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Yadav M, Sharma A, Patne K, Tabasum S, Suryavanshi J, Rawat L, Machaalani M, Eid M, Singh RP, Choueiri TK, Pal S, Sabarwal A. AXL signaling in cancer: from molecular insights to targeted therapies. Signal Transduct Target Ther 2025; 10:37. [PMID: 39924521 PMCID: PMC11808115 DOI: 10.1038/s41392-024-02121-7] [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: 07/22/2024] [Revised: 11/02/2024] [Accepted: 12/19/2024] [Indexed: 02/11/2025] Open
Abstract
AXL, a member of the TAM receptor family, has emerged as a potential target for advanced-stage human malignancies. It is frequently overexpressed in different cancers and plays a significant role in various tumor-promoting pathways, including cancer cell proliferation, invasion, metastasis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, DNA damage response, acquired therapeutic resistance, immunosuppression, and inflammatory responses. Beyond oncology, AXL also facilitates viral infections, including SARS-CoV-2 and Zika highlighting its importance in both cancer and virology. In preclinical models, small-molecule kinase inhibitors targeting AXL have shown promising anti-tumorigenic potential. This review primarily focuses on the induction, regulation and biological functions of AXL in mediating these tumor-promoting pathways. We discuss a range of therapeutic strategies, including recently developed small-molecule tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and antibody-drug conjugates (ADCs), anti-AXL-CAR, and combination therapies. These interventions are being examined in both preclinical and clinical studies, offering the potential for improved drug sensitivity and therapeutic efficacy. We further discuss the mechanisms of acquired therapeutic resistance, particularly the crosstalk between AXL and other critical receptor tyrosine kinases (RTKs) such as c-MET, EGFR, HER2/HER3, VEGFR, PDGFR, and FLT3. Finally, we highlight key research areas that require further exploration to enhance AXL-mediated therapeutic approaches for improved clinical outcomes.
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Affiliation(s)
- Monika Yadav
- Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, Delhi, India
- Laboratory of Nanotechnology and Chemical Biology, Regional Center for Biotechnology, Faridabad, Haryana, India
| | - Akansha Sharma
- Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Ketki Patne
- Chromatin Remodeling Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Saba Tabasum
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Jyoti Suryavanshi
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA
| | - Laxminarayan Rawat
- Harvard Medical School, Boston, MA, USA
- Division of Nephrology, Boston Children's Hospital, Boston, MA, USA
| | - Marc Machaalani
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Marc Eid
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Rana P Singh
- Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, Delhi, India
| | - Toni K Choueiri
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Soumitro Pal
- Harvard Medical School, Boston, MA, USA.
- Division of Nephrology, Boston Children's Hospital, Boston, MA, USA.
| | - Akash Sabarwal
- Harvard Medical School, Boston, MA, USA.
- Division of Nephrology, Boston Children's Hospital, Boston, MA, USA.
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Yao H, Ren Y, Wu F, Cao L, Liu J, Yan M, Li X. The Discovery of a Novel AXL/Triple Angiokinase Inhibitor Based on 6-Chloro-Substituted Indolinone and Side Chain Methyl Substitution Inhibiting Pancreatic Cancer Growth and Metastasis. J Med Chem 2025; 68:465-490. [PMID: 39711508 DOI: 10.1021/acs.jmedchem.4c02130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
In this study, we discovered and identified a novel AXL/triple angiokinase inhibitor 11b by rational structural modification based on the structure of triple angiokinase inhibitor Nintedanib. We found that 11b potently inhibited AXL expression with the IC50 value of 3.75 nM and possessed similar inhibitory activity on KDR as Nintedanib. In the assay of antiproliferative activity on NIH/3T3, HUVEC, Bxpc-3, and MDA-MB-231, 11b showed better inhibitory ability than Nintedanib. In pancreatic cancer xenograft mouse models from Bxpc-3 cells, even when the dosage was halved, 11b exhibited better or comparable effects to Nintedanib (tumor growth inhibition (TGI) based on tumor volume change during the trial or tumor weight). Notably, we also found that 11b prohibited Bxpc-3 resulted lung metastasis by inhibiting its epithelial-mesenchymal transition (EMT) process. Another mechanism assay also proved that 11b inhibited the function of blood vessels and fibroblasts, promoted apoptosis of cancer and fibroblast cells, and exhibited low toxicity and good metabolic stability.
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Affiliation(s)
- Han Yao
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Yuanyuan Ren
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Feng Wu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Longcai Cao
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China
| | - Jiadai Liu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Ming Yan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Xingshu Li
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
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Gao S, Wang Y, Huang M, Guo J, Wu Z, Li J. Knockdown of Gas6 Exerts Anti-Esophageal Cancer Effects by Inhibiting the PI3K/AKT Pathway. Curr Issues Mol Biol 2024; 46:11349-11358. [PMID: 39451556 PMCID: PMC11506498 DOI: 10.3390/cimb46100676] [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: 09/13/2024] [Revised: 10/06/2024] [Accepted: 10/11/2024] [Indexed: 10/26/2024] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a malignant tumor of the digestive tract with strong migratory and invasive abilities. Gas6 is closely associated with the progression of many malignant tumors; however, the role of Gas6 in the progression of esophageal cancer is unclear. Here, we report that the knockdown of Gas6 inhibited esophageal cancer cell proliferation, migration, and invasion. In addition, Gas6 knockdown downregulated the levels of P-PI3K and P-AKT. Taken together, the findings confirm that Gas6 knockdown can inhibit esophageal cancer progression and can exert anti-tumor effects on esophageal cancer through the PI3K/AKT pathway.
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Affiliation(s)
- Shuang Gao
- College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang 050017, China; (S.G.); (Y.W.); (M.H.); (J.G.)
- Institute of Integrated Traditional Chinese and Western Medicine, Hebei Medical University, Shijiazhuang 050017, China
| | - Yu Wang
- College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang 050017, China; (S.G.); (Y.W.); (M.H.); (J.G.)
- Institute of Integrated Traditional Chinese and Western Medicine, Hebei Medical University, Shijiazhuang 050017, China
| | - Ming Huang
- College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang 050017, China; (S.G.); (Y.W.); (M.H.); (J.G.)
- Institute of Integrated Traditional Chinese and Western Medicine, Hebei Medical University, Shijiazhuang 050017, China
| | - Jianxin Guo
- College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang 050017, China; (S.G.); (Y.W.); (M.H.); (J.G.)
| | - Zhongbing Wu
- College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang 050017, China; (S.G.); (Y.W.); (M.H.); (J.G.)
| | - Jing Li
- College of Integrated Chinese and Western Medicine, Hebei Medical University, Shijiazhuang 050017, China; (S.G.); (Y.W.); (M.H.); (J.G.)
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Wang L, An Y, Wei X, Huang X, Tu Y, Qiao L, Zhu W. In silico screening combined with bioactivity evaluation to identify AMI-1 as a novel anticancer compound by targeting AXL. J Biomol Struct Dyn 2024; 42:7686-7698. [PMID: 37691424 DOI: 10.1080/07391102.2023.2255654] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 07/20/2023] [Indexed: 09/12/2023]
Abstract
Recently, some studies have proven that AXL plays a crucial role in the drug resistance of tumors. At present, no AXL inhibitors on the market and it is essential to discover novel compounds targeting AXL to overcome resistance. In this work, based on the anchor structure, 21,313 compounds were obtained by substructure search from more than 400,000 compounds. Then, the Qvina and Ledock were selected for virtual screening to obtain 17 compounds. Next, four compounds (ARRY614, AMI-1, NG25, and Butein) were selected for bioactivity evaluation after hydrogen bond and cluster analysis. Further activity evaluation suggested that the compound AMI-1 is a novel AXL inhibitor with an IC50 value of 1.13 uM. In addition, molecular dynamics simulation demonstrated that compound AMI-1 contained lower binding energy and more key residues than the other three compounds, showing the best inhibitory activity against AXL. Finally, further MM/PBSA prediction showed that AMI-1 is more sensitive to mutant protein 3IKA than wildtype protein 1M17, which means that the AMI-1 may be helpful to overcome the resistance of EGFRT790M mutations. In conclusion, this work successfully discovered a novel compound with moderate inhibitory activity against AXL by a drug discovery workflow, which also could be applied to discover active compounds for other targets quickly.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Linxiao Wang
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
| | - Yufeng An
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
| | - Xiongpiao Wei
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
| | - Xiaoling Huang
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
| | - Yuanbiao Tu
- Cancer Research Center, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Lukai Qiao
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
| | - Wufu Zhu
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China
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Apostolo D, D’Onghia D, Nerviani A, Ghirardi GM, Sola D, Perazzi M, Tonello S, Colangelo D, Sainaghi PP, Bellan M. Could Gas6/TAM Axis Provide Valuable Insights into the Pathogenesis of Systemic Sclerosis? Curr Issues Mol Biol 2024; 46:7486-7504. [PMID: 39057085 PMCID: PMC11275301 DOI: 10.3390/cimb46070444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 07/09/2024] [Accepted: 07/12/2024] [Indexed: 07/28/2024] Open
Abstract
Systemic sclerosis (SSc) is a connective tissue disorder characterized by microvascular injury, extracellular matrix deposition, autoimmunity, inflammation, and fibrosis. The clinical complexity and high heterogeneity of the disease make the discovery of potential therapeutic targets difficult. However, the recent progress in the comprehension of its pathogenesis is encouraging. Growth Arrest-Specific 6 (Gas6) and Tyro3, Axl, and MerTK (TAM) receptors are involved in multiple biological processes, including modulation of the immune response, phagocytosis, apoptosis, fibrosis, inflammation, cancer development, and autoimmune disorders. In the present manuscript, we review the current evidence regarding SSc pathogenesis and the role of the Gas6/TAM system in several human diseases, suggesting its likely contribution in SSc and highlighting areas where further research is necessary to fully comprehend the role of TAM receptors in this condition. Indeed, understanding the involvement of TAM receptors in SSc, which is currently unknown, could provide valuable insights for novel potential therapeutic targets.
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Affiliation(s)
- Daria Apostolo
- Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy; (D.A.); (D.D.); (D.S.); (M.P.); (S.T.); (P.P.S.); (M.B.)
- Centre for Experimental Medicine and Rheumatology, Barts and The London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London E1 4NS, UK;
| | - Davide D’Onghia
- Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy; (D.A.); (D.D.); (D.S.); (M.P.); (S.T.); (P.P.S.); (M.B.)
| | - Alessandra Nerviani
- Centre for Experimental Medicine and Rheumatology, Barts and The London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London E1 4NS, UK;
| | - Giulia Maria Ghirardi
- Centre for Experimental Medicine and Rheumatology, Barts and The London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London E1 4NS, UK;
| | - Daniele Sola
- Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy; (D.A.); (D.D.); (D.S.); (M.P.); (S.T.); (P.P.S.); (M.B.)
- IRCCS Istituto Auxologico Italiano, UO General Medicine, 28824 Oggebbio, Italy
| | - Mattia Perazzi
- Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy; (D.A.); (D.D.); (D.S.); (M.P.); (S.T.); (P.P.S.); (M.B.)
- Internal Medicine and Rheumatology Unit, A.O.U. Maggiore della Carità, 28100 Novara, Italy
| | - Stelvio Tonello
- Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy; (D.A.); (D.D.); (D.S.); (M.P.); (S.T.); (P.P.S.); (M.B.)
| | - Donato Colangelo
- Department of Health Sciences, Pharmacology, University of Piemonte Orientale (UPO), 28100 Novara, Italy;
| | - Pier Paolo Sainaghi
- Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy; (D.A.); (D.D.); (D.S.); (M.P.); (S.T.); (P.P.S.); (M.B.)
- Internal Medicine and Rheumatology Unit, A.O.U. Maggiore della Carità, 28100 Novara, Italy
- Center on Autoimmune and Allergic Diseases (CAAD), University of Piemonte Orientale, 28100 Novara, Italy
| | - Mattia Bellan
- Department of Translational Medicine, University of Piemonte Orientale (UPO), 28100 Novara, Italy; (D.A.); (D.D.); (D.S.); (M.P.); (S.T.); (P.P.S.); (M.B.)
- Internal Medicine and Rheumatology Unit, A.O.U. Maggiore della Carità, 28100 Novara, Italy
- Center on Autoimmune and Allergic Diseases (CAAD), University of Piemonte Orientale, 28100 Novara, Italy
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Luan YZ, Wang CC, Yu CY, Chang YC, Sung WW, Tsai MC. The Therapeutic Role of NPS-1034 in Pancreatic Ductal Adenocarcinoma as Monotherapy and in Combination with Chemotherapy. Int J Mol Sci 2024; 25:6919. [PMID: 39000029 PMCID: PMC11241054 DOI: 10.3390/ijms25136919] [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: 05/17/2024] [Revised: 06/15/2024] [Accepted: 06/20/2024] [Indexed: 07/14/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge in terms of diagnosis and treatment, with limited therapeutic options and a poor prognosis. This study explored the potential therapeutic role of NPS-1034, a kinase inhibitor targeting MET and AXL, in PDAC. The investigation included monotherapy with NPS-1034 and its combination with the commonly prescribed chemotherapy agents, fluorouracil and oxaliplatin. Our study revealed that NPS-1034 induces cell death and reduces the viability and clonogenicity of PDAC cells in a dose-dependent manner. Furthermore, NPS-1034 inhibits the migration of PDAC cells by suppressing MET/PI3K/AKT axis-induced epithelial-to-mesenchymal transition (EMT). The combination of NPS-1034 with fluorouracil or oxaliplatin demonstrated a synergistic effect, significantly reducing cell viability and inducing tumor cell apoptosis compared to monotherapies. Mechanistic insights provided by next-generation sequencing indicated that NPS-1034 modulates immune responses by inducing type I interferon and tumor necrosis factor production in PDAC cells. This suggests a broader role for NPS-1034 beyond MET and AXL inhibition, positioning it as a potential immunity modulator. Overall, these findings highlight the anticancer potential of NPS-1034 in PDAC treatment in vitro, both as a monotherapy and in combination with traditional chemotherapy, offering a promising avenue for further in vivo investigation before clinical exploration.
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Affiliation(s)
- Yu-Ze Luan
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (Y.-Z.L.); (C.-C.W.); (C.-Y.Y.); (Y.-C.C.)
| | - Chi-Chih Wang
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (Y.-Z.L.); (C.-C.W.); (C.-Y.Y.); (Y.-C.C.)
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Chia-Ying Yu
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (Y.-Z.L.); (C.-C.W.); (C.-Y.Y.); (Y.-C.C.)
- Department of Urology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| | - Ya-Chuan Chang
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (Y.-Z.L.); (C.-C.W.); (C.-Y.Y.); (Y.-C.C.)
