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Hao Z, Zhang M, Du Y, Liu J, Zeng G, Li H, Peng X. Invadopodia in cancer metastasis: dynamics, regulation, and targeted therapies. J Transl Med 2025; 23:548. [PMID: 40380267 PMCID: PMC12083038 DOI: 10.1186/s12967-025-06526-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Accepted: 04/21/2025] [Indexed: 05/19/2025] Open
Abstract
Pseudopodia and invadopodia are dynamic, actin-rich membrane structures extending from the cell surface. While pseudopodia are found in various cell types, invadopodia are exclusive to tumor cells and play a key role in cancer progression. These specialized structures enable tumor cells to degrade the extracellular matrix, breach tissue barriers, and invade surrounding tissues and blood vessels, thus facilitating metastasis. Extensive research has elucidated the distinct structure of invadopodia, the signaling pathways driving their formation, and their interaction with the tumor microenvironment. Integrin- and Src kinase-mediated signaling pathways regulate invadopodia dynamics. This review explores the mechanisms underlying invadopodia stabilization and highlights recent insights into their regulation by the tumor microenvironment. Particular emphasis is placed on the role of cell surface signaling in modulating invadopodia activity and the intracellular targeting of matrix metalloproteinases (MMPs) in enhancing invasive potential. A deeper understanding of invadopodia-driven cancer cell migration and metastasis provides valuable implications for therapeutic development. These findings support the potential for receptor-mediated and molecularly targeted therapies to inhibit tumor metastasis, improve clinical outcomes, and enhance the efficacy of existing cancer treatments.
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Affiliation(s)
- Zhixiong Hao
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Manru Zhang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Yao Du
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Jiaxing Liu
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Guolong Zeng
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Hangyu Li
- The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, 121001, China.
| | - Xueqiang Peng
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
- Group of Chronic Disease and Environmental Genomics, School of Public Health, China Medical University, Shenyang, 110122, China.
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2
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Hou X, Ren C, Jin J, Chen Y, Lyu X, Bi K, Carrillo ND, Cryns VL, Anderson RA, Sun J, Chen M. Phosphoinositide signalling in cell motility and adhesion. Nat Cell Biol 2025; 27:736-748. [PMID: 40169755 DOI: 10.1038/s41556-025-01647-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 02/28/2025] [Indexed: 04/03/2025]
Abstract
Cell motility and adhesion are fundamental components for diverse physiological functions, including embryonic development, immune responses and tissue repair. Dysregulation of these processes can lead to a range of diseases, including cancer. Cell motility and adhesion are complex and often require regulation by an intricate network of signalling pathways, with phosphatidylinositol phosphates (PIPs) having a central role. PIPs are derived from phosphatidylinositol phosphorylation and are instrumental in mediating membrane dynamics, intracellular trafficking, cytoskeletal organization and signal transduction, all of which are crucial for cellular responses to environmental stimuli. Here we discuss the mechanisms through which PIPs modulate cell motility and adhesion by examining their roles at focal adhesions, within the cytoskeleton, at protein scaffolds and in the nucleus. By providing a comprehensive overview of PIP signalling, this Review underscores their significance in maintaining cellular homeostasis and highlights their potential as therapeutic targets in diseases characterized by aberrant cell motility and adhesion.
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Affiliation(s)
- Xiaoting Hou
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
- SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Chang Ren
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
- SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Jing Jin
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
- Department of Critical Care Medicine, Shenzhen People's Hospital (The Second Clinical Medical College at Jinan University and The First Affiliated Hospital at the Southern University of Science and Technology), Shenzhen, China
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital, Shenzhen, China
| | - Yu Chen
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
- SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Xinyu Lyu
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Kangle Bi
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
- SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Noah D Carrillo
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Vincent L Cryns
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
- University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Richard A Anderson
- University of Wisconsin Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Jichao Sun
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
- Department of Critical Care Medicine, Shenzhen People's Hospital (The Second Clinical Medical College at Jinan University and The First Affiliated Hospital at the Southern University of Science and Technology), Shenzhen, China.
- Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital, Shenzhen, China.
| | - Mo Chen
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
- SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
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3
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Baster Z, Russell L, Rajfur Z. A Review of Talin- and Integrin-Dependent Molecular Mechanisms in Cancer Invasion and Metastasis. Int J Mol Sci 2025; 26:1798. [PMID: 40076426 PMCID: PMC11899650 DOI: 10.3390/ijms26051798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 02/04/2025] [Accepted: 02/06/2025] [Indexed: 03/14/2025] Open
Abstract
Cancer is the second most common cause of death in the world, representing one of the main economic burdens in health care and research. The effort of research has mainly focused on limiting the growth of a localized tumor, but most recently, there has been more attention focused on restricting the spreading of the cancer via invasion and metastasis. The signaling pathways behind these two processes share many molecules with physiological pathways regulating cell adhesion and migration, and, moreover, adhesion and migration processes themselves underlie tumor potential for invasion. In this work, we reviewed the latest literature about cancer development and invasion and their regulation by cell migration- and adhesion-related proteins, with a specific focus on talins and integrins. We also summarized the most recent developments and approaches to anti-cancer therapies, concentrating on cell migration-related therapies.
