/2025] Open
Abstract
BACKGROUND Recent preclinical and clinical data suggest that leukemia inhibitory factor (LIF) is a potential target for various tumor types including pancreatic ductal adenocarcinoma as LIF is involved in multiple protumor processes including cancer stem cell maintenance, epithelial-mesenchymal transition (EMT), immunosuppression, and chemo/radioresistance. Anti-LIF antibody therapy has demonstrated safety and tolerability but limited efficacy in phase 1 clinical trial in advanced solid tumors. This prompted us to explore combination therapies, suggesting that LIF blockade, when combined with standard-of-care chemotherapy, radiotherapy, and/or immunotherapy, could present a promising therapeutic strategy. METHODS We evaluated the impact of combining systemic inhibition of LIF/programmed death-ligand 1 (PD-L1) with localized stereotactic body radiotherapy (SBRT) on tumor progression across multiple murine orthotopic pancreatic tumor models and examined systemic antitumor immunity using a hepatic rechallenge model. The antitumor immune response was characterized throughflow cytometry and Luminex assays. To identify differentially expressed genes and signaling pathways following treatment, we performed bulk RNA sequencing on pancreatic tumors. Additionally, single-cell RNA sequencing was conducted to further examine changes in tumor-infiltrating immune cells and their signaling pathways. RESULTS We showed that simultaneous inhibition of LIF and PD-L1 significantly amplified the antitumor efficacy of SBRT, resulting in extended survival. The triple therapy (SBRT+anti-LIF+anti-PD-L1) generated an immunostimulatory tumor microenvironment, characterized by a proinflammatory shift in the cytokine/chemokine profile, increased infiltration of effector CD8+ T cells, and upregulated activation or maturation signals in tumor-infiltrating CD8+ T cells and macrophages. The beneficial effects of triple therapy were mostly abrogated by depletion of CD8+ T cells. In addition, triple therapy downregulated pathways related to tumor stemness, proliferation, and metabolism, and reduced EMT. Importantly, the combination of local SBRT treatment with systemic LIF and PD-L1 blockade resulted in long-term systemic antitumor memory.
Collapse
Affiliation(s)
- Jian Ye
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Shuyang S Qin
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
| | - Angela L Hughson
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Gary Hannon
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Noah A Salama
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
| | - Tara G Vrooman
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
| | - Maggie L Lesch
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
| | - Sidney Lesser
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Sarah L Eckl
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
| | - Rachel Jewell
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Lauren Benoodt
- Genomic Research Center, University of Rochester Medical Center, Rochester, New York, USA
| | - Bradley N Mills
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - Carl J Johnston
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, USA
| | - Edith Lord
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
| | - Brian A Belt
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
| | - Laura M Calvi
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Medicine Hematology/Oncology, University of Rochester Medical Center, Rochester, New York, USA
| | - David Linehan
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - Nadia Luheshi
- The Discovery Center, Cambridge Biomedical Campus, Cambridge, UK
| | - Jim Eyles
- Oncology R&D, Research and Early Development, AstraZeneca R&D, Cambridge, Cambridgeshire, UK
| | - Scott A Gerber
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
- Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| |
Collapse
|
3
|
Li Y, Sun Z, Tong Y, Yan C, Huang L, Zhang Z. Leukemia Inhibitory Factor via JAK-STAT Signaling Drives Beryllium Sulfate-Induced Epithelial-Mesenchymal Transition in 16HBE Cells. J Appl Toxicol 2025. [PMID: 40312259 DOI: 10.1002/jat.4802] [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: 02/23/2025] [Revised: 04/08/2025] [Accepted: 04/23/2025] [Indexed: 05/03/2025]
Abstract
Beryllium and its compounds are classified as carcinogens, and prolonged exposure can trigger chronic beryllium disease. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is known to play a critical role in the development and progression of numerous diseases. Leukemia inhibitory factor (LIF), a key upstream cytokine of the JAK-STAT pathway, has been implicated in regulating inflammatory responses and epithelial-mesenchymal transition (EMT) in various diseases. However, the specific involvement of the JAK-STAT pathway and LIF in beryllium sulfate (BeSO₄)-induced EMT in human bronchial epithelial (16HBE) cells remains unclear. To investigate the regulatory mechanisms, we examined the effects of BeSO₄ on 16HBE cells and targeted the JAK-STAT pathway using both pharmacological inhibition (niclosamide) and genetic silencing of LIF. Subsequently, we assessed cell morphology, proliferative capacity, inflammatory protein levels, and EMT marker expression. Our findings demonstrated that BeSO₄ exposure inhibited 16HBE cell proliferation and activated the JAK-STAT pathway. Pretreatment with niclosamide significantly mitigated cellular inflammation and the EMT process induced by BeSO₄. Additionally, silencing LIF markedly reduced JAK-STAT pathway activation and decreased the expression of EMT markers. This study uncovers a novel mechanism underlying BeSO₄-induced EMT in 16HBE cells, providing valuable insights into the molecular mechanisms of toxicity induced by beryllium and its compounds.
Collapse
Affiliation(s)
- Yaqi Li
- Department of Preventive Medicine, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China
| | - Zhanbing Sun
- Hengyang Maternal and Child Health Hospital, Hengyang, China
| | - Yuqi Tong
- Department of Preventive Medicine, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China
| | - Chenxi Yan
- Department of Preventive Medicine, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China
| | - Lian Huang
- Department of Preventive Medicine, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China
| | - Zhaohui Zhang
- Department of Preventive Medicine, School of Public Health, Hengyang Medical School, University of South China, Hengyang, China
| |
Collapse
|
4
|
Park MN, Kim M, Lee S, Kang S, Ahn CH, Tallei TE, Kim W, Kim B. Targeting Redox Signaling Through Exosomal MicroRNA: Insights into Tumor Microenvironment and Precision Oncology. Antioxidants (Basel) 2025; 14:501. [PMID: 40427384 PMCID: PMC12108341 DOI: 10.3390/antiox14050501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Revised: 04/18/2025] [Accepted: 04/20/2025] [Indexed: 05/29/2025] Open
Abstract
Reactive oxygen species (ROS) play a dual role in cancer progression, acting as both signaling molecules and drivers of oxidative damage. Emerging evidence highlights the intricate interplay between ROS, microRNAs (miRNAs), and exosomes within the tumor microenvironment (TME), forming a regulatory axis that modulates immune responses, angiogenesis, and therapeutic resistance. In particular, oxidative stress not only stimulates exosome biogenesis but also influences the selective packaging of redox-sensitive miRNAs (miR-21, miR-155, and miR-210) via RNA-binding proteins such as hnRNPA2B1 and SYNCRIP. These miRNAs, delivered through exosomes, alter gene expression in recipient cells and promote tumor-supportive phenotypes such as M2 macrophage polarization, CD8+ T-cell suppression, and endothelial remodeling. This review systematically explores how this ROS-miRNA-exosome axis orchestrates communication across immune and stromal cell populations under hypoxic and inflammatory conditions. Particular emphasis is placed on the role of NADPH oxidases, hypoxia-inducible factors, and autophagy-related mechanisms in regulating exosomal output. In addition, we analyze the therapeutic relevance of natural products and herbal compounds-such as curcumin, resveratrol, and ginsenosides-which have demonstrated promising capabilities to modulate ROS levels, miRNA expression, and exosome dynamics. We further discuss the clinical potential of leveraging this axis for cancer therapy, including strategies involving mesenchymal stem cell-derived exosomes, ferroptosis regulation, and miRNA-based immune modulation. Incorporating insights from spatial transcriptomics and single-cell analysis, this review provides a mechanistic foundation for the development of exosome-centered, redox-modulating therapeutics. Ultimately, this work aims to guide future research and drug discovery efforts toward integrating herbal medicine and redox biology in the fight against cancer.
Collapse
Affiliation(s)
- Moon Nyeo Park
- College of Korean Medicine, Kyung Hee University, 1-5 Hoegidong, Dongdaemun-gu, Seoul 02447, Republic of Korea; (M.N.P.); (M.K.); (S.L.); (S.K.); (C.-H.A.); (W.K.)
| | - Myoungchan Kim
- College of Korean Medicine, Kyung Hee University, 1-5 Hoegidong, Dongdaemun-gu, Seoul 02447, Republic of Korea; (M.N.P.); (M.K.); (S.L.); (S.K.); (C.-H.A.); (W.K.)
| | - Soojin Lee
- College of Korean Medicine, Kyung Hee University, 1-5 Hoegidong, Dongdaemun-gu, Seoul 02447, Republic of Korea; (M.N.P.); (M.K.); (S.L.); (S.K.); (C.-H.A.); (W.K.)
| | - Sojin Kang
- College of Korean Medicine, Kyung Hee University, 1-5 Hoegidong, Dongdaemun-gu, Seoul 02447, Republic of Korea; (M.N.P.); (M.K.); (S.L.); (S.K.); (C.-H.A.); (W.K.)
| | - Chi-Hoon Ahn
- College of Korean Medicine, Kyung Hee University, 1-5 Hoegidong, Dongdaemun-gu, Seoul 02447, Republic of Korea; (M.N.P.); (M.K.); (S.L.); (S.K.); (C.-H.A.); (W.K.)
| | - Trina Ekawati Tallei
- Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Sam Ratulangi, Manado 95115, Indonesia;
- Department of Biology, Faculty of Medicine, Universitas Sam Ratulangi, Manado 95115, Indonesia
| | - Woojin Kim
- College of Korean Medicine, Kyung Hee University, 1-5 Hoegidong, Dongdaemun-gu, Seoul 02447, Republic of Korea; (M.N.P.); (M.K.); (S.L.); (S.K.); (C.-H.A.); (W.K.)
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Hoegi-dong, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Bonglee Kim
- College of Korean Medicine, Kyung Hee University, 1-5 Hoegidong, Dongdaemun-gu, Seoul 02447, Republic of Korea; (M.N.P.); (M.K.); (S.L.); (S.K.); (C.-H.A.); (W.K.)
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Hoegi-dong, Dongdaemun-gu, Seoul 02447, Republic of Korea
| |
Collapse
|
5
|
Kwon JY, Vera RE, Fernandez-Zapico ME. The multi-faceted roles of cancer-associated fibroblasts in pancreatic cancer. Cell Signal 2025; 127:111584. [PMID: 39756502 PMCID: PMC11807759 DOI: 10.1016/j.cellsig.2024.111584] [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: 10/02/2024] [Revised: 12/13/2024] [Accepted: 12/28/2024] [Indexed: 01/07/2025]
Abstract
The tumor microenvironment (TME) has been linked with the pathogenesis of pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer. A central component of the TME are cancer-associated fibroblasts (CAFs), which can either suppress or promote tumor growth in a context-dependent manner. In this review, we will discuss the multi-faceted roles of CAFs in tumor-stroma interactions influencing cancer initiation, progression and therapeutic response.
Collapse
Affiliation(s)
- John Y Kwon
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Rochester, MN 55901, USA.
| | - Renzo E Vera
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Rochester, MN 55901, USA.
| | | |
Collapse
|
6
|
Romo B, Fuentes Z, Randolph L, Mahajan M, Aller EJ, Ebrahimi B, Santhamma B, Pratap UP, Subbarayalu P, Nagandla H, Thomas C, Nair HB, Vadlamudi RK, Viswanadhapalli S. Targeting the Leukemia Inhibitory Factor/Leukemia Inhibitory Factor Receptor Axis Reduces the Growth of Inflammatory Breast Cancer by Promoting Ferroptosis. Cancers (Basel) 2025; 17:790. [PMID: 40075639 PMCID: PMC11898489 DOI: 10.3390/cancers17050790] [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: 01/01/2025] [Revised: 02/17/2025] [Accepted: 02/21/2025] [Indexed: 03/14/2025] Open
Abstract
Background: Inflammatory breast cancer (IBC) is a rare subtype of breast cancer accounting for 7% of breast cancer-related fatalities. There is an urgent need to develop new targeted treatments for IBC. The progression of IBC has been associated with alterations in growth factor and cytokine signaling; however, the function of the LIF (leukemia inhibitory factor)/LIFR (leukemia inhibitory factor receptor) cytokine pathway in the progression of IBC remains unknown. This study evaluated the role of LIFR signaling and tested the efficacy of the LIFR inhibitor EC359 in treating IBC. Methods: The utility of using LIFR inhibition as a treatment strategy in IBC was tested using cell survival, apoptosis, colony formation, invasion, and pre-clinical KPL4 xenografts. Western blotting, siRNA, RT-qPCR, and lipid peroxidation assays were used to establish the mechanism of EC359 therapy. Results: The reduction in LIFR levels using siRNA markedly decreased growth in colony formation assays and reduced the invasion of IBC cells. Pharmacological inhibition of LIFR with EC359 effectively reduced cell survival and the clonogenic capacity of IBC cells. RT-qPCR assays revealed that EC359 markedly decreased the expression of the LIFR target genes. Western blot analyses confirmed that EC359 treatment suppressed downstream LIF/LIFR signaling pathways and promoted apoptosis. Treatment of cells with the ferroptosis inhibitor Fer-1 negated the capacity of EC359 to induce apoptosis. Mechanistic investigations demonstrated that EC359 predominantly triggered ferroptosis by inhibiting the glutathione antioxidant defense system through the downregulation of Glutathione peroxidase 4 (GPX4) levels. EC359 (5 mg/kg/day) was effective in reducing the growth of the IBC KPL4 xenograft tumors. Conclusion: These findings demonstrates that LIFR inhibition promote ferroptosis-mediated cell death in IBC and that EC359 represent novel therapeutic for IBC treatment.
Collapse
Affiliation(s)
- Bianca Romo
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (B.R.); (Z.F.); (L.R.); (M.M.); (E.J.A.); (B.E.); (U.P.P.)
| | - Zenaida Fuentes
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (B.R.); (Z.F.); (L.R.); (M.M.); (E.J.A.); (B.E.); (U.P.P.)
| | - Lois Randolph
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (B.R.); (Z.F.); (L.R.); (M.M.); (E.J.A.); (B.E.); (U.P.P.)
| | - Megharani Mahajan
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (B.R.); (Z.F.); (L.R.); (M.M.); (E.J.A.); (B.E.); (U.P.P.)
| | - Emily J. Aller
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (B.R.); (Z.F.); (L.R.); (M.M.); (E.J.A.); (B.E.); (U.P.P.)
| | - Behnam Ebrahimi
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (B.R.); (Z.F.); (L.R.); (M.M.); (E.J.A.); (B.E.); (U.P.P.)
| | | | - Uday P. Pratap
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (B.R.); (Z.F.); (L.R.); (M.M.); (E.J.A.); (B.E.); (U.P.P.)
- Mays Cancer Canter, University of Texas Health San Antonio, San Antonio, TX 78229, USA;
| | - Panneerdoss Subbarayalu
- Mays Cancer Canter, University of Texas Health San Antonio, San Antonio, TX 78229, USA;
- Greehey Children Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Harika Nagandla
- Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA; (H.N.); (C.T.)
| | - Christoforos Thomas
- Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA; (H.N.); (C.T.)
| | - Hareesh B. Nair
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (B.R.); (Z.F.); (L.R.); (M.M.); (E.J.A.); (B.E.); (U.P.P.)
- Evestra, Inc., San Antonio, TX 78245, USA;
| | - Ratna K. Vadlamudi
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (B.R.); (Z.F.); (L.R.); (M.M.); (E.J.A.); (B.E.); (U.P.P.)
- Mays Cancer Canter, University of Texas Health San Antonio, San Antonio, TX 78229, USA;
- Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX 78229, USA
| | - Suryavathi Viswanadhapalli
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (B.R.); (Z.F.); (L.R.); (M.M.); (E.J.A.); (B.E.); (U.P.P.)