- Department of Urology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| | - Wen-Wei Sung
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (Y.-Z.L.); (C.-C.W.); (C.-Y.Y.); (Y.-C.C.)
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
- Department of Urology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| | - Ming-Chang Tsai
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (Y.-Z.L.); (C.-C.W.); (C.-Y.Y.); (Y.-C.C.)
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
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Apostolo D, Ferreira LL, Vincenzi F, Vercellino N, Minisini R, Latini F, Ferrari B, Burlone ME, Pirisi M, Bellan M. From MASH to HCC: the role of Gas6/TAM receptors. Front Immunol 2024; 15:1332818. [PMID: 38298195 PMCID: PMC10827955 DOI: 10.3389/fimmu.2024.1332818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 01/02/2024] [Indexed: 02/02/2024] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is the replacement term for what used to be called nonalcoholic steatohepatitis (NASH). It is characterized by inflammation and injury of the liver in the presence of cardiometabolic risk factors and may eventually result in the development of hepatocellular carcinoma (HCC), the most common form of primary liver cancer. Several pathogenic mechanisms are involved in the transition from MASH to HCC, encompassing metabolic injury, inflammation, immune dysregulation and fibrosis. In this context, Gas6 (Growth Arrest-Specific 6) and TAM (Tyro3, Axl, and MerTK) receptors may play important roles. The Gas6/TAM family is involved in the modulation of inflammation, lipid metabolism, fibrosis, tumor progression and metastasis, processes which play an important role in the pathophysiology of acute and chronic liver diseases. In this review, we discuss MASH-associated HCC and the potential involvement of the Gas6/TAM system in disease development and progression. In addition, since therapeutic strategies for MASH and HCC are limited, we also speculate regarding possible future treatments involving the targeting of Gas6 or TAM receptors.
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Affiliation(s)
- Daria Apostolo
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Luciana L. Ferreira
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Federica Vincenzi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Nicole Vercellino
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Federico Latini
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Barbara Ferrari
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Michela E. Burlone
- Department of Internal Medicine, Azienda Ospedaliero-Universitaria Maggiore Della Carità, Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Department of Internal Medicine, Azienda Ospedaliero-Universitaria Maggiore Della Carità, Novara, Italy
- Center on Autoimmune and Allergic Diseases, Università del Piemonte Orientale, Novara, Italy
| | - Mattia Bellan
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Department of Internal Medicine, Azienda Ospedaliero-Universitaria Maggiore Della Carità, Novara, Italy
- Center on Autoimmune and Allergic Diseases, Università del Piemonte Orientale, Novara, Italy
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Kim TH, Lee D, Oh HJ, Ham IH, Lee DM, Lee Y, Zhang Z, Ke D, Hur H. Targeting GAS6/AXL signaling improves the response to immunotherapy by restoring the anti-immunogenic tumor microenvironment in gastric cancer. Life Sci 2023; 335:122230. [PMID: 37952835 DOI: 10.1016/j.lfs.2023.122230] [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: 07/01/2023] [Revised: 09/28/2023] [Accepted: 10/29/2023] [Indexed: 11/14/2023]
Abstract
AIMS Immunotherapy has shown remarkable effects on several malignancies; however, its impact on gastric cancers has been limited. Therefore, a novel strategy to overcome resistance to immunotherapy is required. In this study, we compared the gene expression profiles of two murine GC cell lines that exhibited different effects on tumor immunity. The functions of specific genes related to negative tumor immunity and the impact of a specific inhibitor were evaluated in syngeneic GC mouse models. MATERIALS AND METHODS RT-PCR and Western blotting validated Gas6 and AXL expression in murine cell lines. RT-PCR compared YTN16 and YTN3 GC cell's impact on T cell activation. AXL, the receptor for GAS6 in YTN16, was validated by western blotting. Gas6 was inhibited in YTN16 cells using shRNA, and then the gene expression pattern, effects to T cell activation, and tumor growth were assessed. YTN16 cells were injected into mice and treated with CCB-3233, anti-PD-1 antibody, or both. Immunohistochemistry and flow cytometry evaluated tumor-infiltrating immune cells. KEY FINDINGS YTN16 cells expressed more Gas6 and had reduced T cell activation compared to YTN3 cells. AXL activation was higher in YTN16. CCB-3233 reduced AXL phosphorylation. Knocking down Gas6 in YTN16 reduced immunosuppression-related genes and increased tumor-infiltrating T cells. Combined CCB-3233 and anti-PD-1 treatment reduced tumor growth and increased T-cell infiltration. Human GC data revealed a negative correlation between GAS6 and immune activation-related genes. SIGNIFICANCE The GAS6/AXL pathway contributes to immunotherapy resistance in GC. Targeting this pathway may be a novel therapeutic strategy.
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Affiliation(s)
- Tae Hoon Kim
- Cancer Biology Graduate Program, Ajou University School of Medicine, Suwon, Republic of Korea; Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Dagyeong Lee
- AI-Super Convergence KIURI Translational Research Center, Ajou University School of Medicine, Suwon, Republic of Korea; Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hye Jeong Oh
- Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - In-Hye Ham
- Inflamm-Aging Translational Research Center, Ajou University School of Medicine, Suwon, Republic of Korea; Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Dong Min Lee
- Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Yulim Lee
- Cancer Biology Graduate Program, Ajou University School of Medicine, Suwon, Republic of Korea; Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Zhang Zhang
- School of Pharmacy, Jinan University, Guangzhou, China
| | - Ding Ke
- School of Pharmacy, Jinan University, Guangzhou, China
| | - Hoon Hur
- Cancer Biology Graduate Program, Ajou University School of Medicine, Suwon, Republic of Korea; Inflamm-Aging Translational Research Center, Ajou University School of Medicine, Suwon, Republic of Korea; Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea.
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9
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Bitter EE, Skidmore J, Allen CI, Erickson RI, Morris RM, Mortimer T, Meade A, Brog R, Phares T, Townsend M, Pickett BE, O’Neill KL. TK1 expression influences pathogenicity by cell cycle progression, cellular migration, and cellular survival in HCC 1806 breast cancer cells. PLoS One 2023; 18:e0293128. [PMID: 38033034 PMCID: PMC10688958 DOI: 10.1371/journal.pone.0293128] [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: 03/20/2023] [Accepted: 10/05/2023] [Indexed: 12/02/2023] Open
Abstract
Breast cancer is the most common cancer diagnosis worldwide accounting for 1 out of every 8 cancer diagnoses. The elevated expression of Thymidine Kinase 1 (TK1) is associated with more aggressive tumor grades, including breast cancer. Recent studies indicate that TK1 may be involved in cancer pathogenesis; however, its direct involvement in breast cancer has not been identified. Here, we evaluate potential pathogenic effects of elevated TK1 expression by comparing HCC 1806 to HCC 1806 TK1-knockdown cancer cells (L133). Transcriptomic profiles of HCC 1806 and L133 cells showed cell cycle progression, apoptosis, and invasion as potential pathogenic pathways affected by TK1 expression. Subsequent in-vitro studies confirmed differences between HCC 1806 and L133 cells in cell cycle phase progression, cell survival, and cell migration. Expression comparison of several factors involved in these pathogenic pathways between HCC 1806 and L133 cells identified p21 and AKT3 transcripts were significantly affected by TK1 expression. Creation of a protein-protein interaction map of TK1 and the pathogenic factors we evaluated predict that the majority of factors evaluated either directly or indirectly interact with TK1. Our findings argue that TK1 elevation directly increases HCC 1806 cell pathogenicity and is likely occurring by p21- and AKT3-mediated mechanisms to promote cell cycle arrest, cellular migration, and cellular survival.
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Affiliation(s)
- Eliza E. Bitter
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, Utah, United States of America
- Thunder Biotech Inc., Provo, Utah, United States of America
| | - Jonathan Skidmore
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, Utah, United States of America
| | - Carolyn I. Allen
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, Utah, United States of America
| | - Rachel I. Erickson
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, Utah, United States of America
| | - Rachel M. Morris
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, Utah, United States of America
| | - Toni Mortimer
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, Utah, United States of America
| | - Audrey Meade
- Thunder Biotech Inc., Provo, Utah, United States of America
| | - Rachel Brog
- Thunder Biotech Inc., Provo, Utah, United States of America
| | - Tim Phares
- Thunder Biotech Inc., Provo, Utah, United States of America
| | - Michelle Townsend
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, Utah, United States of America
- Thunder Biotech Inc., Provo, Utah, United States of America
| | - Brett E. Pickett
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, Utah, United States of America
| | - Kim L. O’Neill
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, Utah, United States of America
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10
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DeRyckere D, Huelse JM, Earp HS, Graham DK. TAM family kinases as therapeutic targets at the interface of cancer and immunity. Nat Rev Clin Oncol 2023; 20:755-779. [PMID: 37667010 DOI: 10.1038/s41571-023-00813-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/07/2023] [Indexed: 09/06/2023]
Abstract
Novel treatment approaches are needed to overcome innate and acquired mechanisms of resistance to current anticancer therapies in cancer cells and the tumour immune microenvironment. The TAM (TYRO3, AXL and MERTK) family receptor tyrosine kinases (RTKs) are potential therapeutic targets in a wide range of cancers. In cancer cells, TAM RTKs activate signalling pathways that promote cell survival, metastasis and resistance to a variety of chemotherapeutic agents and targeted therapies. TAM RTKs also function in innate immune cells, contributing to various mechanisms that suppress antitumour immunity and promote resistance to immune-checkpoint inhibitors. Therefore, TAM antagonists provide an unprecedented opportunity for both direct and immune-mediated therapeutic activity provided by inhibition of a single target, and are likely to be particularly effective when used in combination with other cancer therapies. To exploit this potential, a variety of agents have been designed to selectively target TAM RTKs, many of which have now entered clinical testing. This Review provides an essential guide to the TAM RTKs for clinicians, including an overview of the rationale for therapeutic targeting of TAM RTKs in cancer cells and the tumour immune microenvironment, a description of the current preclinical and clinical experience with TAM inhibitors, and a perspective on strategies for continued development of TAM-targeted agents for oncology applications.
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Affiliation(s)
- Deborah DeRyckere
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA
- Department of Paediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Justus M Huelse
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA
- Department of Paediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - H Shelton Earp
- Department of Medicine, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
- Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Douglas K Graham
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.
- Department of Paediatrics, Emory University School of Medicine, Atlanta, GA, USA.
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11
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Pidkovka N, Belkhiri A. Altered expression of AXL receptor tyrosine kinase in gastrointestinal cancers: a promising therapeutic target. Front Oncol 2023; 13:1079041. [PMID: 37469409 PMCID: PMC10353021 DOI: 10.3389/fonc.2023.1079041] [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: 10/24/2022] [Accepted: 05/31/2023] [Indexed: 07/21/2023] Open
Abstract
Gastrointestinal (GI) cancers that include all cancers of the digestive tract organs are generally associated with obesity, lack of exercising, smoking, poor diet, and heavy alcohol consumption. Treatment of GI cancers typically involves surgery followed by chemotherapy and/or radiation. Unfortunately, intrinsic or acquired resistance to these therapies underscore the need for more effective targeted therapies that have been proven in other malignancies. The aggressive features of GI cancers share distinct signaling pathways that are connected to each other by the overexpression and activation of AXL receptor tyrosine kinase. Several preclinical and clinical studies involving anti-AXL antibodies and small molecule AXL kinase inhibitors to test their efficacy in solid tumors, including GI cancers, have been recently carried out. Therefore, AXL may be a promising therapeutic target for overcoming the shortcomings of standard therapies in GI cancers.
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Affiliation(s)
- Nataliya Pidkovka
- Department of Health Science, South College, Nashville, TN, United States
| | - Abbes Belkhiri
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, United States
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, United States
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12
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Mikuteit M, Zschäbitz S, Stöhr C, Herrmann E, Polifka I, Agaimy A, Trojan L, Ströbel P, Becker F, Wülfing C, Barth P, Stöckle M, Staehler M, Stief C, Haferkamp A, Hohenfellner M, Duensing S, Macher-Göppinger S, Wullich B, Noldus J, Brenner W, Roos F, Walter B, Otto W, Burger M, Erlmeier M, Schrader AJ, Hartmann A, Erlmeier F, Steffens S. Evaluation of Gas 6 as a Prognostic Marker in Papillary Renal Cell Carcinoma. Urol Int 2023; 107:713-722. [PMID: 37348477 PMCID: PMC10413799 DOI: 10.1159/000529898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 02/06/2023] [Indexed: 06/24/2023]
Abstract
INTRODUCTION Growth arrest-specific protein 6 (Gas 6) is a ligand that plays a role in proliferation and migration of cells. For several tumor entities, high levels of Gas 6 are associated with poorer survival. We examined the prognostic role of Gas 6 in renal cell carcinoma (RCC), especially in papillary RCC (pRCC), which is still unclear. METHODS The patients' sample collection is a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of Gas 6 was determined by immunohistochemistry. RESULTS In total, Gas 6 staining was evaluable in 180 of 240 type 1 and 110 of 128 type 2 pRCC cases. Kaplan-Meier analysis disclosed no significant difference in 5-year overall survival for all pRCC nor either subtype. Also, Gas+ and Gas- groups did not significantly differ in any tumor or patient characteristics. CONCLUSION Gas 6 was not found to be an independent prognostic marker in pRCC. Future studies are warranted to determine if Gas 6 plays a role as prognostic marker or therapeutic target in pRCC.