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Affiliation(s)
- Zbigniew Baster
- Institute of Physics, Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, 30-348 Kraków, Poland
- Laboratory for Cell and Tissue Engineering, Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands
| | - Lindsay Russell
- Undergraduate Program, Barnard College of Columbia University, New York, NY 10027, USA;
| | - Zenon Rajfur
- Institute of Physics, Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, 30-348 Kraków, Poland
- Jagiellonian Center of Biomedical Imaging, Jagiellonian University, 30-348 Kraków, Poland
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4
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Gamblin C, Chavrier P. [Formation, organization and function of invadosomes in cell motility and tumor invasion]. Med Sci (Paris) 2024; 40:515-524. [PMID: 38986096 DOI: 10.1051/medsci/2024080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/12/2024] Open
Abstract
Invadosome is an umbrella term used to describe a family of cellular structures including podosomes and invadopodia. They serve as contact zones between the cell plasma membrane and extracellular matrix, contributing to matrix remodeling by locally enriched proteolytic enzymes. Invadosomes, which are actin-dependent, are implicated in cellular processes promoting adhesion, migration, and invasion. Invadosomes, which exist in various cell types, play crucial roles in physiological phenomena such as vascularization and bone resorption. Invadosomes are also implicated in pathological processes such as matrix tissue remodeling during metastatic tumor cell invasion. This review summarizes basic information and recent advances about mechanisms underlying podosome and invadopodia formation, their organization and function.
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Affiliation(s)
- Cécile Gamblin
- Institut Curie, CNRS UMR 144, PSL Research University, Paris, France - Sorbonne Université, Paris, France
| | - Philippe Chavrier
- Institut Curie, CNRS UMR 144, PSL Research University, Paris, France
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5
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Arnold L, Yap M, Jackson L, Barry M, Ly T, Morrison A, Gomez JP, Washburn MP, Standing D, Yellapu NK, Li L, Umar S, Anant S, Thomas SM. DCLK1-Mediated Regulation of Invadopodia Dynamics and Matrix Metalloproteinase Trafficking Drives Invasive Progression in Head and Neck Squamous Cell Carcinoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.06.588339. [PMID: 38645056 PMCID: PMC11030349 DOI: 10.1101/2024.04.06.588339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/23/2024]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a major health concern due to its high mortality from poor treatment responses and locoregional tumor invasion into life sustaining structures in the head and neck. A deeper comprehension of HNSCC invasion mechanisms holds the potential to inform targeted therapies that may enhance patient survival. We previously reported that doublecortin like kinase 1 (DCLK1) regulates invasion of HNSCC cells. Here, we tested the hypothesis that DCLK1 regulates proteins within invadopodia to facilitate HNSCC invasion. Invadopodia are specialized subcellular protrusions secreting matrix metalloproteinases that degrade the extracellular matrix (ECM). Through a comprehensive proteome analysis comparing DCLK1 control and shDCLK1 conditions, our findings reveal that DCLK1 plays a pivotal role in regulating proteins that orchestrate cytoskeletal and ECM remodeling, contributing to cell invasion. Further, we demonstrate in TCGA datasets that DCLK1 levels correlate with increasing histological grade and lymph node metastasis. We identified higher expression of DCLK1 in the leading edge of HNSCC tissue. Knockdown of DCLK1 in HNSCC reduced the number of invadopodia, cell adhesion and colony formation. Using super resolution microscopy, we demonstrate localization of DCLK1 in invadopodia and colocalization with mature invadopodia markers TKS4, TKS5, cortactin and MT1-MMP. We carried out phosphoproteomics and validated using immunofluorescence and proximity ligation assays, the interaction between DCLK1 and motor protein KIF16B. Pharmacological inhibition or knockdown of DCLK1 reduced interaction with KIF16B, secretion of MMPs, and cell invasion. This research unveils a novel function of DCLK1 within invadopodia to regulate the trafficking of matrix degrading cargo. The work highlights the impact of targeting DCLK1 to inhibit locoregional invasion, a life-threatening attribute of HNSCC.