- Mays Cancer Canter, University of Texas Health San Antonio, San Antonio, TX 78229, USA;
| |
Collapse
|
7
|
Oh S, Lee S, Cheon I, Ahn YH. miR-224 activates cancer-associated fibroblasts to enhance lung cancer cell migration and invasion by targeting Akirin1. Sci Rep 2025; 15:3050. [PMID: 39856124 PMCID: PMC11760386 DOI: 10.1038/s41598-024-82189-x] [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: 03/02/2024] [Accepted: 12/03/2024] [Indexed: 01/27/2025] Open
Abstract
Cancer-associated fibroblasts (CAFs) actively contribute to the formation of tumor-supportive microenvironments, thereby promoting cancer progression and impacting therapeutic outcomes. This study utilized global microRNA (miRNA) expression profiling to identify specific miRNAs responsible for reprogramming normal lung fibroblasts (LFs) into CAFs. miR-224 demonstrates increased expression in CAFs, and its levels are elevated in lung tumors compared to those in normal tissues, according to data from public databases. Overexpression of miR-224 in LFs increases the overall expression of CAF activation markers. Furthermore, LFs overexpressing miR-224 enhanced the migration and invasion of lung cancer cells via direct cell-to-cell contact in a co-culture system. In a mouse orthotopic injection model, miR-224 overexpression in LFs increased lung cancer metastasis. Using target prediction tools and subsequent 3'-UTR luciferase assay, Akirin1 was validated as a direct target gene of miR-224. In addition, LFs depleted of Akirin1 by siRNAs stimulated the migration and invasion of lung cancer cells compared to control LFs. Overall, these findings indicate that miR-224 induces CAF activation and promotes the migration and invasion of lung cancer cells by targeting Akirin1 in co-culture systems.
Collapse
Affiliation(s)
- Seonyeong Oh
- Department of Molecular Medicine, Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, 25 Magokdong-ro 2-gil, Gangseo-gu, Seoul, 07804, Korea
| | - Sieun Lee
- Department of Molecular Medicine, Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, 25 Magokdong-ro 2-gil, Gangseo-gu, Seoul, 07804, Korea
| | - Inyoung Cheon
- Department of Molecular Medicine, Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, 25 Magokdong-ro 2-gil, Gangseo-gu, Seoul, 07804, Korea
| | - Young-Ho Ahn
- Department of Molecular Medicine, Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, 25 Magokdong-ro 2-gil, Gangseo-gu, Seoul, 07804, Korea.
| |
Collapse
|
8
|
Zhou S, Zhao Z, Wang Z, Xu H, Li Y, Xu K, Li W, Yang J. Cancer-associated fibroblasts in carcinogenesis. J Transl Med 2025; 23:50. [PMID: 39806363 PMCID: PMC11727299 DOI: 10.1186/s12967-025-06071-8] [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: 11/12/2024] [Accepted: 01/06/2025] [Indexed: 01/16/2025] Open
Abstract
In contemporary times, cancer poses the most significant threat to human life and safety. Scientists have relentlessly pursued the intricacies of carcinogenesis and explored ways to prevent and treat cancer. Carcinogenesis is a complex, multi-faceted, and multi-stage process, with numerous underlying causes, including inflammation and fibrosis. Cancer-associated fibroblasts (CAFs), however, occupy a pivotal and substantial role within the tumor microenvironment, facilitating carcinogenesis through diverse mechanisms such as creating inflammation, fostering a fibrotic tumor microenvironment, and immunosuppression. In this paper, we introduce the concept of carcinogenesis, explain its causes, describe the characteristics of CAFs and their sources, and highlight the roles and mechanisms of CAFs in promoting carcinogenesis. Ultimately, our aim is to contribute to the development of novel therapeutic strategies for cancer treatment.
Collapse
Affiliation(s)
- Shufen Zhou
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
- State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Zekun Zhao
- Department of General Surgery, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Zhaojun Wang
- Department of Thyroid and Breast Surgery, The DingLi Clinical, The Wenzhou Central Hospital, College of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Hanzheng Xu
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
- State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Yijie Li
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Ke Xu
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China.
- Wenzhou Institute of Shanghai University, Wenzhou, 325000, China.
| | - Wei Li
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
| | - Jiahua Yang
- Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
| |
Collapse
|
9
|
Liu K, Li Y, Shen M, Xu W, Wu S, Yang X, Zhang B, Lin N. Epigenetic Regulation of Stromal and Immune Cells and Therapeutic Targets in the Tumor Microenvironment. Biomolecules 2025; 15:71. [PMID: 39858465 PMCID: PMC11764280 DOI: 10.3390/biom15010071] [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: 11/18/2024] [Revised: 12/19/2024] [Accepted: 01/04/2025] [Indexed: 01/27/2025] Open
Abstract
The tumor microenvironment (TME) plays a pivotal role in neoplastic initiation and progression. Epigenetic machinery, governing the expression of core oncogenes and tumor suppressor genes in transformed cells, significantly contributes to tumor development at both primary and distant sites. Recent studies have illuminated how epigenetic mechanisms integrate external cues and downstream signals, altering the phenotype of stromal cells and immune cells. This remolds the area surrounding tumor cells, ultimately fostering an immunosuppressive microenvironment. Therefore, correcting the TME by targeting the epigenetic modifications holds substantial promise for cancer treatment. This review synthesizes recent research that elucidates the impact of specific epigenetic regulations-ranging from DNA methylation to histone modifications and chromatin remodeling-on stromal and immune cells within the TME. Notably, we highlight their functional roles in either promoting or restricting tumor progression. We also discuss the potential applications of epigenetic agents for cancer treatment, envisaging their ability to normalize the ecosystem. This review aims to assist researchers in understanding the dynamic interplay between epigenetics and the TME, paving the way for better epigenetic therapy.
Collapse
Affiliation(s)
- Kang Liu
- College of Pharmaceutical Sciences, Hangzhou First People’s Hospital, Zhejiang Chinese Medical University, Hangzhou 311402, China; (K.L.); (Y.L.); (M.S.); (W.X.); (S.W.); (X.Y.)
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, China
| | - Yue Li
- College of Pharmaceutical Sciences, Hangzhou First People’s Hospital, Zhejiang Chinese Medical University, Hangzhou 311402, China; (K.L.); (Y.L.); (M.S.); (W.X.); (S.W.); (X.Y.)
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, China
| | - Minmin Shen
- College of Pharmaceutical Sciences, Hangzhou First People’s Hospital, Zhejiang Chinese Medical University, Hangzhou 311402, China; (K.L.); (Y.L.); (M.S.); (W.X.); (S.W.); (X.Y.)
- Department of Drug Clinical Trial Institution, Huzhou Central Hospital, Huzhou 313000, China
| | - Wei Xu
- College of Pharmaceutical Sciences, Hangzhou First People’s Hospital, Zhejiang Chinese Medical University, Hangzhou 311402, China; (K.L.); (Y.L.); (M.S.); (W.X.); (S.W.); (X.Y.)
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, China
| | - Shanshan Wu
- College of Pharmaceutical Sciences, Hangzhou First People’s Hospital, Zhejiang Chinese Medical University, Hangzhou 311402, China; (K.L.); (Y.L.); (M.S.); (W.X.); (S.W.); (X.Y.)
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, China
| | - Xinxin Yang
- College of Pharmaceutical Sciences, Hangzhou First People’s Hospital, Zhejiang Chinese Medical University, Hangzhou 311402, China; (K.L.); (Y.L.); (M.S.); (W.X.); (S.W.); (X.Y.)
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, China
| | - Bo Zhang
- College of Pharmaceutical Sciences, Hangzhou First People’s Hospital, Zhejiang Chinese Medical University, Hangzhou 311402, China; (K.L.); (Y.L.); (M.S.); (W.X.); (S.W.); (X.Y.)
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, China
| | - Nengming Lin
- College of Pharmaceutical Sciences, Hangzhou First People’s Hospital, Zhejiang Chinese Medical University, Hangzhou 311402, China; (K.L.); (Y.L.); (M.S.); (W.X.); (S.W.); (X.Y.)
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou 310006, China
- Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Westlake University, Hangzhou 310024, China
| |
Collapse
|
10
|
Garajová I, Giovannetti E. Targeting Perineural Invasion in Pancreatic Cancer. Cancers (Basel) 2024; 16:4260. [PMID: 39766161 PMCID: PMC11674953 DOI: 10.3390/cancers16244260] [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: 11/18/2024] [Revised: 12/16/2024] [Accepted: 12/18/2024] [Indexed: 01/11/2025] Open
Abstract
Pancreatic cancer is an aggressive tumor with dismal prognosis. Neural invasion is one of the pathological hallmarks of pancreatic cancer. Peripheral nerves can modulate the phenotype and behavior of the malignant cells, as well as of different components of the tumor microenvironment, and thus affect tumor growth and metastasis. From a clinical point of view, neural invasion is translated into intractable pain and represents a predictor of tumor recurrence and poor prognosis. Several molecules are implicated in neural invasion and pain onset in PDAC, including neutrophins (e.g., NGF), chemokines, adhesion factors, axon-guidance molecules, different proteins, and neurotransmitters. In this review, we discuss the role of nerves within the pancreatic cancer microenvironment, highlighting how infiltrating nerve fibers promote tumor progression and metastasis, while tumor cells, in turn, drive nerve outgrowth in a reciprocal interaction that fuels tumor advancement. We outline key molecules involved in neural invasion in pancreatic cancer and, finally, explore potential therapeutic strategies to target neural invasion, aiming to both inhibit cancer progression and alleviate cancer-associated pain.
Collapse
Affiliation(s)
- Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy
| | - Elisa Giovannetti
- Department of Medical Oncology, Lab of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1007 MB Amsterdam, The Netherlands;
- Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisana per la Scienza, San Giuliano Terme PI, 56017 Pisa, Italy
| |
Collapse
|
11
|
Cui YH, Wei J, Fan H, Li W, Zhao L, Wilkinson E, Peterson J, Xie L, Zou Z, Yang S, Applebaum MA, Kline J, Chen J, He C, He YY. Targeting DTX2/UFD1-mediated FTO degradation to regulate antitumor immunity. Proc Natl Acad Sci U S A 2024; 121:e2407910121. [PMID: 39661064 DOI: 10.1073/pnas.2407910121] [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: 04/19/2024] [Accepted: 11/11/2024] [Indexed: 12/12/2024] Open
Abstract
Here, we show that vitamin E succinate (VES) acts as a degrader for the m6A RNA demethylase fat mass and obesity-associated protein (FTO), thus suppressing tumor growth and resistance to immunotherapy. FTO is ubiquitinated by its E3 ligase DTX2, followed by UFD1 recruitment and subsequent degradation in the proteasome. VES binds to FTO and DTX2, leading to enhanced FTO-DTX2 interaction, FTO ubiquitination, and degradation in FTO-dependent tumor cells. VES suppressed tumor growth and enhanced antitumor immunity and response to immunotherapy in vivo in mouse models. Genetic FTO knockdown or VES treatment increased m6A methylation in the LIF (Leukemia Inhibitory Factor) gene and decreased LIF mRNA decay, and thus sensitized melanoma cells to T cell-mediated cytotoxicity. Taken together, our findings reveal the underlying molecular mechanism for FTO protein degradation and identify a dietary degrader for FTO that inhibits tumor growth and overcomes immunotherapy resistance.
Collapse
Affiliation(s)
- Yan-Hong Cui
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL 60637
| | - Jiangbo Wei
- Departments of Chemistry, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637
- Department of Biochemistry and Molecular Biology Institute for Biophysical Dynamics University of Chicago, Chicago, IL 60637
| | - Hao Fan
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL 60637
| | - Wenlong Li
- Departments of Chemistry, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637
- Department of Biochemistry and Molecular Biology Institute for Biophysical Dynamics University of Chicago, Chicago, IL 60637
| | - Lijie Zhao
- Departments of Chemistry, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637
- Department of Biochemistry and Molecular Biology Institute for Biophysical Dynamics University of Chicago, Chicago, IL 60637
| | - Emma Wilkinson
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL 60637
- Committee on Cancer Biology, University of Chicago, Chicago, IL 60637
| | - Jack Peterson
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL 60637
- The College, University of Chicago, Chicago, IL 60637
| | - Lishi Xie
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL 60637
| | - Zhongyu Zou
- Departments of Chemistry, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637
- Department of Biochemistry and Molecular Biology Institute for Biophysical Dynamics University of Chicago, Chicago, IL 60637
| | - Seungwon Yang
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL 60637
| | - Mark A Applebaum
- Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637
| | - Justin Kline
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL 60637
| | - Jing Chen
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL 60637
| | - Chuan He
- Departments of Chemistry, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637
- Department of Biochemistry and Molecular Biology Institute for Biophysical Dynamics University of Chicago, Chicago, IL 60637
- HHMI, University of Chicago, Chicago, IL 60637
| | - Yu-Ying He
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL 60637
| |
Collapse
|
12
|
Li J, Wang Y, Wang Z, Wei Y, Diao P, Wu Y, Wang D, Jiang H, Wang Y, Cheng J. Super-Enhancer Driven LIF/LIFR-STAT3-SOX2 Regulatory Feedback Loop Promotes Cancer Stemness in Head and Neck Squamous Cell Carcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2404476. [PMID: 39206755 PMCID: PMC11516160 DOI: 10.1002/advs.202404476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 08/17/2024] [Indexed: 09/04/2024]
Abstract
Super-enhancers (SEs) have been recognized as key epigenetic regulators underlying cancer stemness and malignant traits by aberrant transcriptional control and promising therapeutic targets against human cancers. However, the SE landscape and their roles during head and neck squamous cell carcinoma (HNSCC) development especially in cancer stem cells (CSCs) maintenance remain underexplored yet. Here, we identify leukemia inhibitory factor (LIF)-SE as a representative oncogenic SE to activate LIF transcription in HNSCC. LIF secreted from cancer cells and cancer-associated fibroblasts promotes cancer stemness by driving SOX2 transcription in an autocrine/paracrine manner, respectively. Mechanistically, enhancer elements E1, 2, 4 within LIF-SE recruit SOX2/SMAD3/BRD4/EP300 to facilitate LIF transcription; LIF activates downstream LIFR-STAT3 signaling to drive SOX2 transcription, thus forming a previously unknown regulatory feedback loop (LIF-SE-LIF/LIFR-STAT3-SOX2) to maintain LIF overexpression and CSCs stemness. Clinically, increased LIF abundance in clinical samples correlate with malignant clinicopathological features and patient prognosis; higher LIF concentrations in presurgical plasma dramatically diminish following cancer eradication. Therapeutically, pharmacological targeting LIF-SE-LIF/LIFR-STAT3 significantly impairs tumor growth and reduces CSC subpopulations in xenograft and PDX models. Our findings reveal a hitherto uncharacterized LIF-SE-mediated auto-regulatory loop in regulating HNSCC stemness and highlight LIF as a novel noninvasive biomarker and potential therapeutic target for HNSCC.