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Affiliation(s)
- Marie Mikuteit
- Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
- Dean’s Office, Curriculum Development, Hannover Medical School, Hannover, Germany
| | - Stefanie Zschäbitz
- Department of Medical Oncology, National Center of Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Christine Stöhr
- Institute of Pathology, University Hospital Erlangen-Nuernberg, Friedrich Alexander University (FAU), Erlangen, Germany
| | - Edwin Herrmann
- Department of Urology, University Hospital Muenster, Muenster, Germany
| | - Iris Polifka
- Institute of Pathology, University Hospital Erlangen-Nuernberg, Friedrich Alexander University (FAU), Erlangen, Germany
| | - Abbas Agaimy
- Institute of Pathology, University Hospital Erlangen-Nuernberg, Friedrich Alexander University (FAU), Erlangen, Germany
| | - Lutz Trojan
- Department of Urology, University Hospital Göttingen, Göttingen, Germany
| | - Philipp Ströbel
- Department of Pathology, University Hospital Göttingen, Göttingen, Germany
| | - Frank Becker
- Department of Urology and Pediatric Urology, University of Saarland (UKS), Homburg, Germany
| | - Christian Wülfing
- Institute of Pathology, University Hospital Göttingen, Göttingen, Germany
| | - Peter Barth
- Department of Urology, University of Marburg, Marburg, Germany
| | - Michael Stöckle
- Department of Urology and Pediatric Urology, University of Saarland (UKS), Homburg, Germany
| | - Michael Staehler
- Department of Urology, University Hospital Munich, Munich, Germany
| | - Christian Stief
- Department of Urology, University Hospital Munich, Munich, Germany
| | - Axel Haferkamp
- Department of Urology, University Hospital Mainz, Mainz, Germany
| | | | - Stefan Duensing
- Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Bernd Wullich
- Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Joachim Noldus
- Department of Urology, Marien Hospital Herne, Ruhr University Bochum, Herne, Germany
| | - Walburgis Brenner
- Clinic for Obstretics and Woman's Health and Department of Urology, University Medical Center, Mainz, Germany
- Department of Urology, University of Mainz, Mainz, Germany
| | - Frederik Roos
- Department of Urology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Bernhard Walter
- Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Wolfgang Otto
- Department of Urology, University of Regensburg, Regensburg, Germany
| | - Maximilian Burger
- Department of Urology, University of Regensburg, Regensburg, Germany
| | | | | | - Arndt Hartmann
- Institute of Pathology, University Hospital Erlangen-Nuernberg, Friedrich Alexander University (FAU), Erlangen, Germany
| | - Franziska Erlmeier
- Institute of Pathology, University Hospital Erlangen-Nuernberg, Friedrich Alexander University (FAU), Erlangen, Germany
| | - Sandra Steffens
- Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
- Dean’s Office, Curriculum Development, Hannover Medical School, Hannover, Germany
| | - German Network of Kidney Cancer
- Department of Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
- Dean’s Office, Curriculum Development, Hannover Medical School, Hannover, Germany
- Department of Medical Oncology, National Center of Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
- Institute of Pathology, University Hospital Erlangen-Nuernberg, Friedrich Alexander University (FAU), Erlangen, Germany
- Department of Urology, University Hospital Muenster, Muenster, Germany
- Department of Urology, University Hospital Göttingen, Göttingen, Germany
- Department of Pathology, University Hospital Göttingen, Göttingen, Germany
- Department of Urology and Pediatric Urology, University of Saarland (UKS), Homburg, Germany
- Institute of Pathology, University Hospital Göttingen, Göttingen, Germany
- Department of Urology, University of Marburg, Marburg, Germany
- Department of Urology, University Hospital Munich, Munich, Germany
- Department of Urology, University Hospital Mainz, Mainz, Germany
- Department of Urology, University Hospital Heidelberg, Heidelberg, Germany
- Institute of Pathology, University Hospital Mainz, Mainz, Germany
- Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany
- Department of Urology, Marien Hospital Herne, Ruhr University Bochum, Herne, Germany
- Clinic for Obstretics and Woman's Health and Department of Urology, University Medical Center, Mainz, Germany
- Department of Urology, University of Mainz, Mainz, Germany
- Department of Urology, University Hospital Frankfurt, Frankfurt/Main, Germany
- Department of Urology, University of Regensburg, Regensburg, Germany
- Department of Urology, München Klinik Bogenhausen, Munich, Germany
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Pei JP, Wang Y, Ma LP, Wang X, Liu L, Zhang Y, Jin R, Ren ZQ, Deng Y, Shen JK, Meng T, Yu K. AXL antibody and AXL-ADC mediate antitumor efficacy via targeting AXL in tumor-intrinsic epithelial-mesenchymal transition and tumor-associated M2-like macrophage. Acta Pharmacol Sin 2023; 44:1290-1303. [PMID: 36650292 PMCID: PMC10203350 DOI: 10.1038/s41401-022-01047-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 12/27/2022] [Indexed: 01/19/2023]
Abstract
The receptor tyrosine kinase AXL is an emerging driver of cancer recurrence, while its molecular mechanism remains unclear. In this study we investigated how AXL regulated the disease progression and poor prognosis in non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We performed AXL transcriptome analysis from TCGA datasets, and found that AXL expression was significantly elevated in NSCLC and TNBC correlating with poor prognosis, epithelial-mesenchymal transition (EMT) and immune-tolerant tumor microenvironment (TME). Knockdown of AXL or treatment with two independent AXL antibodies (named anti-AXL and AXL02) all diminished cell migration and EMT in AXL-high expressing NSCLC and TNBC cell lines. In a mouse model of 4T1 TNBC, administration of anti-AXL antibody substantially inhibited lung metastases formation and growth, accompanied by reduced downstream signaling activation, EMT and proliferation index, as well as an increased apoptosis and activated anti-tumor immunity. We found that AXL was abundantly activated in tumor nodule-infiltrated M2-macrophages. A specific anti-AXL antibody blocked bone marrow-derived macrophage (BMDM) M2-polarization in vitro. Targeting of AXL in M2-macrophage in addition to tumor cell substantially suppressed CSF-1 production and eliminated M2-macrophage in TME, leading to a coordinated enhancement in both the innate and adaptive immunity reflecting M1-like macrophages, mature dendritic cells, cytotoxic T cells and B cells. We generated a novel and humanized AXL-ADC (AXL02-MMAE) employing a site-specific conjugation platform. AXL02-MMAE exerted potent cytotoxicity against a panel of AXL-high expressing tumor cell lines (IC50 < 0.1 nmol/L) and suppressed in vivo growth of multiple NSCLC and glioma tumors (a minimum efficacy dose<1 mg/kg). Compared to chemotherapy, AXL02-MMAE achieved a superior efficacy in regressing large sized tumors, eliminated AXL-H tumor cell-dependent M2-macrophage infiltration with a robust accumulation of inflammatory macrophages and mature dendritic cells. Our results support AXL-targeted therapy for treatment of advanced NSCLC and TNBC.
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Affiliation(s)
- Jin-Peng Pei
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Yue Wang
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Lan-Ping Ma
- Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xin Wang
- Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Liang Liu
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Yu Zhang
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Rui Jin
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Zhi-Qiang Ren
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Yan Deng
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Jing-Kang Shen
- Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Tao Meng
- Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Ker Yu
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, 201203, China.
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14
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He Y, Huang W, Tang Y, Li Y, Peng X, Li J, Wu J, You N, Li L, Liu C, Zheng L, Huang X. Clinical and genetic characteristics in pancreatic cancer from Chinese patients revealed by whole exome sequencing. Front Oncol 2023; 13:1167144. [PMID: 37313463 PMCID: PMC10258306 DOI: 10.3389/fonc.2023.1167144] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 05/09/2023] [Indexed: 06/15/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide, mostly as a result of the absence of early detection and specific treatment solutions. Consequently, identifying mutational profiles and molecular biomarkers is essential for increasing the viability of precision therapy for pancreatic cancer. METHODS We collected blood and tumor tissue samples from 47 Chinese pancreatic cancer patients and used whole-exome sequencing (WES) to evaluate the genetic landscape. RESULTS Our results showed the most frequently somatic alteration genes were KRAS (74.5%), TP53(51.1%), SMAD4 (17%), ARID1A (12.8%), CDKN2A (12.8%), TENM4 (10.6%), TTN (8.5%), RNF43(8.5%), FLG (8.5%) and GAS6 (6.4%) in Chinese PDAC patients. We also found that three deleterious germline mutations (ATM c.4852C>T/p. R1618*, WRN c.1105C>T/p. R369*, PALB2 c.2760dupA/p. Q921Tfs*7) and two novel fusions (BRCA1-RPRML, MIR943 (intergenic)-FGFR3). When compared to the Cancer Genome Atlas (TCGA) database, there is a greater mutation frequency of TENM4 (10.6% vs. 1.6%, p = 0.01), GAS6(6.4% vs. 0.5%, p = 0.035), MMP17(6.4% vs. 0.5%, p = 0.035), ITM2B (6.4% vs. 0.5%, p = 0.035) and USP7 (6.4% vs. 0.5%, p= 0.035) as well as a reduced mutation frequency of SMAD4 (17.0% vs. 31.5%, p = 0.075) and CDKN2A (12.8% vs. 47.3%, p < 0.001) were observed in the Chinese cohort. Among the 41 individuals examined for programmed cell death ligand 1(PD-L1) expression, 15 (36.6%) had positive PD-L1 expression. The median tumor mutational burden (TMB) was found to be 12muts (range, 0124). The TMB index was higher in patients with mutant-type KRAS MUT/TP53 MUT (p < 0.001), CDKN2A (p = 0.547), or SMAD4 (p = 0.064) compared to patients with wild-type KRAS/TP53, CDKN2A, or SMAD4. CONCLUSIONS We exhibited real-world genetic traits and new alterations in Chinese individuals with cancer of the pancreas, which might have interesting implications for future individualized therapy and medication development.
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Affiliation(s)
- Yonggang He
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Wen Huang
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Yichen Tang
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Yuming Li
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Xuehui Peng
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Jing Li
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Jing Wu
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Nan You
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Ling Li
- Department of Medicine, Yinfeng Gene Technology Co Ltd, Jinan, China
| | - Chuang Liu
- Department of Medicine, Yinfeng Gene Technology Co Ltd, Jinan, China
| | - Lu Zheng
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Xiaobing Huang
- Department of Hepatobiliary, The Second Affiliated Hospital of Army Medical University, Chongqing, China
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15
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Hsu PL, Chien CW, Tang YA, Lin BW, Lin SC, Lin YS, Chen SY, Sun HS, Tsai SJ. Targeting BRD3 eradicates nuclear TYRO3-induced colorectal cancer metastasis. SCIENCE ADVANCES 2023; 9:eade3422. [PMID: 37043564 PMCID: PMC10096587 DOI: 10.1126/sciadv.ade3422] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 03/15/2023] [Indexed: 05/27/2023]
Abstract
Metastasis is the main cause of death in many cancers including colorectal cancer (CRC); however, the underlying mechanisms responsible for metastatic progression remain largely unknown. We found that nuclear TYRO3 receptor tyrosine kinase is a strong predictor of poor overall survival in patients with CRC. The metastasis-promoting function of nuclear TYRO3 requires its kinase activity and matrix metalloproteinase-2 (MMP-2)-mediated cleavage but is independent of ligand binding. Using proteomic analysis, we identified bromodomain-containing protein 3 (BRD3), an acetyl-lysine reading epigenetic regulator, as one of nuclear TYRO3's substrates. Chromatin immunoprecipitation-sequencing data reveal that TYRO3-phosphorylated BRD3 regulates genes involved in anti-apoptosis and epithelial-mesenchymal transition. Inhibition of MMP-2 or BRD3 activity by selective inhibitors abrogates nuclear TYRO3-induced drug resistance and metastasis in organoid culture and in orthotopic mouse models. These data demonstrate that MMP-2/TYRO3/BRD3 axis promotes the metastasis of CRC, and blocking this signaling cascade is a promising approach to ameliorate CRC malignancy.
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Affiliation(s)
- Pei-Ling Hsu
- Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Chun-Wei Chien
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Yen-An Tang
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Bo-Wen Lin
- Division of Colorectal Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Shih-Chieh Lin
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Yi-Syuan Lin
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Sih-Yu Chen
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - H. Sunny Sun
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Shaw-Jenq Tsai
- Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
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16
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Bae D, Chaudhary P, Been JH, Gautam J, Lee J, Shah S, Kim E, Lee H, Nam TG, Jeong BS, Kim JA. Antitumor effect of 3-(quinolin-2-ylmethylene)-4,6-dimethyl-5-hydroxy-7-azaoxindole down-regulating the Gas6-Axl axis. Eur J Med Chem 2023; 251:115274. [PMID: 36921529 DOI: 10.1016/j.ejmech.2023.115274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 03/09/2023] [Accepted: 03/09/2023] [Indexed: 03/12/2023]
Abstract
In this study, a new series of 3-arylidene-4,6-dimethyl-5-hydroxy-7-azaoxindole compounds with a wide range of functional groups were designed, synthesized, and evaluated for their antitumor activity. Among the 35 compounds, compound 6-15, with a quinoline moiety, showed cytotoxic IC50 values superior to those of sunitinib against the seven cancer cell lines (MCF-7, MDA-MB-231, HT-29, DU145, U937, A549, and PANC-1). However, its inhibitory activity against receptor tyrosine kinases (VEGFR2, PDGFRβ, c-KIT, FGFR1, FLT3, CSF1R, EGFR, Axl, and Axl mutant) was 100 -3000-fold weaker than that of sunitinib. Interestingly, compound 6-15 exerted a 3.6-fold stronger cytotoxicity than sunitinib in the gemcitabine-resistant PANC-1 cell line and significantly inhibited Axl, which was in contrast with the effect of sunitinib. Nonetheless, both compounds suppressed the expression of growth arrest-specific 6 (Gas6), the ligand of Axl. The inhibitory effect of compound 6-15 on the Gas6-Axl axis was similar to that of Gas6 knockdown by siRNA in PANC-1 cells in terms of apoptosis induction, increase in Bax/Bcl-2 ratio, Axl down-regulation, and PI3K/Akt inhibition. The inhibitory effect of compound 6-15 on tumor growth in mouse tumor models with A549 and PANC-1 xenografts was much greater than that of cisplatin or gemcitabine. Taken together, the current findings demonstrate that compound 6-15 is a promising anticancer drug candidate that acts by inhibiting the Gas6-Axl axis.
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Affiliation(s)
- Dawon Bae
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Prakash Chaudhary
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Jae-Hui Been
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Jaya Gautam
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Jisu Lee
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Sajita Shah
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Euijung Kim
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Hyunji Lee
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan, 38541, Republic of Korea; College of Pharmacy, Kyungsung University, Busan, 48434, Republic of Korea
| | - Tae-Gyu Nam
- Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, ERICA campus, Ansan, 15588, Republic of Korea
| | - Byeong-Seon Jeong
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
| | - Jung-Ae Kim
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
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17
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Mikuteit M, Zschäbitz S, Erlmeier M, Autenrieth M, Weichert W, Hartmann A, Steffens S, Erlmeier F. Growth Arrest-Specific 6 in Chromophobe Renal Cell Carcinoma. Oncology 2022; 100:536-541. [PMID: 35760058 PMCID: PMC9677856 DOI: 10.1159/000525601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 05/24/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Overexpression of tumor-associated growth arrest-specific protein 6 (Gas6) is found in many tumor entities. The prognostic value of Gas6 in renal cell carcinoma (RCC), especially in non-clear cell RCC, is still unclear. AIM The aim of the study was to evaluate the prognostic impact of Gas6 expression in a large cohort of patients with chromophobe RCC (chRCC). MATERIAL AND METHODS Patients who underwent renal surgery due to chRCC were retrospectively evaluated. Tumor specimens were analyzed for Gas6 expression by immunohistochemistry. RESULTS Eighty-one chRCC patients were eligible for analysis; of these, 24 (29.6%) patients were positive for Gas6. No significant associations were found for Gas6 expression and clinical attributes in patients with chRCC. The Kaplan-Meier analysis revealed no differences in 5-year overall survival for Gas6- compared to Gas6+ (89.6% vs. 100.0%; p = 0.288) tumors. CONCLUSION In chRCC, Gas6 expression is not associated with survival and other parameters of aggressiveness. Due to the rare incidence of chRCC, further studies with larger cohorts are warranted.
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Affiliation(s)
- Marie Mikuteit
- Department for Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
- Dean's Office − Curriculum Development, Hannover Medical School, Hannover, Germany
| | - Stefanie Zschäbitz
- Department of Medical Oncology, National Center of Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Michael Autenrieth
- Department of Urology, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany
| | - Wilko Weichert
- Institute for Pathology and Pathological Anatomy, Technical University Munich, Munich, Germany
- Member of the German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Arndt Hartmann
- Institute of Pathology, University Hospital of Erlangen, Erlangen, Germany
| | - Sandra Steffens
- Department for Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
- Dean's Office − Curriculum Development, Hannover Medical School, Hannover, Germany
- Department of Urology, University Hospital Münster, Münster, Germany
| | - Franziska Erlmeier
- Institute of Pathology, University Hospital of Erlangen, Erlangen, Germany
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18
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Liu Y, Shi M, He X, Cao Y, Liu P, Li F, Zou S, Wen C, Zhan Q, Xu Z, Wang J, Sun B, Shen B. LncRNA-PACERR induces pro-tumour macrophages via interacting with miR-671-3p and m6A-reader IGF2BP2 in pancreatic ductal adenocarcinoma. J Hematol Oncol 2022; 15:52. [PMID: 35526050 PMCID: PMC9077921 DOI: 10.1186/s13045-022-01272-w] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 04/21/2022] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND LncRNA-PACERR plays critical role in the polarization of tissue-associated macrophages (TAMs). In this study, we found the function and molecular mechanism of PACERR in TAMs to regulate pancreatic ductal adenocarcinoma (PDAC) progression. METHODS We used qPCR to analyse the expression of PACERR in TAMs and M1-tissue-resident macrophages (M1-NTRMs) which were isolated from 46 PDAC tissues. The function of PACERR on macrophages polarization and PDAC proliferation, migration and invasion were confirmed through in vivo and in vitro assays. The molecular mechanism of PACERR was discussed via fluorescence in situ hybridization (FISH), RNA pull-down, ChIP-qPCR, RIP-qPCR and luciferase assays. RESULTS LncRNA-PACERR was high expression in TAMs and associated with poor prognosis in PDAC patients. Our finding validated that LncRNA-PACERR increased the number of M2-polarized cells and facilized cell proliferation, invasion and migration in vitro and in vivo. Mechanistically, LncRNA-PACERR activate KLF12/p-AKT/c-myc pathway by binding to miR-671-3p. And LncRNA-PACERR which bound to IGF2BP2 acts as an m6A-dependent manner to enhance the stability of KLF12 and c-myc in cytoplasm. In addition, the promoter of LncRNA-PACERR was a target of KLF12 and LncRNA-PACERR recruited EP300 to increase the acetylation of histone by interacting with KLF12 in nucleus. CONCLUSIONS This study found that LncRNA-PACERR functions as key regulator of TAMs in PDAC microenvironment and revealed the novel mechanisms in cytoplasm and in nucleus.
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Affiliation(s)
- Yihao Liu
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- Department of Zoology, College of Life Science, Nankai University, Tianjin, 300071, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Minmin Shi
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Xingfeng He
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yizhi Cao
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Pengyi Liu
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Fanlu Li
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Siyi Zou
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Chenlei Wen
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Qian Zhan
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Zhiwei Xu
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jiancheng Wang
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China.
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China.
| | - Baofa Sun
- Department of Zoology, College of Life Science, Nankai University, Tianjin, 300071, China.
| | - Baiyong Shen
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China.
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China.
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Engelsen AST, Lotsberg ML, Abou Khouzam R, Thiery JP, Lorens JB, Chouaib S, Terry S. Dissecting the Role of AXL in Cancer Immune Escape and Resistance to Immune Checkpoint Inhibition. Front Immunol 2022; 13:869676. [PMID: 35572601 PMCID: PMC9092944 DOI: 10.3389/fimmu.2022.869676] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 03/16/2022] [Indexed: 12/12/2022] Open
Abstract
The development and implementation of Immune Checkpoint Inhibitors (ICI) in clinical oncology have significantly improved the survival of a subset of cancer patients with metastatic disease previously considered uniformly lethal. However, the low response rates and the low number of patients with durable clinical responses remain major concerns and underscore the limited understanding of mechanisms regulating anti-tumor immunity and tumor immune resistance. There is an urgent unmet need for novel approaches to enhance the efficacy of ICI in the clinic, and for predictive tools that can accurately predict ICI responders based on the composition of their tumor microenvironment. The receptor tyrosine kinase (RTK) AXL has been associated with poor prognosis in numerous malignancies and the emergence of therapy resistance. AXL is a member of the TYRO3-AXL-MERTK (TAM) kinase family. Upon binding to its ligand GAS6, AXL regulates cell signaling cascades and cellular communication between various components of the tumor microenvironment, including cancer cells, endothelial cells, and immune cells. Converging evidence points to AXL as an attractive molecular target to overcome therapy resistance and immunosuppression, supported by the potential of AXL inhibitors to improve ICI efficacy. Here, we review the current literature on the prominent role of AXL in regulating cancer progression, with particular attention to its effects on anti-tumor immune response and resistance to ICI. We discuss future directions with the aim to understand better the complex role of AXL and TAM receptors in cancer and the potential value of this knowledge and targeted inhibition for the benefit of cancer patients.
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Affiliation(s)
- Agnete S. T. Engelsen
- Centre for Cancer Biomarkers and Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Maria L. Lotsberg
- Centre for Cancer Biomarkers and Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Raefa Abou Khouzam
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - Jean-Paul Thiery
- Centre for Cancer Biomarkers and Department of Biomedicine, University of Bergen, Bergen, Norway
- Guangzhou Laboratory, Guangzhou, China
- Inserm, UMR 1186, Integrative Tumor Immunology and Immunotherapy, Villejuif, France
| | - James B. Lorens
- Centre for Cancer Biomarkers and Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Salem Chouaib
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
- Inserm, UMR 1186, Integrative Tumor Immunology and Immunotherapy, Villejuif, France
- Gustave Roussy, Villejuif, France
- Faculty of Medicine, University Paris Sud, Le Kremlin-Bicêtre, France
| | - Stéphane Terry
- Inserm, UMR 1186, Integrative Tumor Immunology and Immunotherapy, Villejuif, France
- Gustave Roussy, Villejuif, France
- Faculty of Medicine, University Paris Sud, Le Kremlin-Bicêtre, France
- Research Department, Inovarion, Paris, France
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20
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Wei K, Zhu H, Qin G, Zhu Z, Tu D. Multiply robust subgroup analysis based on a single-index threshold linear marginal model for longitudinal data with dropouts. Stat Med 2022; 41:2822-2839. [PMID: 35347738 DOI: 10.1002/sim.9386] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 02/21/2022] [Accepted: 03/02/2022] [Indexed: 11/08/2022]
Abstract
Identifying subpopulations that may be sensitive to the specific treatment is an important step toward precision medicine. On the other hand, longitudinal data with dropouts is common in medical research, and subgroup analysis for this data type is still limited. In this paper, we consider a single-index threshold linear marginal model, which can be used simultaneously to identify subgroups with differential treatment effects based on linear combination of the selected biomarkers, estimate the treatment effects in different subgroups based on regression coefficients, and test the significance of the difference in treatment effects based on treatment-subgroup interaction. The regression parameters are estimated by solving a penalized smoothed generalized estimating equation and the selection bias caused by missingness is corrected by a multiply robust weighting matrix, which allows multiple missingness models to be taken account into estimation. The proposed estimator remains consistent when any model for missingness is correctly specified. Under regularity conditions, the asymptotic normality of the estimator is established. Simulation studies confirm the desirable finite-sample performance of the proposed method. As an application, we analyze the data from a clinical trial on pancreatic cancer.
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Affiliation(s)
- Kecheng Wei
- Department of Biostatistics, School of Public Health, Fudan University, Shanghai, China
| | - Huichen Zhu
- Department of Statistics, The Chinese University of Hong Kong, Hong Kong, China
| | - Guoyou Qin
- Department of Biostatistics, School of Public Health, Fudan University, Shanghai, China
| | - Zhongyi Zhu
- Department of Statistics, School of Management, Fudan University, Shanghai, China
| | - Dongsheng Tu
- Canadian Cancer Trials Group, Queen's University, Kingston, Ontario, Canada
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21
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Small-Molecule RAS Inhibitors as Anticancer Agents: Discovery, Development, and Mechanistic Studies. Int J Mol Sci 2022; 23:ijms23073706. [PMID: 35409064 PMCID: PMC8999084 DOI: 10.3390/ijms23073706] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/21/2022] [Accepted: 03/24/2022] [Indexed: 12/11/2022] Open
Abstract
Mutations of RAS oncogenes are responsible for about 30% of all human cancer types, including pancreatic, lung, and colorectal cancers. While KRAS1 is a pseudogene, mutation of KRAS2 (commonly known as KRAS oncogene) is directly or indirectly associated with human cancers. Among the RAS family, KRAS is the most abundant oncogene related to uncontrolled cellular proliferation to generate solid tumors in many types of cancer such as pancreatic carcinoma (over 80%), colon carcinoma (40-50%), lung carcinoma (30-50%), and other types of cancer. Once described as 'undruggable', RAS proteins have become 'druggable', at least to a certain extent, due to the continuous efforts made during the past four decades. In this account, we discuss the chemistry and biology (wherever available) of the small-molecule inhibitors (synthetic, semi-synthetic, and natural) of KRAS proteins that were published in the past decades. Commercial drugs, as well as investigational molecules from preliminary stages to clinical trials, are categorized and discussed in this study. In summary, this study presents an in-depth discussion of RAS proteins, classifies the RAS superfamily, and describes the molecular mechanism of small-molecule RAS inhibitors.
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22
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Martínez-Bosch N, Cristóbal H, Iglesias M, Gironella M, Barranco L, Visa L, Calafato D, Jiménez-Parrado S, Earl J, Carrato A, Manero-Rupérez N, Moreno M, Morales A, Guerra C, Navarro P, García de Frutos P. Soluble AXL is a novel blood marker for early detection of pancreatic ductal adenocarcinoma and differential diagnosis from chronic pancreatitis. EBioMedicine 2022; 75:103797. [PMID: 34973624 PMCID: PMC8724936 DOI: 10.1016/j.ebiom.2021.103797] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 12/10/2021] [Accepted: 12/16/2021] [Indexed: 02/07/2023] Open
Abstract
Background Early diagnosis is crucial for patients with pancreatic ductal adenocarcinoma (PDAC). The AXL receptor tyrosine kinase is proteolytically processed releasing a soluble form (sAXL) into the blood stream. Here we explore the use of sAXL as a biomarker for PDAC. Methods AXL was analysed by immunohistochemistry in human pancreatic tissue samples. RNA expression analysis was performed using TCGA/GTEx databases. The plasma concentrations of sAXL, its ligand GAS6, and CA19-9 were studied in two independent cohorts, the HMar cohort (n = 59) and the HClinic cohort (n = 142), including healthy controls, chronic pancreatitis (CP) or PDAC patients, and in a familial PDAC cohort (n = 68). AXL expression and sAXL release were studied in PDAC cell lines and murine models. Findings AXL is increased in PDAC and precursor lesions as compared to CP or controls. sAXL determined in plasma from two independent cohorts was significantly increased in the PDAC group as compared to healthy controls or CP patients. Patients with high levels of AXL have a lower overall survival. ROC analysis of the plasma levels of sAXL, GAS6, or CA19-9 in our cohorts revealed that sAXL outperformed CA19-9 for discriminating between CP and PDAC. Using both sAXL and CA19-9 increased the diagnostic value. These results were validated in murine models, showing increased sAXL specifically in animals developing PDAC but not those with precursor lesions or acinar tumours. Interpretation sAXL appears as a biomarker for early detection of PDAC and PDAC–CP discrimination that could accelerate treatment and improve its dismal prognosis. Funding This work was supported by grants PI20/00625 (PN), RTI2018-095672-B-I00 (AM and PGF), PI20/01696 (MG) and PI18/01034 (AC) from MICINN-FEDER and grant 2017/SGR/225 (PN) from Generalitat de Catalunya.
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Affiliation(s)
- Neus Martínez-Bosch
- Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, Barcelona, Spain
| | - Helena Cristóbal
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB)-CSIC and Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain
| | - Mar Iglesias
- Department of Pathology, Autonomous University of Barcelona, Hospital del Mar, Centro de Investigación Biomédica en Red de Oncología (CIBERONC), Barcelona, Spain
| | - Meritxell Gironella
- Gastrointestinal & Pancreatic Oncology Group, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD); Hospital Clínic of Barcelona and IDIBAPS; Barcelona, Spain
| | - Luis Barranco
- Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, Barcelona, Spain; Department of Gastroenterology, Hospital del Mar, Barcelona, Spain
| | - Laura Visa
- Department of Medical Oncology, Hospital del Mar, Barcelona, Spain
| | - Domenico Calafato
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB)-CSIC and Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain
| | - Silvia Jiménez-Parrado
- Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Julie Earl
- Molecular Epidemiology and Predictive Tumour Markers Group, Medical Oncology Research Laboratory, Ramón y Cajal Health Research Institute (IRYCIS), Madrid, Spain. CIBERONC
| | - Alfredo Carrato
- Molecular Epidemiology and Predictive Tumour Markers Group, Medical Oncology Research Laboratory, Ramón y Cajal Health Research Institute (IRYCIS), Madrid, Spain. CIBERONC
| | - Noemí Manero-Rupérez
- Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, Barcelona, Spain
| | - Mireia Moreno
- Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, Barcelona, Spain
| | - Albert Morales
- Department of Cell Death and Proliferation, IIBB-CSIC, Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, Hospital Clínic, CIBEREHD and IDIBAPS, Barcelona, Spain
| | - Carmen Guerra
- Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Pilar Navarro
- Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Unidad Asociada IIBB-CSIC, Barcelona, Spain; Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB)-CSIC and Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain.
| | - Pablo García de Frutos
- Department of Cell Death and Proliferation, IIBB-CSIC, Unidad Asociada IMIM/IIBB-CSIC; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), and IDIBAPS, Barcelona, Spain.