Collapse
Affiliation(s)
- Jin Li
- Department of Oral and Maxillofacial SurgeryThe Affiliated Stomatological Hospital of Nanjing Medical UniversityJiangsu210029China
- Jiangsu Key Laboratory of Oral DiseaseNanjing Medical UniversityJiangsu210029China
- Jiangsu Province Engineering Research Center of Stomatological Translational MedicineNanjing Medical UniversityJiangsu210029China
| | - Yuhan Wang
- Department of Oral and Maxillofacial SurgeryThe Affiliated Stomatological Hospital of Nanjing Medical UniversityJiangsu210029China
- Jiangsu Key Laboratory of Oral DiseaseNanjing Medical UniversityJiangsu210029China
- Jiangsu Province Engineering Research Center of Stomatological Translational MedicineNanjing Medical UniversityJiangsu210029China
| | - Ziyu Wang
- Department of Oral and Maxillofacial SurgeryThe Affiliated Stomatological Hospital of Nanjing Medical UniversityJiangsu210029China
- Jiangsu Key Laboratory of Oral DiseaseNanjing Medical UniversityJiangsu210029China
- Jiangsu Province Engineering Research Center of Stomatological Translational MedicineNanjing Medical UniversityJiangsu210029China
| | - Yuxiang Wei
- Jiangsu Key Laboratory of Oral DiseaseNanjing Medical UniversityJiangsu210029China
- Jiangsu Province Engineering Research Center of Stomatological Translational MedicineNanjing Medical UniversityJiangsu210029China
| | - Pengfei Diao
- Jiangsu Key Laboratory of Oral DiseaseNanjing Medical UniversityJiangsu210029China
- Jiangsu Province Engineering Research Center of Stomatological Translational MedicineNanjing Medical UniversityJiangsu210029China
| | - Yaping Wu
- Jiangsu Key Laboratory of Oral DiseaseNanjing Medical UniversityJiangsu210029China
- Jiangsu Province Engineering Research Center of Stomatological Translational MedicineNanjing Medical UniversityJiangsu210029China
| | - Dongmiao Wang
- Department of Oral and Maxillofacial SurgeryThe Affiliated Stomatological Hospital of Nanjing Medical UniversityJiangsu210029China
| | - Hongbing Jiang
- Department of Oral and Maxillofacial SurgeryThe Affiliated Stomatological Hospital of Nanjing Medical UniversityJiangsu210029China
- Jiangsu Key Laboratory of Oral DiseaseNanjing Medical UniversityJiangsu210029China
- Jiangsu Province Engineering Research Center of Stomatological Translational MedicineNanjing Medical UniversityJiangsu210029China
| | - Yanling Wang
- Department of Oral and Maxillofacial SurgeryThe Affiliated Stomatological Hospital of Nanjing Medical UniversityJiangsu210029China
- Jiangsu Key Laboratory of Oral DiseaseNanjing Medical UniversityJiangsu210029China
| | - Jie Cheng
- Department of Oral and Maxillofacial SurgeryThe Affiliated Stomatological Hospital of Nanjing Medical UniversityJiangsu210029China
- Jiangsu Key Laboratory of Oral DiseaseNanjing Medical UniversityJiangsu210029China
- Jiangsu Province Engineering Research Center of Stomatological Translational MedicineNanjing Medical UniversityJiangsu210029China
| |
Collapse
|
13
|
Shahraz A, Penney M, Candido J, Opoku‐Ansah G, Neubauer M, Eyles J, Ojo O, Liu N, Luheshi NM, Phipps A, Vishwanathan K. A mechanistic PK/PD model of AZD0171 (anti-LIF) to support Phase II dose selection. CPT Pharmacometrics Syst Pharmacol 2024; 13:1670-1681. [PMID: 39041713 PMCID: PMC11494920 DOI: 10.1002/psp4.13204] [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: 02/17/2024] [Revised: 06/04/2024] [Accepted: 07/02/2024] [Indexed: 07/24/2024] Open
Abstract
AZD0171 (INN: Falbikitug) is being developed as a humanized monoclonal antibody (mAb), immunoglobulin G subclass 1 (IgG1), which binds specifically to the immunosuppressive human cytokine leukemia inhibitory factor (LIF) and inhibits downstream signaling by blocking recruitment of glycoprotein 130 (gp130) to the LIF receptor (LIFR) subunit (gp190) and the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and is intended to treat adult participants with advanced solid tumors. LIF is a pleiotropic cytokine (and a member of the IL-6 family of cytokines) involved in many physiological and pathological processes and is highly expressed in a subset of solid tumors, including non-small cell lung cancer (NSCLC), colon, ovarian, prostate, and pancreatic cancer. The aim of this work was to develop a mechanistic PK/PD model to investigate the effect of AZD0171 on tumor LIF levels, predict the level of downstream signaling complex (LIF:LIFR:gp130) inhibition, and examine the dose-response relationship to support dose selection for a Phase II clinical study. Modeling results show that tumor LIF is inhibited in a dose-dependent manner with >90% inhibition for 95% of patients at the Phase II clinical dose of 1500 mg Q2W.
Collapse
Affiliation(s)
- Azar Shahraz
- Clinical Pharmacology & Quantitative PharmacologyBioPharmaceuticals R&D, AstraZenecaWalthamMassachusettsUSA
| | - Mark Penney
- Early Oncology DMPK, Oncology R&D, AstraZenecaCambridgeUK
| | | | | | | | - Jim Eyles
- Oncology R&D, AstraZenecaCambridgeUK
| | | | | | | | - Alex Phipps
- Clinical Pharmacology & Quantitative PharmacologyBioPharmaceuticals R&D, AstraZenecaCambridgeUK
| | - Karthick Vishwanathan
- Clinical Pharmacology & Quantitative PharmacologyBioPharmaceuticals R&D, AstraZenecaWalthamMassachusettsUSA
| |
Collapse
|
14
|
Seifati SM, Zare F, Bafghi SAM, Hadinedoushan H. Impact of anti leukemia inhibitory factor antibody on immune related gene expression in breast cancer Balb/c mouse model. Sci Rep 2024; 14:20403. [PMID: 39223212 PMCID: PMC11369080 DOI: 10.1038/s41598-024-71014-0] [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: 05/21/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024] Open
Abstract
Leukemia inhibitory factor (LIF) is involved in the progression of different cancers. In this study, we investigated the effect of anti-LIF antibodies on immune-related gene expression in the Balb/c mouse model of breast cancer. To immunize mice against LIF, recombinant LIF with Freund adjuvant was injected into the test group, whereas the control group received phosphate-buffered saline with adjuvant. Tumor induction (4T1 cell line) was performed by increasing the antibody titer. The expression of immune-related genes was evaluated by real-time PCR. The anti-LIF titer was significantly increased in the immunized group. The expression of genes related to the differentiation of T helper (Th)-1, Th-2, and Th-17 cells was significantly higher in the immunized group than in the control group. In addition, anti-LIF did not have a significant effect on the expression of genes related to the differentiation of regulatory T cells, and immune checkpoint-associated genes. Additionally, the test group had higher survival and lower tumor development rates. The results demonstrated that the anti-LIF antibody may potentially play a role in the differentiation of immune cells or immune responses. However, further studies utilizing advanced techniques are necessary to validate its function.
Collapse
Affiliation(s)
- Seyed Mohammad Seifati
- Reproductive Immunology Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Postal Code: 8916181635, Iran
- Department of Immunology, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Fateme Zare
- Reproductive Immunology Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Postal Code: 8916181635, Iran
| | | | - Hossein Hadinedoushan
- Reproductive Immunology Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Postal Code: 8916181635, Iran.
- Department of Immunology, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
| |
Collapse
|
15
|
Vitale S, Calapà F, Colonna F, Luongo F, Biffoni M, De Maria R, Fiori ME. Advancements in 3D In Vitro Models for Colorectal Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2405084. [PMID: 38962943 PMCID: PMC11348154 DOI: 10.1002/advs.202405084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Indexed: 07/05/2024]
Abstract
The process of drug discovery and pre-clinical testing is currently inefficient, expensive, and time-consuming. Most importantly, the success rate is unsatisfactory, as only a small percentage of tested drugs are made available to oncological patients. This is largely due to the lack of reliable models that accurately predict drug efficacy and safety. Even animal models often fail to replicate human-specific pathologies and human body's complexity. These factors, along with ethical concerns regarding animal use, urge the development of suitable human-relevant, translational in vitro models.
Collapse
Affiliation(s)
- Sara Vitale
- Department of Oncology and Molecular Medicine (OMM)Istituto Superiore di SanitàViale Regina Elena 299Rome00161Italy
| | - Federica Calapà
- Dipartimento di Medicina e Chirurgia traslazionaleUniversità Cattolica del Sacro CuoreLargo F. Vito 1RomeItaly
| | - Francesca Colonna
- Department of Oncology and Molecular Medicine (OMM)Istituto Superiore di SanitàViale Regina Elena 299Rome00161Italy
| | - Francesca Luongo
- Dipartimento di Medicina e Chirurgia traslazionaleUniversità Cattolica del Sacro CuoreLargo F. Vito 1RomeItaly
| | - Mauro Biffoni
- Department of Oncology and Molecular Medicine (OMM)Istituto Superiore di SanitàViale Regina Elena 299Rome00161Italy
| | - Ruggero De Maria
- Dipartimento di Medicina e Chirurgia traslazionaleUniversità Cattolica del Sacro CuoreLargo F. Vito 1RomeItaly
- Fondazione Policlinico Universitario “A. Gemelli” – IRCCSLargo F. Vito 1RomeItaly
| | - Micol E. Fiori
- Department of Oncology and Molecular Medicine (OMM)Istituto Superiore di SanitàViale Regina Elena 299Rome00161Italy
| |
Collapse
|
16
|
Ebrahimi B, Viswanadhapalli S, Pratap UP, Rahul G, Yang X, Pitta Venkata P, Drel V, Santhamma B, Konda S, Li X, Sanchez ALR, Yan H, Sareddy GR, Xu Z, Singh BB, Valente PT, Chen Y, Lai Z, Rao M, Kost ER, Curiel T, Tekmal RR, Nair HB, Vadlamudi RK. Pharmacological inhibition of the LIF/LIFR autocrine loop reveals vulnerability of ovarian cancer cells to ferroptosis. NPJ Precis Oncol 2024; 8:118. [PMID: 38789520 PMCID: PMC11126619 DOI: 10.1038/s41698-024-00612-y] [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: 12/21/2023] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
Of all gynecologic cancers, epithelial-ovarian cancer (OCa) stands out with the highest mortality rates. Despite all efforts, 90% of individuals who receive standard surgical and cytotoxic therapy experience disease recurrence. The precise mechanism by which leukemia inhibitory factor (LIF) and its receptor (LIFR) contribute to the progression of OCa remains unknown. Analysis of cancer databases revealed that elevated expression of LIF or LIFR was associated with poor progression-free survival of OCa patients and a predictor of poor response to chemotherapy. Using multiple primary and established OCa cell lines or tissues that represent five subtypes of epithelial-OCa, we demonstrated that LIF/LIFR autocrine signaling is active in OCa. Moreover, treatment with LIFR inhibitor, EC359 significantly reduced OCa cell viability and cell survival with an IC50 ranging from 5-50 nM. Furthermore, EC359 diminished the stemness of OCa cells. Mechanistic studies using RNA-seq and rescue experiments unveiled that EC359 primarily induced ferroptosis by suppressing the glutathione antioxidant defense system. Using multiple in vitro, ex vivo and in vivo models including cell-based xenografts, patient-derived explants, organoids, and xenograft tumors, we demonstrated that EC359 dramatically reduced the growth and progression of OCa. Additionally, EC359 therapy considerably improved tumor immunogenicity by robust CD45+ leukocyte tumor infiltration and polarizing tumor-associated macrophages (TAMs) toward M1 phenotype while showing no impact on normal T-, B-, and other immune cells. Collectively, our findings indicate that the LIF/LIFR autocrine loop plays an essential role in OCa progression and that EC359 could be a promising therapeutic agent for OCa.
Collapse
Affiliation(s)
- Behnam Ebrahimi
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Suryavathi Viswanadhapalli
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
| | - Uday P Pratap
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Gopalam Rahul
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Xue Yang
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
- Department of Obstetrics and Gynecology, Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, PR China
| | - Prabhakar Pitta Venkata
- Greehey Children's Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Viktor Drel
- Department of Periodontics, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | | | | | - Xiaonan Li
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | | | - Hui Yan
- Department of microbiology and immunology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Gangadhara R Sareddy
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Zhenming Xu
- Department of microbiology and immunology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Brij B Singh
- Department of Periodontics, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Philip T Valente
- Department of Pathology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Yidong Chen
- Department of Population Sciences, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Zhao Lai
- Greehey Children's Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Manjeet Rao
- Greehey Children's Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Edward R Kost
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Tyler Curiel
- Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth, NH, 03755, USA
| | - Rajeshwar R Tekmal
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | | | - Ratna K Vadlamudi
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
- Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, 78229, USA.
| |
Collapse
|
17
|
Di Giorgio C, Bellini R, Lupia A, Massa C, Urbani G, Bordoni M, Marchianò S, Rosselli R, De Gregorio R, Rapacciuolo P, Sepe V, Morretta E, Monti MC, Moraca F, Cari L, Ullah KRS, Natalizi N, Graziosi L, Distrutti E, Biagioli M, Catalanotti B, Donini A, Zampella A, Fiorucci S. The leukemia inhibitory factor regulates fibroblast growth factor receptor 4 transcription in gastric cancer. Cell Oncol (Dordr) 2024; 47:695-710. [PMID: 37945798 PMCID: PMC11090936 DOI: 10.1007/s13402-023-00893-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/14/2023] [Indexed: 11/12/2023] Open
Abstract
PURPOSE The gastric adenocarcinoma (GC) represents the third cause of cancer-related mortality worldwide, and available therapeutic options remain sub-optimal. The Fibroblast growth factor receptors (FGFRs) are oncogenic transmembrane tyrosine kinase receptors. FGFR inhibitors have been approved for the treatment of various cancers and a STAT3-dependent regulation of FGFR4 has been documented in the H.pylori infected intestinal GC. Therefore, the modulation of FGFR4 might be useful for the treatment of GC. METHODS To investigate wich factors could modulate FGFR4 signalling in GC, we employed RNA-seq analysis on GC patients biopsies, human patients derived organoids (PDOs) and cancer cell lines. RESULTS We report that FGFR4 expression/function is regulated by the leukemia inhibitory factor (LIF) an IL-6 related oncogenic cytokine, in JAK1/STAT3 dependent manner. The transcriptomic analysis revealed a direct correlation between the expression of LIFR and FGFR4 in the tissue of an exploratory cohort of 31 GC and confirmed these findings by two external validation cohorts of GC. A LIFR inhibitor (LIR-201) abrogates STAT3 phosphorylation induced by LIF as well as recruitment of pSTAT3 to the promoter of FGFR4. Furthermore, inhibition of FGFR4 by roblitinib or siRNA abrogates STAT3 phosphorylation and oncogentic effects of LIF in GC cells, indicating that FGFR4 is a downstream target of LIF/LIFR complex. Treating cells with LIR-201 abrogates oncogenic potential of FGF19, the physiological ligand of FGFR4. CONCLUSIONS Together these data unreveal a previously unregnized regulatory mechanism of FGFR4 by LIF/LIFR and demonstrate that LIF and FGF19 converge on the regulation of oncogenic STAT3 in GC cells.
Collapse
Affiliation(s)
| | - Rachele Bellini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Antonio Lupia
- Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy
- Net4Science Srl, University "Magna Græcia", Campus Salvatore Venuta, Viale Europa, 88100, Catanzaro, Italy
| | - Carmen Massa
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Ginevra Urbani
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Martina Bordoni
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Silvia Marchianò
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Rosa De Gregorio
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | | | - Valentina Sepe
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Elva Morretta
- Department of Pharmacy, University of Salerno, Salerno, Italy
| | | | - Federica Moraca
- Net4Science Srl, University "Magna Græcia", Campus Salvatore Venuta, Viale Europa, 88100, Catanzaro, Italy
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Luigi Cari
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | | | | | | | - Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Bruno Catalanotti
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Annibale Donini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
- Department Surgical and Biomedical Sciences, University of Perugia Medical School, Perugia, Italy.
| |
Collapse
|
18
|
Grasset EM, Barillé-Nion S, Juin PP. Stress in the metastatic journey - the role of cell communication and clustering in breast cancer progression and treatment resistance. Dis Model Mech 2024; 17:dmm050542. [PMID: 38506114 PMCID: PMC10979546 DOI: 10.1242/dmm.050542] [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] [Indexed: 03/21/2024] Open
Abstract
Breast cancer stands as the most prevalent malignancy afflicting women. Despite significant advancements in its diagnosis and treatment, breast cancer metastasis continues to be a leading cause of mortality among women. To metastasize, cancer cells face numerous challenges: breaking away from the primary tumor, surviving in the circulation, establishing in a distant location, evading immune detection and, finally, thriving to initiate a new tumor. Each of these sequential steps requires cancer cells to adapt to a myriad of stressors and develop survival mechanisms. In addition, most patients with breast cancer undergo surgical removal of their primary tumor and have various therapeutic interventions designed to eradicate cancer cells. Despite this plethora of attacks and stresses, certain cancer cells not only manage to persist but also proliferate robustly, giving rise to substantial tumors that frequently culminate in the patient's demise. To enhance patient outcomes, there is an imperative need for a deeper understanding of the molecular and cellular mechanisms that empower cancer cells to not only survive but also expand. Herein, we delve into the intrinsic stresses that cancer cells encounter throughout the metastatic journey and the additional stresses induced by therapeutic interventions. We focus on elucidating the remarkable strategies adopted by cancer cells, such as cell-cell clustering and intricate cell-cell communication mechanisms, to ensure their survival.