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23
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Lotsberg ML, Davidsen KT, D’Mello Peters S, Haaland GS, Rayford A, Lorens JB, Engelsen AST. The Role of AXL Receptor Tyrosine Kinase in Cancer Cell Plasticity and Therapy Resistance. BIOMARKERS OF THE TUMOR MICROENVIRONMENT 2022:307-327. [DOI: 10.1007/978-3-030-98950-7_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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24
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Muñoz‐San Martín C, Pérez‐Ginés V, Torrente‐Rodríguez RM, Gamella M, Solís‐Fernández G, Montero‐Calle A, Pedrero M, Serafín V, Martínez‐Bosch N, Navarro P, García de Frutos P, Batlle M, Barderas R, Pingarrón JM, Campuzano S. Electrochemical immunosensing of Growth arrest‐specific 6 in human plasma and tumor cell secretomes. ELECTROCHEMICAL SCIENCE ADVANCES 2021. [DOI: 10.1002/elsa.202100096] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- Cristina Muñoz‐San Martín
- Departamento de Química Analítica, Facultad de CC. Químicas Universidad Complutense de Madrid Madrid Spain
| | - Víctor Pérez‐Ginés
- Departamento de Química Analítica, Facultad de CC. Químicas Universidad Complutense de Madrid Madrid Spain
| | | | - Maria Gamella
- Departamento de Química Analítica, Facultad de CC. Químicas Universidad Complutense de Madrid Madrid Spain
| | | | - Ana Montero‐Calle
- Chronic Disease Programme, UFIEC Carlos III Health Institute Majadahonda Madrid Spain
| | - María Pedrero
- Departamento de Química Analítica, Facultad de CC. Químicas Universidad Complutense de Madrid Madrid Spain
| | - Verónica Serafín
- Departamento de Química Analítica, Facultad de CC. Químicas Universidad Complutense de Madrid Madrid Spain
| | - Neus Martínez‐Bosch
- Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM) Unidad Asociada IIBB‐CSIC Barcelona Spain
| | - Pilar Navarro
- Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM) Unidad Asociada IIBB‐CSIC Barcelona Spain
- Departamento de Muerte y Proliferación Celular Instituto de Investigaciones Biomédicas de Barcelona – Centro Superior de Investigaciones Científicas (IIBB‐CSIC) Barcelona Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona Catalonia Spain
| | - Pablo García de Frutos
- Departamento de Muerte y Proliferación Celular Instituto de Investigaciones Biomédicas de Barcelona – Centro Superior de Investigaciones Científicas (IIBB‐CSIC) Barcelona Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona Catalonia Spain
| | - Montserrat Batlle
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona Catalonia Spain
- Centro de Investigación Biomédica en Red de Enfermedades CardioVasculares (CIBERCV) Instituto de Carlos III Madrid Spain
| | - Rodrigo Barderas
- Chronic Disease Programme, UFIEC Carlos III Health Institute Majadahonda Madrid Spain
| | - José M. Pingarrón
- Departamento de Química Analítica, Facultad de CC. Químicas Universidad Complutense de Madrid Madrid Spain
| | - Susana Campuzano
- Departamento de Química Analítica, Facultad de CC. Químicas Universidad Complutense de Madrid Madrid Spain
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25
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Crowley FJ, O'Cearbhaill RE, Collins DC. Exploiting somatic alterations as therapeutic targets in advanced and metastatic cervical cancer. Cancer Treat Rev 2021; 98:102225. [PMID: 34082256 DOI: 10.1016/j.ctrv.2021.102225] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/12/2021] [Accepted: 05/15/2021] [Indexed: 01/05/2023]
Abstract
It is estimated that 604,127 patients were diagnosed with cervical cancer worldwide in 2020. While a small percentage of patients will have metastatic disease at diagnosis, a large percentage (15-61%) later develop advanced disease. For this cohort, treatment with systemic chemotherapy remains the standard of care, with a static 5-year survival rate over the last thirty years. Data on targetable molecular alterations in cervical cancer have lagged behind other more common tumor types thus stunting the development of targeted agents. In recent years, tumor genomic testing has been increasingly incorporated into our clinical practice, opening the door for a potential new era of personalized treatment for advanced cervical cancer. The interim results from the NCI-MATCH study reported an actionability rate of 28.4% for the cervical cancer cohort, suggesting a subset of patients may harbor mutations which that are targetable. This review sets out to summarize the key targeted agents currently under exploration either alone or in combination with existing treatments for cervical cancer.
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Affiliation(s)
- F J Crowley
- Department of Internal Medicine, Mount Sinai Morningside and Mount Sinai West, NY, USA.
| | - R E O'Cearbhaill
- Department of Medicine, Memorial Sloan Kettering Cancer Centre and Weill Cornell Medical College, NY, USA.
| | - D C Collins
- Department of Medical Oncology, Cork University Hospital, Cork, Ireland; Cancer Research @UCC, College of Medicine and Health, University College Cork, Cork, Ireland.
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26
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Du W, Phinney NZ, Huang H, Wang Z, Westcott J, Toombs JE, Zhang Y, Beg MS, Wilkie TM, Lorens JB, Brekken RA. AXL Is a Key Factor for Cell Plasticity and Promotes Metastasis in Pancreatic Cancer. Mol Cancer Res 2021; 19:1412-1421. [PMID: 33811159 DOI: 10.1158/1541-7786.mcr-20-0860] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 02/24/2021] [Accepted: 03/30/2021] [Indexed: 12/12/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDA), a leading cause of cancer-related death in the United States, has a high metastatic rate, and is associated with persistent immune suppression. AXL, a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family, is a driver of metastasis and immune suppression in multiple cancer types. Here we use single-cell RNA-sequencing to reveal that AXL is expressed highly in tumor cells that have a mesenchymal-like phenotype and that AXL expression correlates with classic markers of epithelial-to-mesenchymal transition. We demonstrate that AXL deficiency extends survival, reduces primary and metastatic burden, and enhances sensitivity to gemcitabine in an autochthonous model of PDA. PDA in AXL-deficient mice displayed a more differentiated histology, higher nucleoside transporter expression, and a more active immune microenvironment compared with PDA in wild-type mice. Finally, we demonstrate that AXL-positive poorly differentiated tumor cells are critical for PDA progression and metastasis, emphasizing the potential of AXL as a therapeutic target in PDA. IMPLICATIONS: These studies implicate AXL as a marker of undifferentiated PDA cells and a target for therapy.
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Affiliation(s)
- Wenting Du
- Department of Surgery and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.,Cancer Biology Graduate Program, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Natalie Z Phinney
- Department of Surgery and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.,Cancer Biology Graduate Program, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Huocong Huang
- Department of Surgery and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Zhaoning Wang
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jill Westcott
- Department of Surgery and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jason E Toombs
- Department of Surgery and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Yuqing Zhang
- Department of Surgery and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas.,Cancer Biology Graduate Program, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Muhammad S Beg
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Thomas M Wilkie
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - James B Lorens
- Department of Biomedicine, Centre for Cancer Biomarkers, Norwegian Centre of Excellence, University of Bergen, Bergen, Norway
| | - Rolf A Brekken
- Department of Surgery and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas. .,Cancer Biology Graduate Program, University of Texas Southwestern Medical Center, Dallas, Texas.,Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas
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27
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Tanaka M, Dykes SS, Siemann DW. Inhibition of the Axl pathway impairs breast and prostate cancer metastasis to the bones and bone remodeling. Clin Exp Metastasis 2021; 38:321-335. [PMID: 33791875 PMCID: PMC8179919 DOI: 10.1007/s10585-021-10093-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 03/22/2021] [Indexed: 12/13/2022]
Abstract
Approximately 90% of cancer-related deaths result from cancer metastasis. In prostate and breast cancers, bone is the most common site of cancer cell dissemination. Key steps in the metastatic cascade are promoted through upregulation of critical cell signaling pathways in neoplastic cells. The present study assessed the role of the receptor tyrosine kinase Axl in prostate and breast cancer cell metastasis to bones using (i) Axl knockdown neoplastic cells and osteoclast progenitor cells in vitro, (ii) intracardiac injection of Axl knockdown tumor cells in vivo, and (iii) selective Axl inhibitor BGB324. Axl inhibition in neoplastic cells significantly decreased their metastatic potential, and suppression of Axl signaling in osteoclast precursor cells also reduced the formation of mature osteoclasts. In vivo, Axl knockdown in prostate and breast cancer cells significantly suppressed the formation and progression of bone metastases. Hence, therapeutic targeting of Axl may impair tumor metastasis to the bones through neoplastic and host cell signaling axes.
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Affiliation(s)
- Mai Tanaka
- Department of Radiation Oncology, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.
| | - Samantha S Dykes
- Department of Radiation Oncology, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.,GenCure, a Subsidiary of BioBridge Global, San Antonio, TX, 78201, USA
| | - Dietmar W Siemann
- Department of Radiation Oncology, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
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28
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Opposite trends of GAS6 and GAS6-AS expressions in breast cancer tissues. Exp Mol Pathol 2020; 118:104600. [PMID: 33359886 DOI: 10.1016/j.yexmp.2020.104600] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/26/2020] [Accepted: 12/21/2020] [Indexed: 12/29/2022]
Abstract
Growth arrest-specific gene 6 (GAS6) is a growth factor-like cytokine whose function is related with vitamin K. This protein interacts with receptor tyrosine kinase proteins such as Tyro3, Axl, and TAM Receptor family, therefore affecting the tumorigenic processes via different mechanisms. GAS6-antisense 1 (GAS6-AS1) is a long non-coding RNAs (lncRNAs) that is transcribed from a genomic regions nearby GAS6. This lncRNA is also implicated in the pathobiology of cancer. We intended to judge the role of GAS6 and GAS6-AS1 in the pathogenesis of breast cancer through appraisal of their expression levels in breast cancer tissues and their paired neighboring non-cancerous samples. Expression of GAS6 was up-regulated in breast cancer tissues compared with neighboring tissues (Ratio of Mean Expressions = 2.18, P value = 4.98E-02). On the other hand, expression of GAS6-AS1 was down-regulated in breast tumor tissues compared with controls (Ratio of Mean Expressions = 0.37, P value = 4.26E-03). There were substantial correlations between expression levels GAS6 and GAS6-AS1 in non-cancerous tissues (r = 0.74, P value = 1.47e-13) and cancer tissues (r = 0.85, P value = 2.28e-20). Expression of GAS6-AS was associated with progesterone receptor status (P value = 1.36E-02). However, expressions of this gene and the sense transcript were not linked with any other clinical or demographic variable. Taken together, GAS6 and GAS6-AS1 might partake in the development of breast cancer.
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29
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von Itzstein MS, Burke MC, Brekken RA, Aguilera TA, Zeh HJ, Beg MS. Targeting TAM to Tame Pancreatic Cancer. Target Oncol 2020; 15:579-588. [PMID: 32996059 DOI: 10.1007/s11523-020-00751-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Pancreatic cancer is expected to become the second leading cause of cancer-related death within the next few years. Current therapeutic strategies have limited effectiveness and therefore there is an urgency to develop novel effective therapies. The receptor tyrosine kinase subfamily TAM (Tyro3, Axl, MerTK) is directly implicated in the pathogenesis of the metastatic, chemoresistant, and immunosuppressive phenotype in pancreatic cancer. TAM inhibitors are promising investigational therapies for pancreatic cancer due to their potential to target multiple aspects of pancreatic cancer biology. Specifically, recent mechanistic investigations and therapeutic combinations in the preclinical setting suggest that TAM inhibition with chemotherapy, targeted therapy, and immunotherapy should be evaluated clinically.
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Affiliation(s)
- Mitchell S von Itzstein
- Division of Hematology/Oncology, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-8852, USA
- Division of Hematology and Medical Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Michael C Burke
- Division of Hematology/Oncology, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-8852, USA
- Division of Hematology and Medical Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Rolf A Brekken
- Division of Surgical Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Todd A Aguilera
- Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Herbert J Zeh
- Division of Surgical Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Muhammad Shaalan Beg
- Division of Hematology/Oncology, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-8852, USA.
- Division of Hematology and Medical Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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30
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Ottley EC, Pell R, Brazier B, Hollidge J, Kartsonaki C, Browning L, O'Neill E, Kiltie AE. Greater utility of molecular subtype rather than epithelial-to-mesenchymal transition (EMT) markers for prognosis in high-risk non-muscle-invasive (HGT1) bladder cancer. J Pathol Clin Res 2020; 6:238-251. [PMID: 32374509 PMCID: PMC7578305 DOI: 10.1002/cjp2.167] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 03/10/2020] [Accepted: 03/20/2020] [Indexed: 01/21/2023]
Abstract
Approximately 75% of bladder cancers are non-muscle invasive (NMIBC). Of these, up to 53% of cases progress to life-threatening muscle-invasive bladder cancer (MIBC). Patients with high-grade stage T1 (HGT1) NMIBC frequently undergo radical cystectomy (RC), although this represents overtreatment for many. Identification of progressors versus non-progressors could spare unnecessary treatment. Recent studies have confirmed that urothelial carcinoma is composed of two main molecular subtypes, basal and luminal, with 12% of basal tumours exhibiting epithelial-to-mesenchymal transition (EMT). Levels of immune cell infiltration have been shown to be subtype-specific. Here, we performed immunohistochemistry (IHC) for 11 antibodies relating to molecular subtypes or EMT in 26 cases of HGT1 urothelial carcinoma cases with 6 matched samples subsequently obtained at cystectomy (n = 6; 1 muscle-invasive, 5 non-muscle-invasive; 3 = pTis, 1 = pT1, 1 = pTa) and at recurrence (n = 2, pT2). RNAScope was also conducted in a subset. Expression patterns in HGT1 specimens versus MIBC (pT2+) were examined, and correlated with disease-specific survival (DSS). Levels of stromal tumour-infiltrating lymphocytes (sTILs) were assessed manually to determine whether lymphocyte infiltration was associated with DSS and whether differences existed between HGT1 and MIBC. Molecular subtype markers demonstrated increased prognostic potential compared to the EMT markers assessed. Increased expression of the luminal markers FOXA1 and SCUBE2, were found to be significantly associated with better DFS. No EMT markers were significantly associated with DFS. In areas of non-invasive papillary urothelial carcinoma, but not invasive carcinoma, sTIL levels were found to be significantly associated with DFS. While differences were observed between HGT1 cases that progressed versus those that did not, a larger cohort study is required for validation of these findings. Taken together, an emphasis on molecular subtype markers, rather than EMT markers, may be preferable when studying biomarkers of HGT1 urothelial carcinoma in the future.
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Affiliation(s)
- Edward C Ottley
- CRUK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Robert Pell
- CRUK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Benedict Brazier
- CRUK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Julianne Hollidge
- Nuffield Department of Surgical SciencesUniversity of OxfordOxfordUK
| | | | - Lisa Browning
- Department of Cellular Pathology, and the NIHR Oxford Biomedical Research CentreJohn Radcliffe HospitalOxfordUK
| | - Eric O'Neill
- CRUK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
| | - Anne E Kiltie
- CRUK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK
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31
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Bae CA, Ham IH, Oh HJ, Lee D, Woo J, Son SY, Yoon JH, Lorens JB, Brekken RA, Kim TM, Han SU, Park WS, Hur H. Inhibiting the GAS6/AXL axis suppresses tumor progression by blocking the interaction between cancer-associated fibroblasts and cancer cells in gastric carcinoma. Gastric Cancer 2020; 23:824-836. [PMID: 32239298 DOI: 10.1007/s10120-020-01066-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 03/22/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The effects of cancer-associated fibroblasts (CAF) on the progression of gastric carcinoma (GC) has recently been demonstrated. However, agents targeting the interaction between CAF and GC cells have not been applied in a clinical setting. Here, we examined if inhibition for Axl receptor tyrosine kinase (AXL) can suppress CAF-induced aggressive phenotype in GC. METHODS We investigated the function of CAF-derived growth arrest-specific 6 (GAS6), a major ligand of AXL, on the migration and proliferation of GC cells. The effect of the AXL inhibitor, BGB324, on the CAF-induced aggressive phenotype of GC cells was also investigated. In addition, we performed immunohistochemistry to examine the expression of phosphorylated AXL protein in 175 GC tissues and evaluated its correlation with the prognosis. RESULTS The qPCR and western blot analysis showed that GAS6 expression was higher in CAF relative to other cells. We found that co-culture with CAF increased the phosphorylation of AXL (P-AXL), differentiation into a mesenchymal-like phenotype, and cell survival in GC cell lines. When the expression of AXL was genetically inhibited in GC cells, the effect of CAF was reduced. BGB324, a small molecule inhibitor of AXL, suppressed the effects of CAF on GC cell lines. In GC tissues, high levels of P-AXL were significantly associated with poor overall survival (P = 0.022). CONCLUSIONS We concluded that CAF are a major source of GAS6 and that GAS6 promotes an aggressiveness through AXL activation in GC. We suggested that an AXL inhibitor may be a novel agent for GC treatment.
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Affiliation(s)
- Cheong A Bae
- Department of Surgery, Ajou University School of Medicine, Cancer Biology Graduate Program, Ajou University Graduate School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon-si, Gyunggi-do, 16499, Republic of Korea
- Department of Biomedical Science, Graduated School of Ajou University, Suwon, Republic of Korea
| | - In-Hye Ham
- Department of Surgery, Ajou University School of Medicine, Cancer Biology Graduate Program, Ajou University Graduate School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon-si, Gyunggi-do, 16499, Republic of Korea
| | - Hye Jeong Oh
- Department of Surgery, Ajou University School of Medicine, Cancer Biology Graduate Program, Ajou University Graduate School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon-si, Gyunggi-do, 16499, Republic of Korea
| | - Dagyeong Lee
- Department of Surgery, Ajou University School of Medicine, Cancer Biology Graduate Program, Ajou University Graduate School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon-si, Gyunggi-do, 16499, Republic of Korea
- Department of Biomedical Science, Graduated School of Ajou University, Suwon, Republic of Korea
| | - Jongsu Woo
- Department of Surgery, Ajou University School of Medicine, Cancer Biology Graduate Program, Ajou University Graduate School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon-si, Gyunggi-do, 16499, Republic of Korea
- Department of Biomedical Science, Graduated School of Ajou University, Suwon, Republic of Korea
| | - Sang-Yong Son
- Department of Surgery, Ajou University School of Medicine, Cancer Biology Graduate Program, Ajou University Graduate School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon-si, Gyunggi-do, 16499, Republic of Korea
| | - Jung Hwan Yoon
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - James B Lorens
- Department of Biomedicine, Centre for Cancer Biomarkers (CCBIO), University of Bergen, Bergen, Norway
| | - Rolf A Brekken
- Division of Surgical Oncology, Department of Surgery, Haman Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, US
| | - Tae-Min Kim
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sang-Uk Han
- Department of Surgery, Ajou University School of Medicine, Cancer Biology Graduate Program, Ajou University Graduate School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon-si, Gyunggi-do, 16499, Republic of Korea
| | - Won Sang Park
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hoon Hur
- Department of Surgery, Ajou University School of Medicine, Cancer Biology Graduate Program, Ajou University Graduate School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon-si, Gyunggi-do, 16499, Republic of Korea.
- Department of Biomedical Science, Graduated School of Ajou University, Suwon, Republic of Korea.
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32
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Malfitano AM, Pisanti S, Napolitano F, Di Somma S, Martinelli R, Portella G. Tumor-Associated Macrophage Status in Cancer Treatment. Cancers (Basel) 2020; 12:cancers12071987. [PMID: 32708142 PMCID: PMC7409350 DOI: 10.3390/cancers12071987] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/13/2020] [Accepted: 07/17/2020] [Indexed: 12/14/2022] Open
Abstract
Tumor-associated macrophages (TAMs) represent the most abundant innate immune cells in tumors. TAMs, exhibiting anti-inflammatory phenotype, are key players in cancer progression, metastasis and resistance to therapy. A high TAM infiltration is generally associated with poor prognosis, but macrophages are highly plastic cells that can adopt either proinflammatory/antitumor or anti-inflammatory/protumor features in response to tumor microenvironment stimuli. In the context of cancer therapy, many anticancer therapeutics, apart from their direct effect on tumor cells, display different effects on TAM activation status and density. In this review, we aim to evaluate the indirect effects of anticancer therapies in the modulation of TAM phenotypes and pro/antitumor activity.
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Affiliation(s)
- Anna Maria Malfitano
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (F.N.); (S.D.S.)
- Correspondence: (A.M.M.); (G.P.); Tel.: +39-081-746-3056 (G.P.)
| | - Simona Pisanti
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvador Allende, Baronissi, 84081 Salerno, Italy; (S.P.); (R.M.)
| | - Fabiana Napolitano
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (F.N.); (S.D.S.)
| | - Sarah Di Somma
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (F.N.); (S.D.S.)
| | - Rosanna Martinelli
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvador Allende, Baronissi, 84081 Salerno, Italy; (S.P.); (R.M.)
| | - Giuseppe Portella
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (F.N.); (S.D.S.)
- Correspondence: (A.M.M.); (G.P.); Tel.: +39-081-746-3056 (G.P.)
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33
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Pilli VS, Datta A, Dorsey A, Liu B, Majumder R. Modulation of protein S and growth arrest specific 6 protein signaling inhibits pancreatic cancer cell survival and proliferation. Oncol Rep 2020; 44:1322-1332. [PMID: 32945517 PMCID: PMC7448444 DOI: 10.3892/or.2020.7689] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 05/08/2020] [Indexed: 12/14/2022] Open
Abstract
Thrombotic complications and hypercoagulopathies are commonly associated with the progression of pancreatic ductal adenocarcinoma (PDAC). Although the mechanistic link between the two phenomena is uncertain, there is evidently an increase in procoagulant proteins and a decrease in anticoagulants in PDAC patients. For example, the anticoagulant protein S (PS) is decreased during the progression of PDAC, a condition that possibly contributes to the hypercoagulopathies. PS is also an important signaling molecule that binds a family of tyrosine kinase receptors known as TAM (Tyro3, Axl and Mer) receptors; TAM receptors are often upregulated in different cancers. Growth Arrest Specific 6 or GAS6 protein, a homolog of PS, is also a TAM receptor family ligand. The downstream signaling pathways triggered by this ligand-receptor interaction perform diverse functions, such as cell survival, proliferation, efferocytosis, and apoptosis. Targeting the TAM receptors to treat cancer has had limited success; side effects are a significant obstacle due to the widespread numerous functions of TAM receptors. In the present study, it was revealed that PS-TAM interaction was pro-apoptotic, whereas GAS6-mediated TAM signaling promoted proliferation and survival in select PDAC cell lines. Furthermore, by regulating the balance between these two signaling pathways (by overexpressing PS or knocking down GAS6), the proliferative potential of the cells was decreased. Both long-term and short-term effects of natural PS overexpression were comparable to the treatment of the cells with the drug UNC2025, which inhibits the Mer-receptor. The present study lays the foundation for investigation of PS as a therapeutic agent to control cancer progression and to concurrently arrest thrombotic events.
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Affiliation(s)
- Vijaya S Pilli
- Department of Biochemistry, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Arani Datta
- Department of Biochemistry, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Adrianne Dorsey
- Department of Biochemistry, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Bo Liu
- Department of Surgery, University of Wisconsin, Madison, WI 53705, USA
| | - Rinku Majumder
- Department of Biochemistry, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
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Rocha-Brito KJP, Fonseca EMB, Oliveira BGDF, Fátima ÂD, Ferreira-Halder CV. Calix[6]arene diminishes receptor tyrosine kinase lifespan in pancreatic cancer cells and inhibits their migration and invasion efficiency. Bioorg Chem 2020; 100:103881. [PMID: 32388429 DOI: 10.1016/j.bioorg.2020.103881] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 04/07/2020] [Accepted: 04/22/2020] [Indexed: 12/14/2022]
Abstract
Pancreatic cancer is a challenging malignancy, mainly due to aggressive regional involvement, early systemic dissemination, high recurrence rate, and subsequent low patient survival. Scientific advances have contributed in particular by identification of molecular targets as well as the definition of the mechanism of action of the drug candidate in the cellular microenvironment. Previously, we have reported the identification of the molecular mechanisms by which calix[6]arene (CLX6) reduces the viability and proliferation of pancreatic cancer cells. Now, we show the biochemical mechanisms by which CLX6 decreases the aggressiveness of Panc-1 cells, focusing specifically on receptor tyrosine kinases (RTK). The results show that clathrin-mediated endocytosis is involved in CLX6-induced AXL receptor tyrosine kinase degradation in Panc-1 cells. This response may be related to the interaction of CLX6 with the tyrosine kinase receptor binding site (such as AXL). As a result, RTK is internalized and degraded by endocytosis, a condition that negatively impacts events dependent on its signaling. Additionally, CLX6 inhibits migration and invasion of Panc-1 cells by downregulating FAK (downstream mediator of AXL) activity and reducing expression levels of MMP2 and MMP9, directly related to the metastatic profile of these cells. It is noteworthy that according to the mechanism proposed here, CLX6 appears as a candidate to be used in therapeutic protocols of patients that display high expression of AXL and consequently, poor diagnosis.
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Affiliation(s)
- Karin Juliane Pelizzaro Rocha-Brito
- Department of Biochemistry and Tissue Biology, Biology Institute, University of Campinas, Campinas, São Paulo, Brazil; Department of Medicine, Health Sciences Center, University Center of Maringá, Maringá, Paraná, Brazil
| | - Emanuella Maria Barreto Fonseca
- Department of Biochemistry and Tissue Biology, Biology Institute, University of Campinas, Campinas, São Paulo, Brazil; Federal Institute of Education, Science and Technology of São Paulo, São Roque, São Paulo, Brazil
| | | | - Ângelo de Fátima
- Department of Chemistry, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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35
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Lechertier T, Reynolds LE, Kim H, Pedrosa AR, Gómez-Escudero J, Muñoz-Félix JM, Batista S, Dukinfield M, Demircioglu F, Wong PP, Matchett KP, Henderson NC, D'Amico G, Parsons M, Harwood C, Meier P, Hodivala-Dilke KM. Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth. Nat Commun 2020; 11:2810. [PMID: 32499572 PMCID: PMC7272651 DOI: 10.1038/s41467-020-16618-6] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 05/14/2020] [Indexed: 12/21/2022] Open
Abstract
The overexpression of the protein tyrosine kinase, Focal adhesion kinase (FAK), in endothelial cells has implicated its requirement in angiogenesis and tumour growth, but how pericyte FAK regulates tumour angiogenesis is unknown. We show that pericyte FAK regulates tumour growth and angiogenesis in multiple mouse models of melanoma, lung carcinoma and pancreatic B-cell insulinoma and provide evidence that loss of pericyte FAK enhances Gas6-stimulated phosphorylation of the receptor tyrosine kinase, Axl with an upregulation of Cyr61, driving enhanced tumour growth. We further show that pericyte derived Cyr61 instructs tumour cells to elevate expression of the proangiogenic/protumourigenic transmembrane receptor Tissue Factor. Finally, in human melanoma we show that when 50% or more tumour blood vessels are pericyte-FAK negative, melanoma patients are stratified into those with increased tumour size, enhanced blood vessel density and metastasis. Overall our data uncover a previously unknown mechanism of tumour growth by pericytes that is controlled by pericyte FAK.
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Affiliation(s)
- Tanguy Lechertier
- Centre for Tumour Biology, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK
| | - Louise E Reynolds
- Centre for Tumour Biology, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK
| | - Hyojin Kim
- Cell Death & Inflammation, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK
| | - Ana Rita Pedrosa
- Centre for Tumour Biology, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK
| | - Jesús Gómez-Escudero
- Centre for Tumour Biology, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK
| | - José M Muñoz-Félix
- Centre for Tumour Biology, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK
| | - Silvia Batista
- Systems Oncology Group, Champalimaud Research, Champalimaud Centre for the Unknown Av. Brasília, Doca de Pedrouços, 1400-038, Lisbon, Portugal
| | - Matthew Dukinfield
- Centre for Tumour Biology, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK
| | - Fevzi Demircioglu
- Centre for Tumour Biology, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK
| | - Ping Pui Wong
- Centre for Tumour Biology, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 510120, Guangzhou, China
| | - Kylie P Matchett
- Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, UK
| | - Neil C Henderson
- Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, UK
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, UK
| | - Gabriela D'Amico
- Centre for Tumour Biology, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK
| | - Maddy Parsons
- Nikon Imaging Centre@King's, Randall Division of Cell and Molecular Biophysics, Kings College London, Room 3.22B, New Hunts House Guys Campus, London, SE1 1UL, UK
| | - Catherine Harwood
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK
| | - Pascal Meier
- Cell Death & Inflammation, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK
| | - Kairbaan M Hodivala-Dilke
- Centre for Tumour Biology, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK.