Collapse
Affiliation(s)
- Eloïse M. Grasset
- Université de Nantes, INSERM, CNRS, CRCI2NA, 44000 Nantes, France
- Équipe Labellisée LIGUE Contre le Cancer CRCI2NA, 44000 Nantes, France
| | - Sophie Barillé-Nion
- Université de Nantes, INSERM, CNRS, CRCI2NA, 44000 Nantes, France
- Équipe Labellisée LIGUE Contre le Cancer CRCI2NA, 44000 Nantes, France
| | - Philippe P. Juin
- Université de Nantes, INSERM, CNRS, CRCI2NA, 44000 Nantes, France
- Équipe Labellisée LIGUE Contre le Cancer CRCI2NA, 44000 Nantes, France
- Institut de Cancérologie de l'Ouest, 44805 Saint Herblain, France
| |
Collapse
|
19
|
Wang H, Huo R, He K, Cheng L, Zhang S, Yu M, Zhao W, Li H, Xue J. Perineural invasion in colorectal cancer: mechanisms of action and clinical relevance. Cell Oncol (Dordr) 2024; 47:1-17. [PMID: 37610689 PMCID: PMC10899381 DOI: 10.1007/s13402-023-00857-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/03/2023] [Indexed: 08/24/2023] Open
Abstract
BACKGROUND In recent years, the significance of the nervous system in the tumor microenvironment has gained increasing attention. The bidirectional communication between nerves and cancer cells plays a critical role in tumor initiation and progression. Perineural invasion (PNI) occurs when tumor cells invade the nerve sheath and/or encircle more than 33% of the nerve circumference. PNI is a common feature in various malignancies and is associated with tumor invasion, metastasis, cancer-related pain, and unfavorable clinical outcomes. The colon and rectum are highly innervated organs, and accumulating studies support PNI as a histopathologic feature of colorectal cancer (CRC). Therefore, it is essential to investigate the role of nerves in CRC and comprehend the mechanisms of PNI to impede tumor progression and improve patient survival. CONCLUSION This review elucidates the clinical significance of PNI, summarizes the underlying cellular and molecular mechanisms, introduces various experimental models suitable for studying PNI, and discusses the therapeutic potential of targeting this phenomenon. By delving into the intricate interactions between nerves and tumor cells, we hope this review can provide valuable insights for the future development of CRC treatments.
Collapse
Affiliation(s)
- Hao Wang
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, P.R. China
| | - Ruixue Huo
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, P.R. China
| | - Kexin He
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, P.R. China
| | - Li Cheng
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, P.R. China
| | - Shan Zhang
- State Key Laboratory of Oncogenes and Related Genes, Ren Ji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, 200240, P.R. China
| | - Minhao Yu
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200217, P.R. China
| | - Wei Zhao
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, P.R. China.
| | - Hui Li
- State Key Laboratory of Oncogenes and Related Genes, Ren Ji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, 200240, P.R. China.
| | - Junli Xue
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, P.R. China.
| |
Collapse
|
20
|
Abou Hammoud A, Giraud J, Gauthereau X, Blanchard C, Daburon S, Zese M, Molina-Castro S, Dubus P, Varon C, Boeuf H. The "StemDif Sensor Test": A Straightforward, Non-Invasive Assay to Characterize the Secreted Stemness and/or Differentiation Activities of Tumor-Derived Cancer Cell Lines. Biomedicines 2023; 11:3293. [PMID: 38137514 PMCID: PMC10741605 DOI: 10.3390/biomedicines11123293] [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: 10/16/2023] [Revised: 11/22/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
Cancer stem cells are a subpopulation of tumor cells characterized by their ability to self-renew, induce tumors upon engraftment in animals and exhibit strong resistance to chemotherapy and radiotherapy. These cells exhibit numerous characteristics in common with embryonic stem cells, expressing some of their markers, typically absent in non-pathological adult differentiated cells. The aim of this study was to investigate the potential of conditioned media from cancer stem cells to modulate the fate of Leukemia Inhibitory Factor (LIF)-dependent murine embryonic stem cells (mESCs) as a way to obtain a direct readout of the secretome of cancer cells. A functional assay, "the StemDif sensor test", was developed with two types of cancer stem cells derived from grade IV glioblastoma (adult and pediatric) or from gastric adenocarcinoma. We show that conditioned media from the selection of adult but not pediatric Glioma-Inducing Cells (GICs) maintain mESCs' pluripotency in correlation with LIF secretion and activation of STAT3 protein. In contrast, conditioned media from gastric adenocarcinoma cells display LIF-independent stemness and differentiation activities on mESC. Our test stands out for its user-friendly procedures, affordability and straightforward output, positioning it as a pioneering tool for in-depth exploration of cancer stem cell secretome characteristics.
Collapse
Affiliation(s)
- Aya Abou Hammoud
- Univ. Bordeaux, INSERM, BIOTIS, U1026, F-33000 Bordeaux, France; (A.A.H.); (C.B.); (M.Z.)
- Univ. Bordeaux, INSERM, BRIC-MIRCADE Team, U1312, F-33000 Bordeaux, France
- Univ. Bordeaux, INSERM, BRIC, U1312, F-33000 Bordeaux, France; (J.G.); (S.M.-C.); (P.D.); (C.V.)
| | - Julie Giraud
- Univ. Bordeaux, INSERM, BRIC, U1312, F-33000 Bordeaux, France; (J.G.); (S.M.-C.); (P.D.); (C.V.)
- Univ. Bordeaux, CNRS, ImmunoConcEpT, U5164, F-33000 Bordeaux, France;
| | - Xavier Gauthereau
- Univ. Bordeaux, CNRS, ImmunoConcEpT, U5164, F-33000 Bordeaux, France;
| | - Camille Blanchard
- Univ. Bordeaux, INSERM, BIOTIS, U1026, F-33000 Bordeaux, France; (A.A.H.); (C.B.); (M.Z.)
| | | | - Marco Zese
- Univ. Bordeaux, INSERM, BIOTIS, U1026, F-33000 Bordeaux, France; (A.A.H.); (C.B.); (M.Z.)
| | - Silvia Molina-Castro
- Univ. Bordeaux, INSERM, BRIC, U1312, F-33000 Bordeaux, France; (J.G.); (S.M.-C.); (P.D.); (C.V.)
| | - Pierre Dubus
- Univ. Bordeaux, INSERM, BRIC, U1312, F-33000 Bordeaux, France; (J.G.); (S.M.-C.); (P.D.); (C.V.)
| | - Christine Varon
- Univ. Bordeaux, INSERM, BRIC, U1312, F-33000 Bordeaux, France; (J.G.); (S.M.-C.); (P.D.); (C.V.)
| | - Helene Boeuf
- Univ. Bordeaux, INSERM, BIOTIS, U1026, F-33000 Bordeaux, France; (A.A.H.); (C.B.); (M.Z.)
| |
Collapse
|
21
|
Spencer N, Rodriguez Sanchez AL, Gopalam R, Subbarayalu P, Medina DM, Yang X, Ramirez P, Randolph L, Aller EJ, Santhamma B, Rao MK, Tekmal RR, Nair HB, Kost ER, Vadlamudi RK, Viswanadhapalli S. The LIFR Inhibitor EC359 Effectively Targets Type II Endometrial Cancer by Blocking LIF/LIFR Oncogenic Signaling. Int J Mol Sci 2023; 24:17426. [PMID: 38139260 PMCID: PMC10744027 DOI: 10.3390/ijms242417426] [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: 10/28/2023] [Revised: 12/01/2023] [Accepted: 12/08/2023] [Indexed: 12/24/2023] Open
Abstract
Endometrial cancer (ECa) is the most common female gynecologic cancer. When comparing the two histological subtypes of endometrial cancer, Type II tumors are biologically more aggressive and have a worse prognosis than Type I tumors. Current treatments for Type II tumors are ineffective, and new targeted therapies are urgently needed. LIFR and its ligand, LIF, have been shown to play a critical role in the progression of multiple solid cancers and therapy resistance. The role of LIF/LIFR in the progression of Type II ECa, on the other hand, is unknown. We investigated the role of LIF/LIFR signaling in Type II ECa and tested the efficacy of EC359, a novel small-molecule LIFR inhibitor, against Type II ECa. The analysis of tumor databases has uncovered a correlation between diminished survival rates and increased expression of leukemia inhibitory factor (LIF), suggesting a potential connection between altered LIF expression and unfavorable overall survival in Type II ECa. The results obtained from cell viability and colony formation assays demonstrated a significant decrease in the growth of Type II ECa LIFR knockdown cells in comparison to vector control cells. Furthermore, in both primary and established Type II ECa cells, pharmacological inhibition of the LIF/LIFR axis with EC359 markedly decreased cell viability, long-term cell survival, and invasion, and promoted apoptosis. Additionally, EC359 treatment reduced the activation of pathways driven by LIF/LIFR, such as AKT, mTOR, and STAT3. Tumor progression was markedly inhibited by EC359 treatment in two different patient-derived xenograft models in vivo and patient-derived organoids ex vivo. Collectively, these results suggest LIFR inhibitor EC359 as a possible new small-molecule therapeutics for the management of Type II ECa.
Collapse
Affiliation(s)
- Nicole Spencer
- Division of Reproductive Research, Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (N.S.); (A.L.R.S.); (R.G.); (X.Y.); (P.R.); (L.R.); (E.J.A.); (R.R.T.); (E.R.K.); (R.K.V.)
| | - Alondra Lee Rodriguez Sanchez
- Division of Reproductive Research, Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (N.S.); (A.L.R.S.); (R.G.); (X.Y.); (P.R.); (L.R.); (E.J.A.); (R.R.T.); (E.R.K.); (R.K.V.)
| | - Rahul Gopalam
- Division of Reproductive Research, Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (N.S.); (A.L.R.S.); (R.G.); (X.Y.); (P.R.); (L.R.); (E.J.A.); (R.R.T.); (E.R.K.); (R.K.V.)
| | - Panneerdoss Subbarayalu
- Department of Cell Systems & Anatomy, Greehey Children’s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (P.S.); (D.M.M.); (M.K.R.)
| | - Daisy M. Medina
- Department of Cell Systems & Anatomy, Greehey Children’s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (P.S.); (D.M.M.); (M.K.R.)
| | - Xue Yang
- Division of Reproductive Research, Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (N.S.); (A.L.R.S.); (R.G.); (X.Y.); (P.R.); (L.R.); (E.J.A.); (R.R.T.); (E.R.K.); (R.K.V.)
| | - Paulina Ramirez
- Division of Reproductive Research, Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (N.S.); (A.L.R.S.); (R.G.); (X.Y.); (P.R.); (L.R.); (E.J.A.); (R.R.T.); (E.R.K.); (R.K.V.)
| | - Lois Randolph
- Division of Reproductive Research, Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (N.S.); (A.L.R.S.); (R.G.); (X.Y.); (P.R.); (L.R.); (E.J.A.); (R.R.T.); (E.R.K.); (R.K.V.)
| | - Emily Jean Aller
- Division of Reproductive Research, Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (N.S.); (A.L.R.S.); (R.G.); (X.Y.); (P.R.); (L.R.); (E.J.A.); (R.R.T.); (E.R.K.); (R.K.V.)
| | | | - Manjeet K. Rao
- Department of Cell Systems & Anatomy, Greehey Children’s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (P.S.); (D.M.M.); (M.K.R.)
| | - Rajeshwar Rao Tekmal
- Division of Reproductive Research, Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (N.S.); (A.L.R.S.); (R.G.); (X.Y.); (P.R.); (L.R.); (E.J.A.); (R.R.T.); (E.R.K.); (R.K.V.)
| | | | - Edward R. Kost
- Division of Reproductive Research, Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (N.S.); (A.L.R.S.); (R.G.); (X.Y.); (P.R.); (L.R.); (E.J.A.); (R.R.T.); (E.R.K.); (R.K.V.)
| | - Ratna K. Vadlamudi
- Division of Reproductive Research, Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (N.S.); (A.L.R.S.); (R.G.); (X.Y.); (P.R.); (L.R.); (E.J.A.); (R.R.T.); (E.R.K.); (R.K.V.)
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX 78229, USA
| | - Suryavathi Viswanadhapalli
- Division of Reproductive Research, Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; (N.S.); (A.L.R.S.); (R.G.); (X.Y.); (P.R.); (L.R.); (E.J.A.); (R.R.T.); (E.R.K.); (R.K.V.)
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| |
Collapse
|
22
|
Soler MF, Abaurrea A, Azcoaga P, Araujo AM, Caffarel MM. New perspectives in cancer immunotherapy: targeting IL-6 cytokine family. J Immunother Cancer 2023; 11:e007530. [PMID: 37945321 PMCID: PMC10649711 DOI: 10.1136/jitc-2023-007530] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2023] [Indexed: 11/12/2023] Open
Abstract
Chronic inflammation has been recognized as a canonical cancer hallmark. It is orchestrated by cytokines, which are master regulators of the tumor microenvironment (TME) as they represent the main communication bridge between cancer cells, the tumor stroma, and the immune system. Interleukin (IL)-6 represents a keystone cytokine in the link between inflammation and cancer. Many cytokines from the IL-6 family, which includes IL-6, oncostatin M, leukemia inhibitory factor, IL-11, IL-27, IL-31, ciliary neurotrophic factor, cardiotrophin 1, and cardiotrophin-like cytokine factor 1, have been shown to elicit tumor-promoting roles by modulating the TME, making them attractive therapeutic targets for cancer treatment.The development of immune checkpoint blockade (ICB) immunotherapies has radically changed the outcome of some cancers including melanoma, lung, and renal, although not without hurdles. However, ICB shows limited efficacy in other solid tumors. Recent reports support that chronic inflammation and IL-6 cytokine signaling are involved in resistance to immunotherapy. This review summarizes the available preclinical and clinical data regarding the implication of IL-6-related cytokines in regulating the immune TME and the response to ICB. Moreover, the potential clinical benefit of combining ICB with therapies targeting IL-6 cytokine members for cancer treatment is discussed.
Collapse
Affiliation(s)
- Maria Florencia Soler
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, Donostia-San Sebastian, Spain
| | - Andrea Abaurrea
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, Donostia-San Sebastian, Spain
| | - Peio Azcoaga
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, Donostia-San Sebastian, Spain
| | - Angela M Araujo
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, Donostia-San Sebastian, Spain
| | - Maria M Caffarel
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, Donostia-San Sebastian, Spain
- Ikerbasque Basque Foundation for Science, Bilbao, Spain
| |
Collapse
|
23
|
Remley VA, Linden J, Bauer TW, Dimastromatteo J. Unlocking antitumor immunity with adenosine receptor blockers. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2023; 6:748-767. [PMID: 38263981 PMCID: PMC10804392 DOI: 10.20517/cdr.2023.63] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 10/06/2023] [Accepted: 10/16/2023] [Indexed: 01/25/2024]
Abstract
Tumors survive by creating a tumor microenvironment (TME) that suppresses antitumor immunity. The TME suppresses the immune system by limiting antigen presentation, inhibiting lymphocyte and natural killer (NK) cell activation, and facilitating T cell exhaustion. Checkpoint inhibitors like anti-PD-1 and anti-CTLA4 are immunostimulatory antibodies, and their blockade extends the survival of some but not all cancer patients. Extracellular adenosine triphosphate (ATP) is abundant in inflamed tumors, and its metabolite, adenosine (ADO), is a driver of immunosuppression mediated by adenosine A2A receptors (A2AR) and adenosine A2B receptors (A2BR) found on tumor-associated lymphoid and myeloid cells. This review will focus on adenosine as a key checkpoint inhibitor-like immunosuppressive player in the TME and how reducing adenosine production or blocking A2AR and A2BR enhances antitumor immunity.
Collapse
Affiliation(s)
- Victoria A. Remley
- Department of Surgery, University of Virginia, Charlottesville, VA 22903, USA
- University of Virginia Comprehensive Cancer Center, Charlottesville, VA 22903, USA
| | | | - Todd W. Bauer
- Department of Surgery, University of Virginia, Charlottesville, VA 22903, USA
- University of Virginia Comprehensive Cancer Center, Charlottesville, VA 22903, USA
| | | |
Collapse
|
24
|
Cammarota AL, Falco A, Basile A, Molino C, Chetta M, D’Angelo G, Marzullo L, De Marco M, Turco MC, Rosati A. Pancreatic Cancer-Secreted Proteins: Targeting Their Functions in Tumor Microenvironment. Cancers (Basel) 2023; 15:4825. [PMID: 37835519 PMCID: PMC10571538 DOI: 10.3390/cancers15194825] [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: 08/06/2023] [Revised: 09/25/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a ravaging disease with a poor prognosis, requiring a more detailed understanding of its biology to foster the development of effective therapies. The unsatisfactory results of treatments targeting cell proliferation and its related mechanisms suggest a shift in focus towards the inflammatory tumor microenvironment (TME). Here, we discuss the role of cancer-secreted proteins in the complex TME tumor-stroma crosstalk, shedding lights on druggable molecular targets for the development of innovative, safer and more efficient therapeutic strategies.
Collapse
Affiliation(s)
- Anna Lisa Cammarota
- Department of Medicine, Surgery and Dentistry “Schola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (A.L.C.); (A.F.); (A.B.); (L.M.); (M.C.T.)
| | - Antonia Falco
- Department of Medicine, Surgery and Dentistry “Schola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (A.L.C.); (A.F.); (A.B.); (L.M.); (M.C.T.)
| | - Anna Basile
- Department of Medicine, Surgery and Dentistry “Schola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (A.L.C.); (A.F.); (A.B.); (L.M.); (M.C.T.)
| | - Carlo Molino
- General Surgery Unit, A.O.R.N. Cardarelli, 80131 Naples, Italy;
| | - Massimiliano Chetta
- Medical and Laboratory Genetics Unit, A.O.R.N., Cardarelli, 80131 Naples, Italy;
| | - Gianni D’Angelo
- Department of Computer Science, University of Salerno, 84084 Fisciano, Italy;
| | - Liberato Marzullo
- Department of Medicine, Surgery and Dentistry “Schola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (A.L.C.); (A.F.); (A.B.); (L.M.); (M.C.T.)