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Mao S, Wu Y, Wang R, Guo Y, Bi D, Ma W, Zhang W, Zhang J, Yan Y, Yao X. Overexpression of GAS6 Promotes Cell Proliferation and Invasion in Bladder Cancer by Activation of the PI3K/AKT Pathway. Onco Targets Ther 2020; 13:4813-4824. [PMID: 32547108 PMCID: PMC7261663 DOI: 10.2147/ott.s237174] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 05/07/2020] [Indexed: 12/19/2022] Open
Abstract
Background Growth arrest-specific 6 (GAS6) is a secreted vitamin K-dependent protein abnormally expressed in various human tumor tissues and can activate the receptor Tyro3, Axl, and Mer to promote cancer cell proliferation and invasion. Until now, the role of GAS6 has been poorly understood in bladder cancer (BCa). Materials and Methods Using bioinformatics analysis, we screened genes significantly associated with overall survival in BCa. The association between GAS6 and survival was evaluated by tissue microarray and IHC staining. We investigated the effect of GAS6 on the development of BCa through in vitro and in vivo experiments. Results Here, we report that GAS6 is highly expressed in bladder cancer and is significantly associated with tumor grade, T stage, and worse prognosis. We found that GAS6 depletion inhibited proliferation, migration, and invasion of BCa cells. In addition, bioinformatics analysis revealed that GAS6 may be involved in the regulation of PI3K-AKT signaling pathway by binding to receptor TAM and has a significant positive correlation with PI3K family gene expression. Furthermore, Western blot experiments have shown that GAS6 might modulate the PI3K-AKT signaling to regulate proliferation and invasion of BCa cells. Treatment of BCa cells with SC79, an AKT activator, partially restored the effect of GAS6 silencing on cell proliferation and invasion. Conclusion The present study suggests that GAS6 may play a pivotal role in the development of BCa and may be a potential target for its treatment.
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Affiliation(s)
- Shiyu Mao
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Yuan Wu
- Department of Urology, Shanghai Tenth People's Hospital, Anhui Medical University, Hefei 230032, People's Republic of China
| | - Ruiliang Wang
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Yadong Guo
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Dexi Bi
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Wenchao Ma
- Department of Urology, Shanghai Tenth People's Hospital, Anhui Medical University, Hefei 230032, People's Republic of China
| | - Wentao Zhang
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Junfeng Zhang
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Yang Yan
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
| | - Xudong Yao
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, People's Republic of China
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Ireland L, Luckett T, Schmid MC, Mielgo A. Blockade of Stromal Gas6 Alters Cancer Cell Plasticity, Activates NK Cells, and Inhibits Pancreatic Cancer Metastasis. Front Immunol 2020; 11:297. [PMID: 32174917 PMCID: PMC7056881 DOI: 10.3389/fimmu.2020.00297] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 02/05/2020] [Indexed: 12/16/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers due to its aggressive and metastatic nature. PDA is characterized by a rich tumor stroma with abundant macrophages, fibroblasts, and collagen deposition that can represent up to 90% of the tumor mass. Activation of the tyrosine kinase receptor AXL and expression of its ligand growth arrest-specific protein 6 (Gas6) correlate with a poor prognosis and increased metastasis in pancreatic cancer patients. Gas6 is a multifunctional protein that can be secreted by several cell types and regulates multiple processes, including cancer cell plasticity, angiogenesis, and immune cell functions. However, the role of Gas6 in pancreatic cancer metastasis has not been fully investigated. In these studies we find that, in pancreatic tumors, Gas6 is mainly produced by tumor associated macrophages (TAMs) and cancer associated fibroblasts (CAFs) and that pharmacological blockade of Gas6 signaling partially reverses epithelial-to-mesenchymal transition (EMT) of tumor cells and supports NK cell activation, thereby inhibiting pancreatic cancer metastasis. Our data suggest that Gas6 simultaneously acts on both the tumor cells and the NK cells to support pancreatic cancer metastasis. This study supports the rationale for targeting Gas6 in pancreatic cancer and use of NK cells as a potential biomarker for response to anti-Gas6 therapy.
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Affiliation(s)
| | | | | | - Ainhoa Mielgo
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom
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Song X, Akasaka H, Wang H, Abbasgholizadeh R, Shin JH, Zang F, Chen J, Logsdon CD, Maitra A, Bean AJ, Wang H. Hematopoietic progenitor kinase 1 down-regulates the oncogenic receptor tyrosine kinase AXL in pancreatic cancer. J Biol Chem 2020; 295:2348-2358. [PMID: 31959629 PMCID: PMC7039544 DOI: 10.1074/jbc.ra119.012186] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 01/14/2020] [Indexed: 12/23/2022] Open
Abstract
The oncogenic receptor tyrosine kinase AXL is overexpressed in cancer and plays an important role in carcinomas of multiple organs. However, the mechanisms of AXL overexpression in cancer remain unclear. In this study, using HEK293T, Panc-1, and Panc-28 cells and samples of human pancreatic intraepithelial neoplasia (PanIN), along with several biochemical approaches and immunofluorescence microscopy analyses, we sought to investigate the mechanisms that regulate AXL over-expression in pancreatic ductal adenocarcinoma (PDAC). We found that AXL interacts with hematopoietic progenitor kinase 1 (HPK1) and demonstrate that HPK1 down-regulates AXL and decreases its half-life. The HPK1-mediated AXL degradation was inhibited by the endocytic pathway inhibitors leupeptin, bafilomycin A1, and monensin. HPK1 accelerated the movement of AXL from the plasma membrane to endosomes in pancreatic cancer cells treated with the AXL ligand growth arrest-specific 6 (GAS6). Moreover, HPK1 increased the binding of AXL to the Cbl proto-oncogene (c-Cbl); promoted AXL ubiquitination; decreased AXL-mediated signaling, including phospho-AKT and phospho-ERK signaling; and decreased the invasion capability of PDAC cells. Importantly, we show that AXL expression inversely correlates with HPK1 expression in human PanINs and that patients whose tumors have low HPK1 and high AXL expression levels have shorter survival than those with low AXL or high HPK1 expression (p < 0.001). Our results suggest that HPK1 is a tumor suppressor that targets AXL for degradation via the endocytic pathway. HPK1 loss of function may contribute to AXL overexpression and thereby enhance AXL-dependent downstream signaling and tumor invasion in PDAC.
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Affiliation(s)
- Xianzhou Song
- Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030
| | - Hironari Akasaka
- Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030
| | - Hua Wang
- Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030
| | - Reza Abbasgholizadeh
- Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030
| | - Ji-Hyun Shin
- Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030
| | - Fenglin Zang
- Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030
| | - Jiayi Chen
- Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030
| | - Craig D Logsdon
- Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030
| | - Anirban Maitra
- Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030; Department of Translational Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030
| | - Andrew J Bean
- Department of Neurobiology and Anatomy, University of Texas McGovern Medical School, Houston, Texas 77030
| | - Huamin Wang
- Department of Anatomical Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030; Department of Translational Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
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Lérias JR, de Sousa E, Paraschoudi G, Martins J, Condeço C, Figueiredo N, Carvalho C, Dodoo E, Maia A, Castillo-Martin M, Beltrán A, Ligeiro D, Rao M, Zumla A, Maeurer M. Trained Immunity for Personalized Cancer Immunotherapy: Current Knowledge and Future Opportunities. Front Microbiol 2020; 10:2924. [PMID: 31998254 PMCID: PMC6967396 DOI: 10.3389/fmicb.2019.02924] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 12/04/2019] [Indexed: 12/17/2022] Open
Abstract
Memory formation, guided by microbial ligands, has been reported for innate immune cells. Epigenetic imprinting plays an important role herein, involving histone modification after pathogen-/danger-associated molecular patterns (PAMPs/DAMPs) recognition by pattern recognition receptors (PRRs). Such "trained immunity" affects not only the nominal target pathogen, yet also non-related targets that may be encountered later in life. The concept of trained innate immunity warrants further exploration in cancer and how these insights can be implemented in immunotherapeutic approaches. In this review, we discuss our current understanding of innate immune memory and we reference new findings in this field, highlighting the observations of trained immunity in monocytic and natural killer cells. We also provide a brief overview of trained immunity in non-immune cells, such as stromal cells and fibroblasts. Finally, we present possible strategies based on trained innate immunity that may help to devise host-directed immunotherapies focusing on cancer, with possible extension to infectious diseases.
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Affiliation(s)
- Joana R Lérias
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Eric de Sousa
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | | | - João Martins
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Carolina Condeço
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Nuno Figueiredo
- Digestive Unit, Champalimaud Clinical Centre, Lisbon, Portugal
| | - Carlos Carvalho
- Digestive Unit, Champalimaud Clinical Centre, Lisbon, Portugal
| | - Ernest Dodoo
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Andreia Maia
- Molecular and Experimental Pathology Laboratory, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Mireia Castillo-Martin
- Molecular and Experimental Pathology Laboratory, Champalimaud Centre for the Unknown, Lisbon, Portugal.,Department of Pathology, Champalimaud Clinical Centre, Lisbon, Portugal
| | - Antonio Beltrán
- Department of Pathology, Champalimaud Clinical Centre, Lisbon, Portugal
| | - Dário Ligeiro
- Lisbon Centre for Blood and Transplantation, Instituto Português do Sangue e Transplantação, Lisbon, Portugal
| | - Martin Rao
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Alimuddin Zumla
- Division of Infection and Immunity, NIHR Biomedical Research Centre, UCL Hospitals, NHS Foundation Trust, University College London, London, United Kingdom
| | - Markus Maeurer
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
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Westerfield JM, Barrera FN. Membrane receptor activation mechanisms and transmembrane peptide tools to elucidate them. J Biol Chem 2019; 295:1792-1814. [PMID: 31879273 DOI: 10.1074/jbc.rev119.009457] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Single-pass membrane receptors contain extracellular domains that respond to external stimuli and transmit information to intracellular domains through a single transmembrane (TM) α-helix. Because membrane receptors have various roles in homeostasis, signaling malfunctions of these receptors can cause disease. Despite their importance, there is still much to be understood mechanistically about how single-pass receptors are activated. In general, single-pass receptors respond to extracellular stimuli via alterations in their oligomeric state. The details of this process are still the focus of intense study, and several lines of evidence indicate that the TM domain (TMD) of the receptor plays a central role. We discuss three major mechanistic hypotheses for receptor activation: ligand-induced dimerization, ligand-induced rotation, and receptor clustering. Recent observations suggest that receptors can use a combination of these activation mechanisms and that technical limitations can bias interpretation. Short peptides derived from receptor TMDs, which can be identified by screening or rationally developed on the basis of the structure or sequence of their targets, have provided critical insights into receptor function. Here, we explore recent evidence that, depending on the target receptor, TMD peptides cannot only inhibit but also activate target receptors and can accommodate novel, bifunctional designs. Furthermore, we call for more sharing of negative results to inform the TMD peptide field, which is rapidly transforming into a suite of unique tools with the potential for future therapeutics.
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Affiliation(s)
- Justin M Westerfield
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996
| | - Francisco N Barrera
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996.
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41
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Arner EN, Du W, Brekken RA. Behind the Wheel of Epithelial Plasticity in KRAS-Driven Cancers. Front Oncol 2019; 9:1049. [PMID: 31681587 PMCID: PMC6798880 DOI: 10.3389/fonc.2019.01049] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 09/26/2019] [Indexed: 12/15/2022] Open
Abstract
Cellular plasticity, a feature associated with epithelial-to-mesenchymal transition (EMT), contributes to tumor cell survival, migration, invasion, and therapy resistance. Phenotypic plasticity of the epithelium is a critical feature in multiple phases of human cancer in an oncogene- and tissue-specific context. Many factors can drive epithelial plasticity, including activating mutations in KRAS, which are found in an estimated 30% of all cancers. In this review, we will introduce cellular plasticity and its effect on cancer progression and therapy resistance and then summarize the drivers of EMT with an emphasis on KRAS effector signaling. Lastly, we will discuss the contribution of cellular plasticity to metastasis and its potential clinical implications. Understanding oncogenic KRAS cellular reprogramming has the potential to reveal novel strategies to control metastasis in KRAS-driven cancers.
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Affiliation(s)
- Emily N Arner
- Cancer Biology Graduate Program, Department of Surgery and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Wenting Du
- Cancer Biology Graduate Program, Department of Surgery and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Rolf A Brekken
- Cancer Biology Graduate Program, Department of Surgery and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, United States.,Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, United States
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42
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Nam RK, Benatar T, Wallis CJD, Kobylecky E, Amemiya Y, Sherman C, Seth A. MicroRNA-139 is a predictor of prostate cancer recurrence and inhibits growth and migration of prostate cancer cells through cell cycle arrest and targeting IGF1R and AXL. Prostate 2019; 79:1422-1438. [PMID: 31269290 DOI: 10.1002/pros.23871] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 05/21/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND We previously identified a panel of five microRNAs (miRNAs) associated with biochemical recurrence and metastasis following prostatectomy from prostate cancer patients using next-generation sequencing-based whole miRNome sequencing and quantitative polymerase chain reaction-based validation analysis. In this study, we examined the mechanism of action of miR-139-5p, one of the downregulated miRNAs identified in the panel. METHODS Using a cohort of 585 patients treated with radical prostatectomy, we examined the prognostic significance of miR-139 (dichotomized around the median) using the Kaplan-Meier method and Cox proportional hazard models. We validated these results using The Cancer Genome Atlas (TCGA) data. We created cell lines that overexpressed miR-139 to confirm its targets as well as examine pathways through which miR-139 may function using cell-based assays. RESULTS Low miR-139 expression was significantly associated with a variety of prognostic factors in prostate cancer, including Gleason score, pathologic stage, margin positivity, and lymph node status. MiR-139 expression was associated with prognosis: the cumulative incidence of biochemical recurrence and metastasis were significantly lower among patients with high miR-139 expression (P = .0004 and .038, respectively). Validation in the TCGA data set showed a significant association between dichotomized miR-139 expression and biochemical recurrence (odds ratio, 0.52; 95% confidence interval, 0.33-0.82). Overexpression of miR-139 in prostate cancer cells led to a significant reduction in cell proliferation and migration compared with control cells, with cells arrested in G2 of cell cycle. IGF1R and AXL were identified as potential targets of miR-139 based on multiple miRNA-binding sites in 3'-untranslated regions of both the genes and their association with prostate cancer growth pathways. Luciferase assays verified AXL and IGF1R as direct targets of miR-139. Furthermore, immunoblotting of prostate cancer cells demonstrated IGF1R and AXL protein expression were inhibited by miR-139 treatment, which was reversed by the addition of miR-139 antagomir. Examination of the molecular mechanism of growth inhibition by miR-139 revealed the downregulation of activated AKT and cyclin D1, with upregulation of the CDK inhibitor p21. CONCLUSIONS miR-139 is associated with improved prognosis in patients with localized prostate cancer, which may be mediated through downregulation of IGF1R and/or AXL and associated signaling pathway components.