- FIBROSYS s.r.l., University of Salerno, 84081 Baronissi, Italy
| | - Margot De Marco
- Department of Medicine, Surgery and Dentistry “Schola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (A.L.C.); (A.F.); (A.B.); (L.M.); (M.C.T.)
- FIBROSYS s.r.l., University of Salerno, 84081 Baronissi, Italy
| | - Maria Caterina Turco
- Department of Medicine, Surgery and Dentistry “Schola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (A.L.C.); (A.F.); (A.B.); (L.M.); (M.C.T.)
- FIBROSYS s.r.l., University of Salerno, 84081 Baronissi, Italy
| | - Alessandra Rosati
- Department of Medicine, Surgery and Dentistry “Schola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (A.L.C.); (A.F.); (A.B.); (L.M.); (M.C.T.)
- FIBROSYS s.r.l., University of Salerno, 84081 Baronissi, Italy
| |
Collapse
|
25
|
Raudenska M, Balvan J, Hanelova K, Bugajova M, Masarik M. Cancer-associated fibroblasts: Mediators of head and neck tumor microenvironment remodeling. Biochim Biophys Acta Rev Cancer 2023; 1878:188940. [PMID: 37331641 DOI: 10.1016/j.bbcan.2023.188940] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/05/2023] [Accepted: 06/12/2023] [Indexed: 06/20/2023]
Abstract
Cancer-associated fibroblasts (CAFs) are involved in critical aspects of head and neck squamous cell carcinoma (HNSCC) pathogenesis, such as the formation of a tumor-permissive extracellular matrix structure, angiogenesis, or immune and metabolic reprogramming of the tumor microenvironment (TME), with implications for metastasis and resistance to radiotherapy and chemotherapy. The pleiotropic effect of CAFs in TME is likely to reflect the heterogeneity and plasticity of their population, with context-dependent effects on carcinogenesis. The specific properties of CAFs provide many targetable molecules that could play an important role in the future therapy of HNSCC. In this review article, we will focus on the role of CAFs in the TME of HNSCC tumors. We will also discuss clinically relevant agents targeting CAFs, their signals, and signaling pathways, which are activated by CAFs in cancer cells, with the potential for repurposing for HNSCC therapy.
Collapse
Affiliation(s)
- Martina Raudenska
- Department of Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Jan Balvan
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Klara Hanelova
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Maria Bugajova
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic
| | - Michal Masarik
- Department of Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University / Kamenice 5, CZ-625 00 Brno, Czech Republic; Institute of Pathophysiology, First Faculty of Medicine, Charles University, / U Nemocnice 5, CZ-128 53 Prague, Czech Republic.
| |
Collapse
|
26
|
Rashidfarrokhi A, Pillai R, Hao Y, Wu WL, Karadal-Ferrena B, Dimitriadoy SG, Cross M, Yeaton AH, Huang SM, Bhutkar AJ, Herrera A, Rajalingam S, Hayashi M, Huang KL, Bartnicki E, Zavitsanou AM, Wohlhieter CA, Leboeuf SE, Chen T, Loomis C, Mezzano V, Kulicke R, Davis FP, Stransky N, Smolen GA, Rudin CM, Moreira AL, Khanna KM, Pass HI, Wong KK, Koide S, Tsirigos A, Koralov SB, Papagiannakopoulos T. Tumor-intrinsic LKB1-LIF signaling axis establishes a myeloid niche to promote immune evasion and tumor growth. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.15.549147. [PMID: 37502974 PMCID: PMC10370066 DOI: 10.1101/2023.07.15.549147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Tumor mutations can influence the surrounding microenvironment leading to suppression of anti-tumor immune responses and thereby contributing to tumor progression and failure of cancer therapies. Here we use genetically engineered lung cancer mouse models and patient samples to dissect how LKB1 mutations accelerate tumor growth by reshaping the immune microenvironment. Comprehensive immune profiling of LKB1 -mutant vs wildtype tumors revealed dramatic changes in myeloid cells, specifically enrichment of Arg1 + interstitial macrophages and SiglecF Hi neutrophils. We discovered a novel mechanism whereby autocrine LIF signaling in Lkb1 -mutant tumors drives tumorigenesis by reprogramming myeloid cells in the immune microenvironment. Inhibiting LIF signaling in Lkb1 -mutant tumors, via gene targeting or with a neutralizing antibody, resulted in a striking reduction in Arg1 + interstitial macrophages and SiglecF Hi neutrophils, expansion of antigen specific T cells, and inhibition of tumor progression. Thus, targeting LIF signaling provides a new therapeutic approach to reverse the immunosuppressive microenvironment of LKB1 -mutant tumors.
Collapse
|
27
|
Laface C, Memeo R, Maselli FM, Santoro AN, Iaia ML, Ambrogio F, Laterza M, Cazzato G, Guarini C, De Santis P, Perrone M, Fedele P. Immunotherapy and Pancreatic Cancer: A Lost Challenge? Life (Basel) 2023; 13:1482. [PMID: 37511856 PMCID: PMC10381818 DOI: 10.3390/life13071482] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 06/22/2023] [Accepted: 06/29/2023] [Indexed: 07/30/2023] Open
Abstract
Although immunotherapy has proved to be a very efficient therapeutic strategy for many types of tumors, the results for pancreatic cancer (PC) have been very poor. Indeed, chemotherapy remains the standard treatment for this tumor in the advanced stage. Clinical data showed that only a small portion of PC patients with high microsatellite instability/mismatch repair deficiency benefit from immunotherapy. However, the low prevalence of these alterations was not sufficient to lead to a practice change in the treatment strategy of this tumor. The main reasons for the poor efficacy of immunotherapy probably lie in the peculiar features of the pancreatic tumor microenvironment in comparison with other malignancies. In addition, the biomarkers usually evaluated to define immunotherapy efficacy in other cancers appear to be useless in PC. This review aims to describe the main features of the pancreatic tumor microenvironment from an immunological point of view and to summarize the current data on immunotherapy efficacy and immune biomarkers in PC.
Collapse
Affiliation(s)
- Carmelo Laface
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Riccardo Memeo
- Unit of Hepato-Pancreatic-Biliary Surgery, “F. Miulli” General Regional Hospital, 70021 Acquaviva Delle Fonti, Italy
| | | | | | - Maria Laura Iaia
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Francesca Ambrogio
- Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, 70124 Bari, Italy
| | - Marigia Laterza
- Division of Cardiac Surgery, University of Bari, 70124 Bari, Italy
| | - Gerardo Cazzato
- Department of Emergency and Organ Transplantation, Pathology Section, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Chiara Guarini
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Pierluigi De Santis
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Martina Perrone
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Palma Fedele
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| |
Collapse
|
28
|
Barisas DAG, Kabir AU, Wu J, Krchma K, Kim M, Subramanian M, Zinselmeyer BH, Stewart CL, Choi K. Tumor-derived interleukin-1α and leukemia inhibitory factor promote extramedullary hematopoiesis. PLoS Biol 2023; 21:e3001746. [PMID: 37134077 PMCID: PMC10155962 DOI: 10.1371/journal.pbio.3001746] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 02/06/2023] [Indexed: 05/04/2023] Open
Abstract
Extramedullary hematopoiesis (EMH) expands hematopoietic capacity outside of the bone marrow in response to inflammatory conditions, including infections and cancer. Because of its inducible nature, EMH offers a unique opportunity to study the interaction between hematopoietic stem and progenitor cells (HSPCs) and their niche. In cancer patients, the spleen frequently serves as an EMH organ and provides myeloid cells that may worsen pathology. Here, we examined the relationship between HSPCs and their splenic niche in EMH in a mouse breast cancer model. We identify tumor produced IL-1α and leukemia inhibitory factor (LIF) acting on splenic HSPCs and splenic niche cells, respectively. IL-1α induced TNFα expression in splenic HSPCs, which then activated splenic niche activity, while LIF induced proliferation of splenic niche cells. IL-1α and LIF display cooperative effects in activating EMH and are both up-regulated in some human cancers. Together, these data expand avenues for developing niche-directed therapies and further exploring EMH accompanying inflammatory pathologies like cancer.
Collapse
Affiliation(s)
- Derek A. G. Barisas
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
- Immunology Program, Washington University School of Medicine, St. Louis, Missouri, United States of America
- Medical Scientist Training Program, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Ashraf Ul Kabir
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Jun Wu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Karen Krchma
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Minseo Kim
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Madhav Subramanian
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Bernd H. Zinselmeyer
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Colin L. Stewart
- Developmental and Regenerative Biology, A*STAR Skin Research Laboratories, Singapore, Singapore
| | - Kyunghee Choi
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
- Immunology Program, Washington University School of Medicine, St. Louis, Missouri, United States of America
| |
Collapse
|
29
|
Kehrberg RJ, Bhyravbhatla N, Batra SK, Kumar S. Epigenetic regulation of cancer-associated fibroblast heterogeneity. Biochim Biophys Acta Rev Cancer 2023; 1878:188901. [PMID: 37120098 PMCID: PMC10375465 DOI: 10.1016/j.bbcan.2023.188901] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 04/13/2023] [Accepted: 04/22/2023] [Indexed: 05/01/2023]
Abstract
Cancer-associated fibroblasts (CAFs), a significant component of the tumor microenvironment (TME), contribute to cancer progression through the secretion of extracellular matrix (ECM), growth factors, and metabolites. It is now well recognized that CAFs are a heterogenous population with ablation experiments leading to reduced tumor growth and single-cell RNA sequencing demonstrating CAF subgroups. CAFs lack genetic mutations yet substantially differ from their normal stromal precursors. Here, we review epigenetic changes in CAF maturation, focusing on DNA methylation and histone modifications. DNA methylation changes in CAFs have been demonstrated globally, while roles of methylation at specific genes affect tumor growth. Further, loss of CAF histone methylation and gain of histone acetylation has been shown to promote CAF activation and tumor promotion. Many CAF activating factors, such as transforming growth factor β (TGFβ), lead to these epigenetic changes. MicroRNAs (miRNAs) serve as targets and orchestrators of epigenetic modifications that influence gene expression. Bromodomain and extra-terminal domain (BET), an epigenetic reader, recognizes histone acetylation and activates the transcription of genes leading to the pro-tumor phenotype of CAFs.
Collapse
Affiliation(s)
- Rachel J Kehrberg
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Namita Bhyravbhatla
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
| |
Collapse
|
30
|
Wang J, Karime C, Majeed U, Starr JS, Borad MJ, Babiker HM. Targeting Leukemia Inhibitory Factor in Pancreatic Adenocarcinoma. Expert Opin Investig Drugs 2023:1-13. [PMID: 37092893 DOI: 10.1080/13543784.2023.2206558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
INTRODUCTION Leukemia Inhibitory Factor (LIF) is a member of the interleukin-6 (IL-6) cytokine family. Known to induce differentiation of myeloid leukemia cells, evidence has accumulated supporting its role in cancer evolution though regulating cell differentiation, renewal, and survival. LIF has recently emerged as a biomarker and therapeutic target for pancreatic ductal adenocarcinoma (PDAC). The first-in-human clinical trial has shown promising safety profile and has suggested a potential role for LIF inhibitor in combination regimen. AREAS COVERED Herein, we summarize, discuss, and give an expert opinion on the role of LIF in PDAC promotion, and its potential role as a biomarker and target of anti-cancer therapy. We conducted an exhaustive PubMed search for English-language articles published from January 1, 1970, to August 1, 2022. EXPERT OPINION PDAC carries a devastating prognosis for patients, highlighting the need for advancing drug development. The results of the phase 1 trial with MSC-1 demonstrated tolerability and safety but modest efficacy. Future research should focus on investigating LIF targets in combination with current standard-of-care chemotherapy and immunotherapy can be a promising approach. Further, larger multicenter clinical trials are needed to define the use of LIF as a new biomarker in PDAC patients.
Collapse
Affiliation(s)
- Jing Wang
- Department of Medicine, Mayo Clinic, Jacksonville, Florida, USA
| | | | - Umair Majeed
- Department of Medicine, Division of Hematology Oncology, Mayo Clinic, Jacksonville, Florida, USA
| | - Jason S Starr
- Department of Medicine, Division of Hematology Oncology, Mayo Clinic, Jacksonville, Florida, USA
| | - Mitesh J Borad
- Department of Medicine, Division of Hematology Oncology, Mayo Clinic, Phoenix, Arizona USA
| | - Hani M Babiker
- Department of Medicine, Division of Hematology Oncology, Mayo Clinic, Jacksonville, Florida, USA
| |
Collapse
|
31
|
Hu C, Zhang Y, Wu C, Huang Q. Heterogeneity of cancer-associated fibroblasts in head and neck squamous cell carcinoma: opportunities and challenges. Cell Death Discov 2023; 9:124. [PMID: 37055382 PMCID: PMC10102018 DOI: 10.1038/s41420-023-01428-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/25/2023] [Accepted: 04/03/2023] [Indexed: 04/15/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is among the most severe and complex malignant diseases with a high level of heterogeneity and, as a result, a wide range of therapeutic responses, regardless of clinical stage. Tumor progression depends on ongoing co-evolution and cross-talk with the tumor microenvironment (TME). In particular, cancer-associated fibroblasts (CAFs), embedded in the extracellular matrix (ECM), induce tumor growth and survival by interacting with tumor cells. Origin of CAFs is quite varied, and the activation patterns of CAFs are also heterogeneous. Crucially, the heterogeneity of CAFs appears to play a key role in ongoing tumor expansion, including facilitating proliferation, enhancing angiogenesis and invasion, and promoting therapy resistance, through the production of cytokines, chemokines, and other tumor-promotive molecules in the TME. This review describes the various origin and heterogeneous activation mechanisms of CAFs, and biological heterogeneity of CAFs in HNSCC is also included. Moreover, we have highlighted versatility of CAFs heterogeneity in HNSCC progression, and have discussed different tumor-promotive functions of CAFs respectively. In the future, it is a promising strategy for the therapy of HNSCC that specifically targeting tumor-promoting CAF subsets or the tumor-promoting functional targets of CAFs.
Collapse
Affiliation(s)
- Chen Hu
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, 100730, Beijing, China
| | - Yifan Zhang
- Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, 200031, Shanghai, China
| | - Chunping Wu
- Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, 200031, Shanghai, China.
| | - Qiang Huang
- Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, 200031, Shanghai, China.
| |
Collapse
|
32
|
Wright K, Ly T, Kriet M, Czirok A, Thomas SM. Cancer-Associated Fibroblasts: Master Tumor Microenvironment Modifiers. Cancers (Basel) 2023; 15:cancers15061899. [PMID: 36980785 PMCID: PMC10047485 DOI: 10.3390/cancers15061899] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/17/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Cancer cells rely on the tumor microenvironment (TME), a composite of non-malignant cells, and extracellular matrix (ECM), for survival, growth, and metastasis. The ECM contributes to the biomechanical properties of the surrounding tissue, in addition to providing signals for tissue development. Cancer-associated fibroblasts (CAFs) are stromal cells in the TME that are integral to cancer progression. Subtypes of CAFs across a variety of cancers have been revealed, and each play a different role in cancer progression or suppression. CAFs secrete signaling molecules and remodel the surrounding ECM by depositing its constituents as well as degrading enzymes. In cancer, a remodeled ECM can lead to tumor-promoting effects. Not only does the remodeled ECM promote growth and allow for easier metastasis, but it can also modulate the immune system. A better understanding of how CAFs remodel the ECM will likely yield novel therapeutic targets. In this review, we summarize the key factors secreted by CAFs that facilitate tumor progression, ECM remodeling, and immune suppression.
Collapse
Affiliation(s)
- Kellen Wright
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Thuc Ly
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Matthew Kriet
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Andras Czirok
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Sufi Mary Thomas
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| |
Collapse
|
33
|
Wang J, Chang CY, Yang X, Zhou F, Liu J, Feng Z, Hu W. Leukemia inhibitory factor, a double-edged sword with therapeutic implications in human diseases. Mol Ther 2023; 31:331-343. [PMID: 36575793 PMCID: PMC9931620 DOI: 10.1016/j.ymthe.2022.12.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 12/01/2022] [Accepted: 12/22/2022] [Indexed: 12/27/2022] Open
Abstract
Leukemia inhibitory factor (LIF) is a pleiotropic cytokine of the interleukin-6 (IL-6) superfamily. LIF was initially discovered as a factor to induce the differentiation of myeloid leukemia cells and thus inhibit their proliferation. Subsequent studies have highlighted the multi-functions of LIF under a wide variety of physiological and pathological conditions in a highly cell-, tissue-, and context-dependent manner. Emerging evidence has demonstrated that LIF plays an essential role in the stem cell niche, where it maintains the homeostasis and regeneration of multiple somatic tissues, including intestine, neuron, and muscle. Further, LIF exerts a crucial regulatory role in immunity and functions as a protective factor against many immunopathological diseases, such as infection, inflammatory bowel disease (IBD), and graft-verse-host disease (GVHD). It is worth noting that while LIF displays a tumor-suppressive function in leukemia, recent studies have highlighted the oncogenic role of LIF in many types of solid tumors, further demonstrating the complexities and context-dependent effects of LIF. In this review, we summarize the recent insights into the roles and mechanisms of LIF in stem cell homeostasis and regeneration, immunity, and cancer, and discuss the potential therapeutic options for human diseases by modulating LIF levels and functions.
Collapse
Affiliation(s)
- Jianming Wang
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08903, USA
| | - Chun-Yuan Chang
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08903, USA
| | - Xue Yang
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08903, USA
| | - Fan Zhou
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08903, USA
| | - Juan Liu
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08903, USA
| | - Zhaohui Feng
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08903, USA.
| | - Wenwei Hu
- Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08903, USA.
| |
Collapse
|
34
|
Sarkar M, Nguyen T, Gundre E, Ogunlusi O, El-Sobky M, Giri B, Sarkar TR. Cancer-associated fibroblasts: The chief architect in the tumor microenvironment. Front Cell Dev Biol 2023; 11:1089068. [PMID: 36793444 PMCID: PMC9923123 DOI: 10.3389/fcell.2023.1089068] [Citation(s) in RCA: 66] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 01/12/2023] [Indexed: 01/31/2023] Open
Abstract
Stromal heterogeneity of tumor microenvironment (TME) plays a crucial role in malignancy and therapeutic resistance. Cancer-associated fibroblasts (CAFs) are one of the major players in tumor stroma. The heterogeneous sources of origin and subsequent impacts of crosstalk with breast cancer cells flaunt serious challenges before current therapies to cure triple-negative breast cancer (TNBC) and other cancers. The positive and reciprocal feedback of CAFs to induce cancer cells dictates their mutual synergy in establishing malignancy. Their substantial role in creating a tumor-promoting niche has reduced the efficacy of several anti-cancer treatments, including radiation, chemotherapy, immunotherapy, and endocrine therapy. Over the years, there has been an emphasis on understanding CAF-induced therapeutic resistance in order to enhance cancer therapy results. CAFs, in the majority of cases, employ crosstalk, stromal management, and other strategies to generate resilience in surrounding tumor cells. This emphasizes the significance of developing novel strategies that target particular tumor-promoting CAF subpopulations, which will improve treatment sensitivity and impede tumor growth. In this review, we discuss the current understanding of the origin and heterogeneity of CAFs, their role in tumor progression, and altering the tumor response to therapeutic agents in breast cancer. In addition, we also discuss the potential and possible approaches for CAF-mediated therapies.
Collapse
Affiliation(s)
- Mrinmoy Sarkar
- Department of Biology, Texas A&M University, College Station, TX, United States
- Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Tristan Nguyen
- Department of Biology, Texas A&M University, College Station, TX, United States
| | - Esheksha Gundre
- Department of Biology, Texas A&M University, College Station, TX, United States
| | - Olajumoke Ogunlusi
- Department of Biology, Texas A&M University, College Station, TX, United States
| | - Mohanad El-Sobky
- Department of Biology, Texas A&M University, College Station, TX, United States
| | - Biplab Giri
- Department of Physiology, University of Gour Banga, English Bazar, India
| | - Tapasree Roy Sarkar
- Department of Biology, Texas A&M University, College Station, TX, United States
| |
Collapse
|
35
|
Swetha KL, Maravajjala KS, Li SD, Singh MS, Roy A. Breaking the niche: multidimensional nanotherapeutics for tumor microenvironment modulation. Drug Deliv Transl Res 2023; 13:105-134. [PMID: 35697894 DOI: 10.1007/s13346-022-01194-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2022] [Indexed: 12/13/2022]
Abstract
Most of the current antitumor therapeutics were developed targeting the cancer cells only. Unfortunately, in the majority of tumors, this single-dimensional therapy is found to be ineffective. Advanced research has shown that cancer is a multicellular disorder. The tumor microenvironment (TME), which is made by a complex network of the bulk tumor cells and other supporting cells, plays a crucial role in tumor progression. Understanding the importance of the TME in tumor growth, different treatment modalities have been developed targeting these supporting cells. Recent clinical results suggest that simultaneously targeting multiple components of the tumor ecosystem with drug combinations can be highly effective. This type of "multidimensional" therapy has a high potential for cancer treatment. However, tumor-specific delivery of such multi-drug combinations remains a challenge. Nanomedicine could be utilized for the tumor-targeted delivery of such multidimensional therapeutics. In this review, we first give a brief overview of the major components of TME. We then highlight the latest developments in nanoparticle-based combination therapies, where one drug targets cancer cells and other drug targets tumor-supporting components in the TME for a synergistic effect. We include the latest preclinical and clinical studies and discuss innovative nanoparticle-mediated targeting strategies.
Collapse
Affiliation(s)
- K Laxmi Swetha
- Department of Pharmacy, Birla Institute of Technology & Science, Vidya Vihar, Pilani, Rajasthan, 333031, India
| | - Kavya Sree Maravajjala
- Department of Pharmacy, Birla Institute of Technology & Science, Vidya Vihar, Pilani, Rajasthan, 333031, India
| | - Shyh-Dar Li
- Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Westbrook Mall, Vancouver, BC, Canada
| | - Manu Smriti Singh
- Department of Biotechnology, Bennett University, Greater Noida, Uttar Pradesh, 201310, India. .,Center of Excellence for Nanosensors and Nanomedicine, Bennett University, Greater Noida, Uttar Pradesh, 201310, India.
| | - Aniruddha Roy
- Department of Pharmacy, Birla Institute of Technology & Science, Vidya Vihar, Pilani, Rajasthan, 333031, India.
| |
Collapse
|
36
|
Xu S, Yang X, Chen Q, Liu Z, Chen Y, Yao X, Xiao A, Tian J, Xie L, Zhou M, Hu Z, Zhu F, Xu X, Hou F, Nie J. Leukemia inhibitory factor is a therapeutic target for renal interstitial fibrosis. EBioMedicine 2022; 86:104312. [PMID: 36335669 PMCID: PMC9646860 DOI: 10.1016/j.ebiom.2022.104312] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 09/28/2022] [Accepted: 10/04/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND The role of the IL6 family members in organ fibrosis, including renal interstitial fibrosis (TIF), has been widely explored. However, few studies have ever simultaneously examined them in the same cohort of patients. Besides, the role of leukemia inhibitory factor (LIF) in TIF remains unclear. METHODS RNA-seq data of kidney biopsies from chronic kidney disease (CKD) patients, in both public databases and our assays, were used to analyze transcript levels of IL6 family members. Two TIF mouse models, the unilateral ureteral obstruction (UUO) and the ischemia reperfusion injury (IRI), were employed to validate the finding. To assess the role of LIF in vivo, short hairpin RNA, lenti-GFP-LIF was used to knockdown LIF receptor (LIFR), overexpress LIF, respectively. LIF-neutralizing antibody was used in therapeutic studies. Whether urinary LIF could be used as a promising predictor for CKD progression was investigated in a prospective observation patient cohort. FINDINGS Among IL6 family members, LIF is the most upregulated one in both human and mouse renal fibrotic lesions. The mRNA level of LIF negatively correlated with eGFR with the strongest correlation and the smallest P value. Baseline urinary concentrations of LIF in CKD patients predict the risk of CKD progression to end-stage kidney disease by Kaplan-Meier analysis. In mouse TIF models, knockdown of LIFR alleviated TIF; conversely, overexpressing LIF exacerbated TIF. Most encouragingly, visible efficacy against TIF was observed by administering LIF-neutralizing antibodies to mice. Mechanistically, LIF-LIFR-EGR1 axis and Sonic Hedgehog signaling formed a vicious cycle between fibroblasts and proximal tubular cells to augment LIF expression and promote the pro-fibrotic response via ERK and STAT3 activation. INTERPRETATION This study discovered that LIF is a noninvasive biomarker for the progression of CKD and a potential therapeutic target of TIF. FUNDINGS Stated in the Acknowledgements section of the manuscript.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Fanfan Hou
- Corresponding author. Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Jing Nie
- Corresponding author. Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| |
Collapse
|
37
|
Blankenship L, Pratap UP, Yang X, Liu Z, Altwegg KA, Santhamma B, Ramasamy K, Konda S, Chen Y, Lai Z, Zheng S, Sareddy GR, Valente PT, Kost ER, Nair HB, Tekmal RR, Vadlamudi RK, Viswanadhapalli S. Inhibition of LIFR Blocks Adiposity-Driven Endometrioid Endometrial Cancer Growth. Cancers (Basel) 2022; 14:5400. [PMID: 36358818 PMCID: PMC9657203 DOI: 10.3390/cancers14215400] [Citation(s) in RCA: 3] [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: 09/21/2022] [Revised: 10/21/2022] [Accepted: 10/29/2022] [Indexed: 11/06/2022] Open
Abstract
Endometrial cancer (EC) is the fourth most common cancer in women, and half of the endometrioid EC (EEC) cases are attributable to obesity. However, the underlying mechanism(s) of obesity-driven EEC remain(s) unclear. In this study, we examined whether LIF signaling plays a role in the obesity-driven progression of EEC. RNA-seq analysis of EEC cells stimulated by adipose conditioned medium (ADP-CM) showed upregulation of LIF/LIFR-mediated signaling pathways including JAK/STAT and interleukin pathways. Immunohistochemistry analysis of normal and EEC tissues collected from obese patients revealed that LIF expression is upregulated in EEC tissues compared to the normal endometrium. Treatment of both primary and established EEC cells with ADP-CM increased the expression of LIF and its receptor LIFR and enhanced proliferation of EEC cells. Treatment of EEC cells with the LIFR inhibitor EC359 abolished ADP-CM induced colony formation andcell viability and decreased growth of EEC organoids. Mechanistic studies using Western blotting, RT-qPCR and reporter assays confirmed that ADP-CM activated LIF/LIFR downstream signaling, which can be effectively attenuated by the addition of EC359. In xenograft assays, co-implantation of adipocytes significantly enhanced EEC xenograft tumor growth. Further, treatment with EC359 significantly attenuated adipocyte-induced EEC progression in vivo. Collectively, our data support the premise that LIF/LIFR signaling plays an important role in obesity-driven EEC progression and the LIFR inhibitor EC359 has the potential to suppress adipocyte-driven tumor progression.
Collapse
Affiliation(s)
- Logan Blankenship
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Uday P. Pratap
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Xue Yang
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Department of Obstetrics and Gynecology, Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Zexuan Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Kristin A. Altwegg
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | | | - Kumaraguruparan Ramasamy
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | | | - Yidong Chen
- Greehey Children’s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Department of Population Health Sciences, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Zhao Lai
- Greehey Children’s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Siyuan Zheng
- Greehey Children’s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Department of Population Health Sciences, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Gangadhara R. Sareddy
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Philip T. Valente
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Edward R. Kost
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | | | - Rajeshwar R. Tekmal
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Ratna K. Vadlamudi
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX 78229, USA
| | - Suryavathi Viswanadhapalli
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| |
Collapse
|
38
|
Wong KY, Cheung AH, Chen B, Chan WN, Yu J, Lo KW, Kang W, To KF. Cancer-associated fibroblasts in nonsmall cell lung cancer: From molecular mechanisms to clinical implications. Int J Cancer 2022; 151:1195-1215. [PMID: 35603909 PMCID: PMC9545594 DOI: 10.1002/ijc.34127] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 05/08/2022] [Accepted: 05/12/2022] [Indexed: 11/14/2022]
Abstract
Lung cancer is the common and leading cause of cancer death worldwide. The tumor microenvironment has been recognized to be instrumental in tumorigenesis. To have a deep understanding of the molecular mechanism of nonsmall cell lung carcinoma (NSCLC), cancer-associated fibroblasts (CAFs) have gained increasing research interests. CAFs belong to the crucial and dominant cell population in the tumor microenvironment to support the cancer cells. The interplay and partnership between cancer cells and CAFs contribute to each stage of tumorigenesis. CAFs exhibit prominent heterogeneity and secrete different kinds of cytokines and chemokines, growth factors and extracellular matrix proteins involved in cancer cell proliferation, invasion, metastasis and chemoresistance. Many studies focused on the protumorigenic functions of CAFs, yet many challenges about the heterogeneity of CAFS remain unresolved. This review comprehensively summarized the tumor-promoting role and molecular mechanisms of CAFs in NSCLC, including their origin, phenotypic changes and heterogeneity and their functional roles in carcinogenesis. Meanwhile, we also highlighted the updated molecular classifications based on the molecular features and functional roles of CAFs. With the development of cutting-edge platforms and further investigations of CAFs, novel therapeutic strategies for accurately targeting CAFs in NSCLC may be developed based on the increased understanding of the relevant molecular mechanisms.
Collapse
Affiliation(s)
- Kit Yee Wong
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational OncologyPrince of Wales Hospital, The Chinese University of Hong KongHong KongSARChina
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong KongHong KongSARChina
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongHong KongSARChina
| | - Alvin Ho‐Kwan Cheung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational OncologyPrince of Wales Hospital, The Chinese University of Hong KongHong KongSARChina
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong KongHong KongSARChina
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongHong KongSARChina
| | - Bonan Chen
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational OncologyPrince of Wales Hospital, The Chinese University of Hong KongHong KongSARChina
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong KongHong KongSARChina
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongHong KongSARChina
| | - Wai Nok Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational OncologyPrince of Wales Hospital, The Chinese University of Hong KongHong KongSARChina
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong KongHong KongSARChina
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongHong KongSARChina
| | - Jun Yu
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong KongHong KongSARChina
- Department of Medicine and TherapeuticsThe Chinese University of Hong KongHong KongSARChina
| | - Kwok Wai Lo
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational OncologyPrince of Wales Hospital, The Chinese University of Hong KongHong KongSARChina
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong KongHong KongSARChina
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongHong KongSARChina
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational OncologyPrince of Wales Hospital, The Chinese University of Hong KongHong KongSARChina
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong KongHong KongSARChina
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongHong KongSARChina
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational OncologyPrince of Wales Hospital, The Chinese University of Hong KongHong KongSARChina
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong KongHong KongSARChina
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong KongHong KongSARChina
| |
Collapse
|
39
|
Heidary Z, Haghjooy Javanmard S, Izadi I, Zare N, Ghaisari J. Multiscale modeling of collective cell migration elucidates the mechanism underlying tumor-stromal interactions in different spatiotemporal scales. Sci Rep 2022; 12:16242. [PMID: 36171274 PMCID: PMC9519582 DOI: 10.1038/s41598-022-20634-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 09/15/2022] [Indexed: 11/09/2022] Open
Abstract
Metastasis is the pathogenic spread of cancer cells from a primary tumor to a secondary site which happens at the late stages of cancer. It is caused by a variety of biological, chemical, and physical processes, such as molecular interactions, intercellular communications, and tissue-level activities. Complex interactions of cancer cells with their microenvironment components such as cancer associated fibroblasts (CAFs) and extracellular matrix (ECM) cause them to adopt an invasive phenotype that promotes tumor growth and migration. This paper presents a multiscale model for integrating a wide range of time and space interactions at the molecular, cellular, and tissue levels in a three-dimensional domain. The modeling procedure starts with presenting nonlinear dynamics of cancer cells and CAFs using ordinary differential equations based on TGFβ, CXCL12, and LIF signaling pathways. Unknown kinetic parameters in these models are estimated using hybrid unscented Kalman filter and the models are validated using experimental data. Then, the principal role of CAFs on metastasis is revealed by spatial-temporal modeling of circulating signals throughout the TME. At this stage, the model has evolved into a coupled ODE-PDE system that is capable of determining cancer cells' status in one of the quiescent, proliferating or migratory conditions due to certain metastasis factors and ECM characteristics. At the tissue level, we consider a force-based framework to model the cancer cell proliferation and migration as the final step towards cancer cell metastasis. The ability of the multiscale model to depict cancer cells' behavior in different levels of modeling is confirmed by comparing its outputs with the results of RT PCR and wound scratch assay techniques. Performance evaluation of the model indicates that the proposed multiscale model can pave the way for improving the efficiency of therapeutic methods in metastasis prevention.