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Affiliation(s)
- Robert K Nam
- Division of Urology, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada
| | - Tania Benatar
- Platform Biological Sciences, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada
| | - Christopher J D Wallis
- Division of Urology, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada
| | - Elizabeth Kobylecky
- Platform Biological Sciences, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada
| | - Yutaka Amemiya
- Genomics Core Facility, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Christopher Sherman
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Arun Seth
- Platform Biological Sciences, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada
- Genomics Core Facility, Sunnybrook Research Institute, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
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Targeting acquired oncogenic burden in resilient pancreatic cancer: a novel benefit from marine polyphenols. Mol Cell Biochem 2019; 460:175-193. [PMID: 31367889 DOI: 10.1007/s11010-019-03579-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 06/21/2019] [Indexed: 02/07/2023]
Abstract
The upsurge of marine-derived therapeutics for cancer treatment is evident, with many drugs in clinical use and in clinical trials. Seaweeds harbor large amounts of polyphenols and their anti-cancer benefit is linear to their anti-oxidant activity. Our studies identified three superlative anti-cancer seaweed polyphenol drug candidates (SW-PD). We investigated the acquisition of oncogenic burden in radiation-resilient pancreatic cancer (PC) that could drive tumor relapse, and elucidated the efficacy of SW-PD candidates as adjuvants in genetically diverse in vitro systems and a mouse model of radiation-residual disease. QPCR profiling of 88 oncogenes in therapy-resilient PC cells identified a 'shared' activation of 40 oncogenes. SW-PD pretreatment inflicted a significant mitigation of acquired (shared) oncogenic burden, in addition to drug- and cell-line-specific repression signatures. Tissue microarray with IHC of radiation-residual tumors in mice signified acquired cellular localization of key oncoproteins and other critical architects. Conversely, SW-PD treatment inhibited the acquisition of these critical drivers of tumor genesis, dissemination, and evolution. Heightened death of resilient PC cells with SW-PD treatment validated the translation aspects. The results defined the acquisition of oncogenic burden in resilient PC and demonstrated that the marine polyphenols effectively target the acquired oncogenic burden and could serve as adjuvant(s) for PC treatment.
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44
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ssExpression level of GAS6-mRNA influences the prognosis of acute myeloid leukemia patients with allogeneic hematopoietic stem cell transplantation. Biosci Rep 2019; 39:BSR20190389. [PMID: 31028135 PMCID: PMC6527924 DOI: 10.1042/bsr20190389] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 04/20/2019] [Accepted: 04/24/2019] [Indexed: 11/17/2022] Open
Abstract
As high expression level of growth arrest-specific 6 (GAS6) had an adverse effect on prognosis in acute myeloid leukemia (AML) patients, it is interesting to reveal the relationship between GAS6-mRNA level and the survival condition of AML patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). We screened The Cancer Genome Atlas database and found 71 AML patients with GAS6-mRNA expression and received allo-HSCT treatments. We divided them into two groups based on the median expression of GAS6-mRNA. Patients with GAS6-mRNAhigh (n=36) seemed to have lower bone marrow (BM) blast (P=0.022), lower percentage of type M5 (P=0.034), lower percentage of inv(16)/CBFβ-MYH11 karyotype (P=0.020), and lower rate of good risk classification (P=0.005) than the group GAS6-mRNAlow (n= 35). Higher expression level of GAS6-mRNA also brought higher RUNX1 mutations (P=0.003), MLL-PTD mutations (P=0.042), TP53 mutations (P=0.042), and lower NRAS/KRAS mutations (P=0.042). Univariate analyses showed that GAS6-mRNA was unfavorable for overall survival (OS) (P=0.044), as RUNX1 and WT1 also gave negative influences. Multivariate analyses confirmed that GAS6-mRNA cut down the event-free servival (EFS) and OS of AML patients with HSCT (P=0.029, P=0.025). Our study indicated that higher expression of GAS6-mRNA related with adverse effects in AML patients with HSCT treatment.
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Antony J, Thiery JP, Huang RYJ. Epithelial-to-mesenchymal transition: lessons from development, insights into cancer and the potential of EMT-subtype based therapeutic intervention. Phys Biol 2019; 16:041004. [PMID: 30939460 DOI: 10.1088/1478-3975/ab157a] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Epithelial-to-mesenchymal transition (EMT) is a fundamental developmental process wherein polarized epithelial cells lose their junctional architecture and apical-basal polarity to become motile mesenchymal cells, and there is emerging evidence for its role in propagating tumor dissemination. While many multifaceted nodules converge onto the EMT program, in this review we will highlight the fundamental biology of the signaling schemas that enable EMT. In many cancers, the property of tumor dissemination and metastasis is closely associated with re-enabling developmental properties such as EMT. We discuss the molecular complexity of the tumor heterogeneity in terms of EMT-based gene expression molecular subtypes, and the rewiring of critical signaling nodules in the subtypes displaying higher degrees of EMT can be therapeutically exploited. Specifically in the context of a deadly malignancy such as ovarian cancer where there are no defined mutations or limited biomarkers for developing targeted therapy or personalized medicine, we highlight the importance of identifying EMT-based subtypes that will improve therapeutic intervention. In ovarian cancer, the poor prognosis mesenchymal 'Mes' subtype presents with amplified signaling of the receptor tyrosine kinase (RTK) AXL, extensive crosstalk with other RTKs such as cMET, EGFR and HER2, and sustained temporal activation of extracellular-signal regulated kinase (ERK) leading to induction of EMT transcription factor Slug, underscoring a pathway addiction in Mes that can be therapeutically targeted. We will further examine the emergence of therapeutic modalities in these EMT subtypes and finally conclude with potential interdisciplinary biophysical methodologies to provide additional insights in deciphering the mechanistic and biochemical aspects of EMT. This review intends to provide an overview of the cellular and molecular changes accompanying epithelial-to-mesenchymal transition (EMT) in development and the requisition of this evolutionarily conserved pathway in cancer progression and metastatic disease. Specifically, in a heterogeneous disease such as ovarian cancer lacking defined targetable mutations, the identification of EMT-based subtypes has opened avenues to tailor precision personalized medicine. In particular, using the oncogenic RTK AXL as an example, we will highlight how this classification enables EMT-subtype specific identification of targets that could improve treatment options for patients and how there is a growing need for biophysical approaches to model dynamic processes such as EMT.
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Affiliation(s)
- Jane Antony
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, United States of America
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Abstract
IMPACT STATEMENT Cancer is among the leading causes of death worldwide. In 2016, 8.9 million people are estimated to have died from various forms of cancer. The current treatments, including surgery with chemotherapy and/or radiation therapy, are not effective enough to provide full protection from cancer, which highlights the need for developing novel therapy strategies. In this review, we summarize the molecular biology of a unique member of a subfamily of receptor tyrosine kinase, TYRO3 and discuss the new insights in TYRO3-targeted treatment for cancer therapy.
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Affiliation(s)
- Pei-Ling Hsu
- 1 Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Jonathan Jou
- 2 College of Medicine, University of Illinois, IL 60612, USA
| | - Shaw-Jenq Tsai
- 1 Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
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Dynamics of Axl Receptor Shedding in Hepatocellular Carcinoma and Its Implication for Theranostics. Int J Mol Sci 2018; 19:ijms19124111. [PMID: 30567378 PMCID: PMC6321118 DOI: 10.3390/ijms19124111] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 12/14/2018] [Accepted: 12/17/2018] [Indexed: 12/20/2022] Open
Abstract
Signaling of the receptor tyrosine kinase Axl and its ligand Gas6 is crucially involved in the development of liver fibrosis and hepatocellular carcinoma (HCC) by activation of hepatic stellate cells and modulation of hepatocyte differentiation. Shedding of Axl’s ectodomain leads to the release of soluble Axl (sAxl), which is increased in advanced fibrosis and in early-to-late stage HCC in the presence and absence of cirrhosis. Here, we focus on the dynamics of Axl receptor shedding and delineate possible scenarios how Axl signaling might act as driver of fibrosis progression and HCC development. Based on experimental and clinical data, we discuss the consequences of modifying Axl signaling by sAxl cleavage, as well as cellular strategies to escape from antagonizing effects of Axl shedding by the involvement of the hepatic microenvironment. We emphasize a correlation between free Gas6 and free sAxl levels favoring abundant Gas6/Axl signaling in advanced fibrosis and HCC. The raised scenario provides a solid basis for theranostics allowing the use of sAxl as an accurate diagnostic biomarker of liver cirrhosis and HCC, as well as Axl receptor signaling for therapeutic intervention in stratified HCC patients.
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AXL phosphorylates and up-regulates TNS2 and its implications in IRS-1-associated metabolism in cancer cells. J Biomed Sci 2018; 25:80. [PMID: 30419905 PMCID: PMC6233515 DOI: 10.1186/s12929-018-0465-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 08/15/2018] [Indexed: 12/21/2022] Open
Abstract
Background TNS2 is a focal adhesions protein and a binding partner for many proteins, including the receptor tyrosine kinase Axl. Although TNS2 can bind with Axl, the details of their interactions have not been elucidated. TNS2 is involved in IRS-1 signaling pathway. In this study, we confirmed the relationship between TNS2 expression and the expression of Axl, IRS-1, PDK1 and Glut4 in pancreatic cancer patients. Methods The expression levels of TNS2, Axl, IRS-1, PDK1 and Glut4 in human cancer cells were measured by Western blot and/or IP-Western blot assays. Paired samples of pancreatic cancer and non-cancer tissues were obtained from 33 patients and were used to construct tissue microarrays. The expression levels of these markers in the tissue microarrays were measured by enzyme-linked Immunohistochemistry assay, and the relationships were analyzed by Pearson’s chi-square test and two-tailed t-test analysis. Results We demonstrated for the first time that TNS2 is a phosphorylation substrate of Axl. Moreover, we found a positive relationship between TNS2 expression and the expression of Axl, IRS-1, PDK1 and Glut4 in pancreatic cancer patients. Based on these results, we suggest that Axl modulates glucose metabolism potentially through TNS2 and IRS-1. We hypothesize that there exists a novel mechanism whereby Axl binds to and phosphorylates TNS2, releasing TNS2 from interaction with IRS-1 and resulting in increased stability of IRS-1. The two key enzymes of aerobic glycolysis (Glut4 and PDK1) were found to be up-regulated by Axl/TNS2/IRS-1 cross-talk and may play a critical role in glucose metabolism of cancer cells. Conclusions Our results revealed for the first time that Axl binds to and phosphorylates TNS2 and that Axl/TNS2/IRS-1 cross-talk may potentially play a critical role in glucose metabolism of cancer cells. Electronic supplementary material The online version of this article (10.1186/s12929-018-0465-x) contains supplementary material, which is available to authorized users.
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Du W, Brekken RA. Does Axl have potential as a therapeutic target in pancreatic cancer? Expert Opin Ther Targets 2018; 22:955-966. [PMID: 30244621 PMCID: PMC6292430 DOI: 10.1080/14728222.2018.1527315] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Pancreatic cancer is a leading cause of cancer-related death. Metastasis, therapy resistance, and immunosuppression are dominant characteristics of pancreatic tumors. Strategies that enhance the efficacy of standard of care and/or immune therapy are likely the most efficient route to improve overall survival in this disease. Areas covered: Axl, a member of the TAM (Tyro3, Axl, MerTK) family of receptor tyrosine kinases, is involved in cell plasticity, chemoresistance, immune suppression, and metastasis in various cancers, including pancreatic cancer. This review provides an overview of Axl and its function in normal conditions, summarizes the regulation and function of Axl in cancer, and highlights the contribution of Axl to pancreatic cancer as well as its potential as a therapeutic target. Expert opinion: Axl is an attractive therapeutic target in pancreatic cancer because it contributes to many of the roadblocks that hamper therapeutic efficacy. Clinical evidence supporting Axl inhibition in pancreatic cancer is currently limited; however, multiple clinical trials have been initiated or are in the planning phase to test the effect of inhibiting Axl in conjunction with standard therapy in pancreatic cancer patients. We anticipate that these studies will provide robust validation of Axl as a therapeutic target in pancreatic cancer.
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McDaniel NK, Cummings CT, Iida M, Hülse J, Pearson HE, Vasileiadi E, Parker RE, Orbuch RA, Ondracek OJ, Welke NB, Kang GH, Davies KD, Wang X, Frye SV, Earp HS, Harari PM, Kimple RJ, DeRyckere D, Graham DK, Wheeler DL. MERTK Mediates Intrinsic and Adaptive Resistance to AXL-targeting Agents. Mol Cancer Ther 2018; 17:2297-2308. [PMID: 30093568 PMCID: PMC6215511 DOI: 10.1158/1535-7163.mct-17-1239] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 05/23/2018] [Accepted: 07/31/2018] [Indexed: 12/17/2022]
Abstract
The TAM (TYRO3, AXL, MERTK) family receptor tyrosine kinases (RTK) play an important role in promoting growth, survival, and metastatic spread of several tumor types. AXL and MERTK are overexpressed in head and neck squamous cell carcinoma (HNSCC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC), malignancies that are highly metastatic and lethal. AXL is the most well-characterized TAM receptor and mediates resistance to both conventional and targeted cancer therapies. AXL is highly expressed in aggressive tumor types, and patients with cancer are currently being enrolled in clinical trials testing AXL inhibitors. In this study, we analyzed the effects of AXL inhibition using a small-molecule AXL inhibitor, a monoclonal antibody (mAb), and siRNA in HNSCC, TNBC, and NSCLC preclinical models. Anti-AXL-targeting strategies had limited efficacy across these different models that, our data suggest, could be attributed to upregulation of MERTK. MERTK expression was increased in cell lines and patient-derived xenografts treated with AXL inhibitors and inhibition of MERTK sensitized HNSCC, TNBC, and NSCLC preclinical models to AXL inhibition. Dual targeting of AXL and MERTK led to a more potent blockade of downstream signaling, synergistic inhibition of tumor cell expansion in culture, and reduced tumor growth in vivo Furthermore, ectopic overexpression of MERTK in AXL inhibitor-sensitive models resulted in resistance to AXL-targeting strategies. These observations suggest that therapeutic strategies cotargeting both AXL and MERTK could be highly beneficial in a variety of tumor types where both receptors are expressed, leading to improved survival for patients with lethal malignancies. Mol Cancer Ther; 17(11); 2297-308. ©2018 AACR.
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Affiliation(s)
- Nellie K McDaniel
- University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Christopher T Cummings
- Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Mari Iida
- University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Justus Hülse
- Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia
| | - Hannah E Pearson
- University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Eleana Vasileiadi
- Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia
| | - Rebecca E Parker
- Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia
| | - Rachel A Orbuch
- University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Olivia J Ondracek
- University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Noah B Welke
- University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Grace H Kang
- University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Kurtis D Davies
- Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Xiaodong Wang
- Center for Integrative Chemical Biology and Drug Discovery and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Stephen V Frye
- Center for Integrative Chemical Biology and Drug Discovery and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- Department of Medicine, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina
| | - H Shelton Earp
- Department of Medicine, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina
- Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Paul M Harari
- University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Randall J Kimple
- University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Deborah DeRyckere
- Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia
| | - Douglas K Graham
- Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Department of Pediatrics, School of Medicine, Emory University, Atlanta, Georgia.
| | - Deric L Wheeler
- University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
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