Collapse
Affiliation(s)
- Zarifeh Heidary
- Department of Electrical and Computer Engineering, Isfahan University of Technology, Isfahan, 84156-83111, Iran
| | - Shaghayegh Haghjooy Javanmard
- Department of Physiology, Applied Physiology Research Center, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
| | - Iman Izadi
- Department of Electrical and Computer Engineering, Isfahan University of Technology, Isfahan, 84156-83111, Iran
| | - Nasrin Zare
- School of Medicine, Najafabad Branch, Islamic Azad University, Isfahan, Iran
| | - Jafar Ghaisari
- Department of Electrical and Computer Engineering, Isfahan University of Technology, Isfahan, 84156-83111, Iran.
| |
Collapse
|
40
|
Perdrix Rosell A, Maiques O, Martin JAJ, Chakravarty P, Ombrato L, Sanz-Moreno V, Malanchi I. Early functional mismatch between breast cancer cells and their tumour microenvironment suppresses long term growth. Cancer Lett 2022; 544:215800. [PMID: 35803476 DOI: 10.1016/j.canlet.2022.215800] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 05/26/2022] [Accepted: 06/15/2022] [Indexed: 02/02/2023]
Abstract
Cancer cells thrive when embedded in a fine-tuned cellular and extracellular environment or tumour microenvironment (TME). There is a general understanding of a co-evolution between cancer cells and their surrounding TME, pointing at a functional connection between cancer cells characteristics and the perturbations induced in their surrounding tissue. However, it has never been formally proven whether this functional connection needs to be set from the start or if aggressive cancer cells always dominate their microenvironmental any point in time. This would require a dedicated experimental setting where malignant cells are challenged to grow in a different TME from the one they would naturally create. Here we generated an experimental setting where we transiently perturb the secretory profile of aggressive breast cancer cells without affecting their intrinsic growth ability, which led to the initial establishment of an atypical TME. Interestingly, even if initially tumours are formed, this atypical TME evolves to impair long term in vivo cancer growth. Using a combination of in vivo transcriptomics, protein arrays and in vitro co-cultures, we found that the atypical TME culminates in the infiltration of macrophages with STAT1high activity. These macrophages show strong anti-tumoural functions which reduce long-term tumour growth, despite lacking canonical M1 markers. Importantly, gene signatures of the mesenchymal compartment of the TME, as well as the anti-tumoural macrophages, show striking prognostic power that correlates with less aggressive human breast cancers.
Collapse
Affiliation(s)
- Anna Perdrix Rosell
- Tumour Host Interaction Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK; Sanz-Moreno Lab, Centre for Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK; Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London, SE1 1UL, UK
| | - Oscar Maiques
- Sanz-Moreno Lab, Centre for Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK; Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London, SE1 1UL, UK
| | - Joshua Alexander James Martin
- Sanz-Moreno Lab, Centre for Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Probir Chakravarty
- Bioinformatics and Biostatistics Unit, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK
| | - Luigi Ombrato
- Tumour Host Interaction Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK
| | - Victoria Sanz-Moreno
- Sanz-Moreno Lab, Centre for Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK; Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London, SE1 1UL, UK.
| | - Ilaria Malanchi
- Tumour Host Interaction Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK.
| |
Collapse
|
41
|
Imai Y, Mori N, Nihashi Y, Kumagai Y, Shibuya Y, Oshima J, Sasaki M, Sasaki K, Aihara Y, Sekido M, Kida YS. Therapeutic Potential of Adipose Stem Cell-Derived Conditioned Medium on Scar Contraction Model. Biomedicines 2022; 10:biomedicines10102388. [PMID: 36289649 PMCID: PMC9598573 DOI: 10.3390/biomedicines10102388] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/08/2022] [Accepted: 09/13/2022] [Indexed: 11/16/2022] Open
Abstract
Scars are composed of stiff collagen fibers, which contract strongly owing to the action of myofibroblasts. To explore the substances that modulate scar contracture, the fibroblast-populated collagen lattice (FPCL) model has been used. However, the molecular signature of the patient-derived FPCL model has not been verified. Here, we examined whether the patient-derived keloid FPCL model reflects scar contraction, analyzing detailed gene expression changes using comprehensive RNA sequencing and histological morphology, and revealed that these models are consistent with the changes during human scar contracture. Moreover, we examined whether conditioned media derived from adipose stem cells (ASC-CM) suppress the scar contracture of the collagen disc. Detailed time-series measurements of changes in disc area showed that the addition of ASC-CM significantly inhibited the shrinkage of collagen discs. In addition, a deep sequencing data analysis revealed that ASC-CM suppressed inflammation-related gene expression in the early phase of contraction; in the later phase, this suppression was gradually replaced by extracellular matrix (ECM)-related gene expression. These lines of data suggested the effectiveness of ASC-CM in suppressing scar contractures. Therefore, the molecular analysis of the ASC-CM actions found in this study will contribute to solving medical problems regarding pathological scarring in wound prognosis.
Collapse
Affiliation(s)
- Yukiko Imai
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba 305-8565, Ibaraki, Japan
- Department of Plastic and Reconstructive surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Nobuhito Mori
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba 305-8565, Ibaraki, Japan
| | - Yuma Nihashi
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba 305-8565, Ibaraki, Japan
| | - Yutaro Kumagai
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba 305-8565, Ibaraki, Japan
| | - Yoichiro Shibuya
- Department of Plastic and Reconstructive surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Junya Oshima
- Department of Plastic and Reconstructive surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Masahiro Sasaki
- Department of Plastic and Reconstructive surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Kaoru Sasaki
- Department of Plastic and Reconstructive surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Yukiko Aihara
- Department of Plastic and Reconstructive surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Mitsuru Sekido
- Department of Plastic and Reconstructive surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
| | - Yasuyuki S. Kida
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba 305-8565, Ibaraki, Japan
- School of Integrative and Global Majors, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
- Correspondence: ; Tel.: +81-29-861-3000
| |
Collapse
|
42
|
Popovic A, Tartare-Deckert S. Role of extracellular matrix architecture and signaling in melanoma therapeutic resistance. Front Oncol 2022; 12:924553. [PMID: 36119516 PMCID: PMC9479148 DOI: 10.3389/fonc.2022.924553] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 08/15/2022] [Indexed: 12/03/2022] Open
Abstract
The extracellular matrix (ECM) is critical for maintaining tissue homeostasis therefore its production, assembly and mechanical stiffness are highly regulated in normal tissues. However, in solid tumors, increased stiffness resulting from abnormal ECM structural changes is associated with disease progression, an increased risk of metastasis and poor survival. As a dynamic and key component of the tumor microenvironment, the ECM is becoming increasingly recognized as an important feature of tumors, as it has been shown to promote several hallmarks of cancer via biochemical and biomechanical signaling. In this regard, melanoma cells are highly sensitive to ECM composition, stiffness and fiber alignment because they interact directly with the ECM in the tumor microenvironment via cell surface receptors, secreted factors or enzymes. Importantly, seeing as the ECM is predominantly deposited and remodeled by myofibroblastic stromal fibroblasts, it is a key avenue facilitating their paracrine interactions with melanoma cells. This review gives an overview of melanoma and further describes the critical roles that ECM properties such as ECM remodeling, ECM-related proteins and stiffness play in cutaneous melanoma progression, tumor cell plasticity and therapeutic resistance. Finally, given the emerging importance of ECM dynamics in melanoma, future perspectives on therapeutic strategies to normalize the ECM in tumors are discussed.
Collapse
Affiliation(s)
- Ana Popovic
- Université Côte d’Azur, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France
- Team Microenvironnement, Signaling and Cancer, Equipe Labellisée Ligue Contre le Cancer, Nice, France
| | - Sophie Tartare-Deckert
- Université Côte d’Azur, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France
- Team Microenvironnement, Signaling and Cancer, Equipe Labellisée Ligue Contre le Cancer, Nice, France
| |
Collapse
|
43
|
Shen H, Huang F, Zhang X, Ojo OA, Li Y, Trummell HQ, Anderson JC, Fiveash J, Bredel M, Yang ES, Willey CD, Chong Z, Bonner JA, Shi LZ. Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling. Nat Commun 2022; 13:5013. [PMID: 36008408 PMCID: PMC9411168 DOI: 10.1038/s41467-022-32754-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Accepted: 08/16/2022] [Indexed: 11/09/2022] Open
Abstract
Therapeutic resistance to immune checkpoint blockers (ICBs) in melanoma patients is a pressing issue, of which tumor loss of IFN-γ signaling genes is a major underlying mechanism. However, strategies of overcoming this resistance mechanism have been largely elusive. Moreover, given the indispensable role of tumor-infiltrating T cells (TILs) in ICBs, little is known about how tumor-intrinsic loss of IFN-γ signaling (IFNγR1KO) impacts TILs. Here, we report that IFNγR1KO melanomas have reduced infiltration and function of TILs. IFNγR1KO melanomas harbor a network of constitutively active protein tyrosine kinases centered on activated JAK1/2. Mechanistically, JAK1/2 activation is mediated by augmented mTOR. Importantly, JAK1/2 inhibition with Ruxolitinib selectively suppresses the growth of IFNγR1KO but not scrambled control melanomas, depending on T cells and host TNF. Together, our results reveal an important role of tumor-intrinsic IFN-γ signaling in shaping TILs and manifest a targeted therapy to bypass ICB resistance of melanomas defective of IFN-γ signaling.
Collapse
Affiliation(s)
- Hongxing Shen
- Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham (UAB-SOM), Birmingham, AL, 35233, USA
| | - Fengyuan Huang
- Department of Genetics and Informatics Institute, UAB-SOM, Birmingham, AL, USA
| | - Xiangmin Zhang
- Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, 48201, USA
| | - Oluwagbemiga A Ojo
- Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham (UAB-SOM), Birmingham, AL, 35233, USA
| | - Yuebin Li
- Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham (UAB-SOM), Birmingham, AL, 35233, USA
| | - Hoa Quang Trummell
- Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham (UAB-SOM), Birmingham, AL, 35233, USA
| | - Joshua C Anderson
- Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham (UAB-SOM), Birmingham, AL, 35233, USA
| | - John Fiveash
- Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham (UAB-SOM), Birmingham, AL, 35233, USA
- O'Neal Comprehensive Cancer Center, UAB-SOM, Birmingham, AL, USA
| | - Markus Bredel
- Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham (UAB-SOM), Birmingham, AL, 35233, USA
- O'Neal Comprehensive Cancer Center, UAB-SOM, Birmingham, AL, USA
| | - Eddy S Yang
- Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham (UAB-SOM), Birmingham, AL, 35233, USA
- O'Neal Comprehensive Cancer Center, UAB-SOM, Birmingham, AL, USA
| | - Christopher D Willey
- Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham (UAB-SOM), Birmingham, AL, 35233, USA
- O'Neal Comprehensive Cancer Center, UAB-SOM, Birmingham, AL, USA
| | - Zechen Chong
- Department of Genetics and Informatics Institute, UAB-SOM, Birmingham, AL, USA.
- O'Neal Comprehensive Cancer Center, UAB-SOM, Birmingham, AL, USA.
| | - James A Bonner
- Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham (UAB-SOM), Birmingham, AL, 35233, USA.
- O'Neal Comprehensive Cancer Center, UAB-SOM, Birmingham, AL, USA.
| | - Lewis Zhichang Shi
- Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham (UAB-SOM), Birmingham, AL, 35233, USA.
- O'Neal Comprehensive Cancer Center, UAB-SOM, Birmingham, AL, USA.
- Department of Microbiology, UAB-SOM, Birmingham, AL, USA.
- Department of Pharmacology and Toxicology, UAB-SOM, Birmingham, AL, USA.
- Programs in Immunology, UAB-SOM, Birmingham, AL, USA.
| |
Collapse
|
44
|
Borazanci E, Schram AM, Garralda E, Brana I, Vieito Villar M, Spreafico A, Oliva M, Lakhani NJ, Hoffman K, Hallett RM, Maetzel D, Hua F, Hilbert J, Giblin P, Anido J, Kelly A, Vickers PJ, Wasserman R, Seoane J, Siu LL, Hyman DM, Hoff DV, Tabernero J. Phase I, first-in-human study of MSC-1 (AZD0171), a humanized anti-leukemia inhibitory factor monoclonal antibody, for advanced solid tumors. ESMO Open 2022; 7:100530. [PMID: 35921760 PMCID: PMC9434412 DOI: 10.1016/j.esmoop.2022.100530] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 05/26/2022] [Accepted: 06/09/2022] [Indexed: 11/17/2022] Open
Affiliation(s)
| | - A M Schram
- Memorial Sloan Kettering Cancer Center, New York, USA
| | - E Garralda
- Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), Barcelona, Spain
| | - I Brana
- Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), Barcelona, Spain
| | - M Vieito Villar
- Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), Barcelona, Spain
| | - A Spreafico
- Princess Margaret Cancer Centre, Toronto, Canada
| | - M Oliva
- Princess Margaret Cancer Centre, Toronto, Canada
| | | | - K Hoffman
- Northern Biologics, Inc., Toronto, Canada
| | | | - D Maetzel
- Northern Biologics, Inc., Toronto, Canada
| | - F Hua
- Applied BioMath, Concord, USA
| | | | - P Giblin
- Northern Biologics, Inc., Toronto, Canada
| | - J Anido
- Northern Biologics, Inc., Toronto, Canada
| | - A Kelly
- Northern Biologics, Inc., Toronto, Canada
| | | | | | - J Seoane
- Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Universitat Autònoma de Barcelona (UAB), CIBERONC, Barcelona
| | - L L Siu
- Princess Margaret Cancer Centre, Toronto, Canada
| | - D M Hyman
- Memorial Sloan Kettering Cancer Center, New York, USA
| | | | - J Tabernero
- Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), Barcelona, Spain; UVic-UCC, IOB-Quiron, Barcelona, Spain
| |
Collapse
|
45
|
Viswanadhapalli S, Dileep KV, Zhang KY, Nair HB, Vadlamudi RK. Targeting LIF/LIFR signaling in cancer. Genes Dis 2022; 9:973-980. [PMID: 35685476 PMCID: PMC9170604 DOI: 10.1016/j.gendis.2021.04.003] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 04/05/2021] [Accepted: 04/09/2021] [Indexed: 12/19/2022] Open
Abstract
Leukemia inhibitory factor (LIF), and its receptor (LIFR), are commonly over-expressed in many solid cancers and recent studies have implicated LIF/LIFR axis as a promising clinical target for cancer therapy. LIF/LIFR activate oncogenic signaling pathways including JAK/STAT3 as immediate effectors and MAPK, AKT, mTOR further downstream. LIF/LIFR signaling plays a key role in tumor growth, progression, metastasis, stemness and therapy resistance. Many solid cancers show overexpression of LIF and autocrine stimulation of the LIF/LIFR axis; these are associated with a poorer relapse-free survival. LIF/LIFR signaling also plays a role in modulating multiple immune cell types present in tumor micro environment (TME). Recently, two targeted agents that target LIF (humanized anti-LIF antibody, MSC-1) and LIFR inhibitor (EC359) were under development. Both agents showed effectivity in preclinical models and clinical trials using MSC-1 antibody are in progress. This article reviews the significance of LIF/LIFR pathways and inhibitors that disrupt this process for the treatment of cancer.
Collapse
Key Words
- AKT, protein kinase B
- HER2, human epidermal growth factor receptor 2
- JAK, Janus kinase
- LIF
- LIF receptor, (LIFR)
- LIFR
- LIFR inhibitor
- STAT3
- Targeted therapy
- breast cancer, (BCa)
- cancer stem cells, (CSCs)
- cardiotrophin 1, (CTF1)
- ciliary neurotrophic factor, (CNTF)
- colorectal cancer, (CRC)
- endometrial cancer, (ECa)
- humanized Anti-LIF antibody, (MSC-1)
- leukemia inhibitory factor, (LIF)
- mammalian target of rapamycin, (mTOR)
- mitogen activated protein kinase, (MAPK)
- oncostatin M, (OSM)
- ovarian cancer, (OCa)
- pancreatic ductal adenocarcinoma, (PDAC)
- programmed death-ligand 1, (PD-L1)
- prostate cancer, (PCa)
- signal transducer and activator of transcription 3, (STAT3)
- triple negative breast cancer, (TNBC)
- tumor micro environment, (TME)
Collapse
Affiliation(s)
- Suryavathi Viswanadhapalli
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Kalarickal V. Dileep
- Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, Yokohama, Kanagawa 230-0045, Japan
| | - Kam Y.J. Zhang
- Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, Yokohama, Kanagawa 230-0045, Japan
| | | | - Ratna K. Vadlamudi
- Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA
- Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| |
Collapse
|
46
|
Yang X, Chen J, Wang J, Ma S, Feng W, Wu Z, Guo Y, Zhou H, Mi W, Chen W, Yin B, Lin Y. Very-low-density lipoprotein receptor-enhanced lipid metabolism in pancreatic stellate cells promotes pancreatic fibrosis. Immunity 2022; 55:1185-1199.e8. [PMID: 35738281 DOI: 10.1016/j.immuni.2022.06.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 03/22/2022] [Accepted: 05/31/2022] [Indexed: 11/05/2022]
Abstract
Lipoprotein disorder is a common feature of chronic pancreatitis (CP); however, the relationship between lipoprotein disorder and pancreatic fibrotic environment is unclear. Here, we investigated the occurrence and mechanism of pancreatic stellate cell (PSC) activation by lipoprotein metabolites and the subsequent regulation of type 2 immune responses, as well as the driving force of fibrotic aggressiveness in CP. Single-cell RNA sequencing revealed the heterogeneity of PSCs and identified very-low-density lipoprotein receptor (VLDLR)+ PSCs that were characterized by a higher lipid metabolism. VLDLR promoted intracellular lipid accumulation, followed by interleukin-33 (IL-33) expression and release in PSCs. PSC-derived IL-33 strongly induced pancreatic group 2 innate lymphoid cells (ILC2s) to trigger a type 2 immune response accompanied by the activation of PSCs, eventually leading to fibrosis during pancreatitis. Our findings indicate that VLDLR-enhanced lipoprotein metabolism in PSCs promotes pancreatic fibrosis and highlight a dominant role of IL-33 in this pro-fibrotic cascade.
Collapse
Affiliation(s)
- Xuguang Yang
- Clinical Research Center, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Shanghai Pudong Hospital, Fudan University, Shanghai 201399, China.
| | - Jie Chen
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China; Department of Pediatric Surgery, Jiaxing Maternity and Child Health Care Hospital Affiliated to Jiaxing University, Jiaxing 314000, China
| | - Jun Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200032, China
| | - Shuai Ma
- Division of Nephrology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China
| | - Wenxue Feng
- Department of Radiology, Huashan Hospital, Fudan University, Shanghai 200032, China
| | - Zhihao Wu
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China
| | - Yangyang Guo
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Hong Zhou
- Department of Immunology, Anhui Medical University, Hefei, An Hui 230031, China
| | - Wenli Mi
- Department of Integrative Medicine and Neurobiology, Institutes of Integrative Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Wei Chen
- Clinical Research Center, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Bo Yin
- Department of Radiology, Huashan Hospital, Fudan University, Shanghai 200032, China.
| | - Yuli Lin
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Shanghai Pudong Hospital, Fudan University, Shanghai 201399, China.
| |
Collapse
|
47
|
The Molecular Basis and Therapeutic Potential of Leukemia Inhibitory Factor in Cancer Cachexia. Cancers (Basel) 2022; 14:cancers14122955. [PMID: 35740622 PMCID: PMC9221449 DOI: 10.3390/cancers14122955] [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: 05/05/2022] [Revised: 06/01/2022] [Accepted: 06/11/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary The mechanism of cancer cachexia is linked to a variety of factors, and inflammatory factors are thought to play a key role. We summarize the main roles of LIF in the development of cancer cachexia, including promoting fat loss, inducing skeletal muscle atrophy and causing anorexia nervosa. The main aim of this review is to increase the understanding of the effects of LIF in cachexia and to provide new insights into the treatment of cancer cachexia. Abstract Cachexia is a chronic metabolic syndrome that is characterized by sustained weight and muscle mass loss and anorexia. Cachexia can be secondary to a variety of diseases and affects the prognosis of patients significantly. The increase in inflammatory cytokines in plasma is deeply related to the occurrence of cachexia. As a member of the IL-6 cytokine family, leukemia inhibitory factor (LIF) exerts multiple biological functions. LIF is over-expressed in the cancer cells and stromal cells of various tumors, promoting the malignant development of tumors via the autocrine and paracrine systems. Intriguingly, increasing studies have confirmed that LIF contributes to the progression of cachexia, especially in patients with metastatic tumors. This review combines all of the evidence to summarize the mechanism of LIF-induced cachexia from the following four aspects: (i) LIF and cancer-associated cachexia, (ii) LIF and alterations of adipose tissue in cachexia, (iii) LIF and anorexia nervosa in cachexia, and (iv) LIF and muscle atrophy in cachexia. Considering the complex mechanisms in cachexia, we also focus on the interactions between LIF and other key cytokines in cachexia and existing therapeutics targeting LIF.
Collapse
|
48
|
Di Federico A, Mosca M, Pagani R, Carloni R, Frega G, De Giglio A, Rizzo A, Ricci D, Tavolari S, Di Marco M, Palloni A, Brandi G. Immunotherapy in Pancreatic Cancer: Why Do We Keep Failing? A Focus on Tumor Immune Microenvironment, Predictive Biomarkers and Treatment Outcomes. Cancers (Basel) 2022; 14:cancers14102429. [PMID: 35626033 PMCID: PMC9139656 DOI: 10.3390/cancers14102429] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/06/2022] [Accepted: 05/11/2022] [Indexed: 12/20/2022] Open
Abstract
Simple Summary In pancreatic cancer, immunotherapy and targeted therapies have not brought about the therapeutic revolution that has been observed in other malignancies. Among the reasons to explain this difference is the possibly crucial role played by the pancreatic tumor microenvironment, which has unique features and is different from that of other neoplasms. The aim of this review is to provide a comprehensive overview of the distinctive tumor immune microenvironment of pancreatic cancer and to summarize existing data about the use of immunotherapy and immune biomarkers in this cancer. Abstract The advent of immunotherapy and targeted therapies has dramatically changed the outcomes of patients affected by many malignancies. Pancreatic cancer (PC) remains one the few tumors that is not treated with new generation therapies, as chemotherapy still represents the only effective therapeutic strategy in advanced-stage disease. Agents aiming to reactivate the host immune system against cancer cells, such as those targeting immune checkpoints, failed to demonstrate significant activity, despite the success of these treatments in other tumors. In many cases, the proportion of patients who derived benefits in early-phase trials was too small and unpredictable to justify larger studies. The population of PC patients with high microsatellite instability/mismatch repair deficiency is currently the only population that may benefit from immunotherapy; nevertheless, the prevalence of these alterations is too low to determine a real change in the treatment scenario of this tumor. The reasons for the unsuccess of immunotherapy may lie in the extremely peculiar tumor microenvironment, including distinctive immune composition and cross talk between different cells. These unique features may also explain why the biomarkers commonly used to predict immunotherapy efficacy in other tumors seem to be useless in PC. In the current paper, we provide a comprehensive and up-to-date review of immunotherapy in PC, from the analysis of the tumor immune microenvironment to immune biomarkers and treatment outcomes, with the aim to highlight that simply transferring the knowledge acquired on immunotherapy in other tumors might not be a successful strategy in patients affected by PC.
Collapse
Affiliation(s)
- Alessandro Di Federico
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, 40138 Bologna, Italy; (M.M.); (R.P.); (R.C.); (A.D.G.); (M.D.M.); (A.P.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
- Correspondence:
| | - Mirta Mosca
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, 40138 Bologna, Italy; (M.M.); (R.P.); (R.C.); (A.D.G.); (M.D.M.); (A.P.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
| | - Rachele Pagani
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, 40138 Bologna, Italy; (M.M.); (R.P.); (R.C.); (A.D.G.); (M.D.M.); (A.P.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
| | - Riccardo Carloni
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, 40138 Bologna, Italy; (M.M.); (R.P.); (R.C.); (A.D.G.); (M.D.M.); (A.P.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
| | - Giorgio Frega
- Osteoncology, Bone and Soft Tissue Sarcomas, and Innovative Therapies, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy;
| | - Andrea De Giglio
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, 40138 Bologna, Italy; (M.M.); (R.P.); (R.C.); (A.D.G.); (M.D.M.); (A.P.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
| | - Alessandro Rizzo
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico “Don Tonino Bello”, I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy;
| | - Dalia Ricci
- Departmental Unit of Medical Oncology, ASL BA, 20142 Milan, Italy;
| | - Simona Tavolari
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
| | - Mariacristina Di Marco
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, 40138 Bologna, Italy; (M.M.); (R.P.); (R.C.); (A.D.G.); (M.D.M.); (A.P.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
| | - Andrea Palloni
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, 40138 Bologna, Italy; (M.M.); (R.P.); (R.C.); (A.D.G.); (M.D.M.); (A.P.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
| | - Giovanni Brandi
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, 40138 Bologna, Italy; (M.M.); (R.P.); (R.C.); (A.D.G.); (M.D.M.); (A.P.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
| |
Collapse
|
49
|
Ratnayake GM, Laskaratos FM, Mandair D, Caplin ME, Rombouts K, Toumpanakis C. What Causes Desmoplastic Reaction in Small Intestinal Neuroendocrine Neoplasms? Curr Oncol Rep 2022; 24:1281-1286. [PMID: 35554845 PMCID: PMC9474437 DOI: 10.1007/s11912-022-01211-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/04/2021] [Indexed: 11/30/2022]
Abstract
Purpose of Review Mesenteric desmoplasia in small intestinal neuroendocrine neoplasms (SINENs) is associated with increased morbidity and mortality. In this paper, we discuss the development of desmoplasia in SINENs. Recent Findings The fibrotic reactions associated with these tumours could be limited to the loco-regional environment of the tumour and/or at distant sites. Mesenteric fibrotic mass forms around a local lymph node. Formation of desmoplasia is mediated by interactions between the neoplastic cells and its microenvironment via number of profibrotic mediators and signalling pathways. Profibrotic molecules that are mainly involved in the desmoplastic reaction include serotonin, TGFβ (transforming growth factor β) and CTGF (connective tissue growth factor), although there is some evidence to suggest that there are a number of other molecules involved in this process. Summary Desmoplasia is a result of autocrine and paracrine effects of multiple molecules and signalling pathways. However, more research is needed to understand these mechanisms and to develop targeted therapy to minimise desmoplasia.
Collapse
Affiliation(s)
- Gowri M Ratnayake
- Neuroendocrine Tumour Unit - ENETS Centre of Excellence, Royal Free Hospital, London, NW3 2QG, UK
| | | | - Dalvinder Mandair
- Neuroendocrine Tumour Unit - ENETS Centre of Excellence, Royal Free Hospital, London, NW3 2QG, UK
| | - Martyn E Caplin
- Neuroendocrine Tumour Unit - ENETS Centre of Excellence, Royal Free Hospital, London, NW3 2QG, UK
| | - Krista Rombouts
- Regenerative Medicine & Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, NW3 2PF, UK
| | - Christos Toumpanakis
- Neuroendocrine Tumour Unit - ENETS Centre of Excellence, Royal Free Hospital, London, NW3 2QG, UK.
| |
Collapse
|
50
|
Rovera C, Berestjuk I, Lecacheur M, Tavernier C, Diazzi S, Pisano S, Irondelle M, Mallavialle A, Albrengues J, Gaggioli C, Girard CA, Passeron T, Deckert M, Tartare-Deckert S, Prod'homme V. Secretion of IL1 by Dedifferentiated Melanoma Cells Inhibits JAK1-STAT3-Driven Actomyosin Contractility of Lymph Node Fibroblastic Reticular Cells. Cancer Res 2022; 82:1774-1788. [PMID: 35502542 DOI: 10.1158/0008-5472.can-21-0501] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 02/02/2022] [Accepted: 02/18/2022] [Indexed: 11/16/2022]
Abstract
Fibroblastic reticular cells (FRC) are immunologically specialized myofibroblasts that control the elasticity of the lymph node, in part through their contractile properties. Swelling of tumor-draining lymph nodes is a hallmark of lymphophilic cancers such as cutaneous melanoma. Melanoma displays high intratumoral heterogeneity with the coexistence of melanoma cells with variable differentiation phenotypes from melanocytic to dedifferentiated states. Factors secreted by melanoma cells promote premetastatic lymph node reprograming and tumor spreading. Elucidating the impact of the melanoma secretome on FRC could help identify approaches to prevent metastasis. Here we show that melanocytic and dedifferentiated melanoma cells differentially impact the FRC contractile phenotype. Factors secreted by dedifferentiated cells, but not by melanocytic cells, strongly inhibited actomyosin-dependent contractile forces of FRC by decreasing the activity of the RHOA-RHO-kinase (ROCK) pathway and the mechano-responsive transcriptional coactivator Yes1 associated transcriptional regulator (YAP). Transcriptional profiling and biochemical analyses indicated that actomyosin cytoskeleton relaxation in FRC is driven by inhibition of the JAK1-STAT3 pathway. This FRC relaxation was associated with increased FRC proliferation and activation and with elevated tumor invasion in vitro. The secretome of dedifferentiated melanoma cells also modulated the biomechanical properties of distant lymph node in premetastatic mouse models. Finally, IL1 produced by dedifferentiated cells was involved in the inhibition of FRC contractility. These data highlight the role of the JAK1-STAT3 and YAP pathways in spontaneous contractility of resting FRC. They also suggest that dedifferentiated melanoma cells specifically target FRC biomechanical properties to favor tumor spreading in the premetastatic lymph node niche. Targeting this remote communication could be an effective strategy to prevent metastatic spread of the disease. SIGNIFICANCE Communication between dedifferentiated melanoma cells and lymph node fibroblasts reprograms the biomechanical properties of the premetastatic lymph node niche to promote tumor invasion. See related commentary by Lund, p. 1692.
Collapse
Affiliation(s)
- Christopher Rovera
- Mediterranean Center for Molecular Medicine (C3M), Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Nice, France
- Team 11, Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Ilona Berestjuk
- Mediterranean Center for Molecular Medicine (C3M), Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Nice, France
- Team 11, Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Margaux Lecacheur
- Mediterranean Center for Molecular Medicine (C3M), Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Nice, France
- Team 11, Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Cassandre Tavernier
- Mediterranean Center for Molecular Medicine (C3M), Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Nice, France
- Team 11, Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Serena Diazzi
- Mediterranean Center for Molecular Medicine (C3M), Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Nice, France
- Team 11, Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Sabrina Pisano
- Institute for Research on Cancer and Aging Nice (IRCAN), Université Côte d'Azur, CNRS, Institut National de la Santé et de la Recherche Médicale (Inserm), Nice, France
| | - Marie Irondelle
- Mediterranean Center for Molecular Medicine (C3M), Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Nice, France
| | - Aude Mallavialle
- Mediterranean Center for Molecular Medicine (C3M), Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Nice, France
- Team 11, Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Jean Albrengues
- Institute for Research on Cancer and Aging Nice (IRCAN), Université Côte d'Azur, CNRS, Institut National de la Santé et de la Recherche Médicale (Inserm), Nice, France
| | - Cédric Gaggioli
- Institute for Research on Cancer and Aging Nice (IRCAN), Université Côte d'Azur, CNRS, Institut National de la Santé et de la Recherche Médicale (Inserm), Nice, France
| | - Christophe A Girard
- Mediterranean Center for Molecular Medicine (C3M), Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Nice, France
- Team 11, Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Thierry Passeron
- Team 12, Mediterranean Center for Molecular Medicine (C3M), Université Côte d'Azur, Institut National de la Santé et de la Recherche Médicale (Inserm), Nice, France
- Department of Dermatology, Université Côte d'Azur, CHU Nice, Nice, France
| | - Marcel Deckert
- Mediterranean Center for Molecular Medicine (C3M), Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Nice, France
- Team 11, Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Sophie Tartare-Deckert
- Mediterranean Center for Molecular Medicine (C3M), Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Nice, France
- Team 11, Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Virginie Prod'homme
- Mediterranean Center for Molecular Medicine (C3M), Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Nice, France
- Team 11, Equipe labellisée Ligue Contre le Cancer, Nice, France
| |
Collapse
|