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Affiliation(s)
- Levi Arnold
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Marion Yap
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Laura Jackson
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Michael Barry
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Thuc Ly
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Austin Morrison
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Juan P. Gomez
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Michael P. Washburn
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - David Standing
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Nanda Kumar Yellapu
- Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Linheng Li
- Stowers Institute, Kansas City, Kansas, USA
| | - Shahid Umar
- Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Shrikant Anant
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Sufi Mary Thomas
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
- Department of Otolaryngology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
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Zhang X, Zhao Y, Li M, Wang M, Qian J, Wang Z, Wang Y, Wang F, Guo K, Gao D, Zhao Y, Chen R, Ren Z, Song H, Cui J. A synergistic regulation works in matrix stiffness-driven invadopodia formation in HCC. Cancer Lett 2024; 582:216597. [PMID: 38145655 DOI: 10.1016/j.canlet.2023.216597] [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: 09/15/2023] [Revised: 11/23/2023] [Accepted: 12/08/2023] [Indexed: 12/27/2023]
Abstract
Growing evidence has suggested that increased matrix stiffness can significantly strengthen the malignant characteristics of hepatocellular carcinoma (HCC) cells. However, whether and how increased matrix stiffness regulates the formation of invadopodia in HCC cells remain largely unknown. In the study, we developed different experimental systems in vitro and in vivo to explore the effects of matrix stiffness on the formation of invadopodia and its relevant molecular mechanism. Our results demonstrated that increased matrix stiffness remarkably augmented the migration and invasion abilities of HCC cells, upregulated the expressions of invadopodia-associated genes and enhanced the number of invadopodia. Two regulatory pathways contribute to matrix stiffness-driven invadopodia formation together in HCC cells, including direct triggering invadopodia formation through activating integrin β1 or Piezo1/ FAK/Src/Arg/cortactin pathway, and indirect stimulating invadopodia formation through improving EGF production to activate EGFR/Src/Arg/cortactin pathway. Src was identified as the common hub molecule of two synergistic regulatory pathways. Simultaneously, activation of integrin β1/RhoA/ROCK1/MLC2 and Piezo1/Ca2+/MLCK/MLC2 pathways mediate matrix stiffness-reinforced cell migration. This study uncovers a new mechanism by which mechanosensory pathway and biochemical signal pathway synergistically regulate the formation of invadopodia in HCC cells.
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Affiliation(s)
- Xi Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, 180 Feng Lin Road, Shanghai, 200032, PR China
| | - Yingying Zhao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, 180 Feng Lin Road, Shanghai, 200032, PR China
| | - Miao Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, 180 Feng Lin Road, Shanghai, 200032, PR China
| | - Mimi Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, 180 Feng Lin Road, Shanghai, 200032, PR China
| | - Jiali Qian
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, 180 Feng Lin Road, Shanghai, 200032, PR China
| | - Zhiming Wang
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China
| | - Yaohui Wang
- Department of Radiology, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China
| | - Fan Wang
- Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, PR China
| | - Kun Guo
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, 180 Feng Lin Road, Shanghai, 200032, PR China
| | - Dongmei Gao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, 180 Feng Lin Road, Shanghai, 200032, PR China
| | - Yan Zhao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, 180 Feng Lin Road, Shanghai, 200032, PR China
| | - Rongxin Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, 180 Feng Lin Road, Shanghai, 200032, PR China
| | - Zhenggang Ren
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, 180 Feng Lin Road, Shanghai, 200032, PR China
| | - Haiyan Song
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, PR China.
| | - Jiefeng Cui
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, 180 Feng Lin Road, Shanghai, 200032, PR China.
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7
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Monteiro P, Remy D, Lemerle E, Routet F, Macé AS, Guedj C, Ladoux B, Vassilopoulos S, Lamaze C, Chavrier P. A mechanosensitive caveolae-invadosome interplay drives matrix remodelling for cancer cell invasion. Nat Cell Biol 2023; 25:1787-1803. [PMID: 37903910 PMCID: PMC10709148 DOI: 10.1038/s41556-023-01272-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 09/22/2023] [Indexed: 11/01/2023]
Abstract
Invadosomes and caveolae are mechanosensitive structures that are implicated in metastasis. Here, we describe a unique juxtaposition of caveola clusters and matrix degradative invadosomes at contact sites between the plasma membrane of cancer cells and constricting fibrils both in 2D and 3D type I collagen matrix environments. Preferential association between caveolae and straight segments of the fibrils, and between invadosomes and bent segments of the fibrils, was observed along with matrix remodelling. Caveola recruitment precedes and is required for invadosome formation and activity. Reciprocally, invadosome disruption results in the accumulation of fibril-associated caveolae. Moreover, caveolae and the collagen receptor β1 integrin co-localize at contact sites with the fibrils, and integrins control caveola recruitment to fibrils. In turn, caveolae mediate the clearance of β1 integrin and collagen uptake in an invadosome-dependent and collagen-cleavage-dependent mechanism. Our data reveal a reciprocal interplay between caveolae and invadosomes that coordinates adhesion to and proteolytic remodelling of confining fibrils to support tumour cell dissemination.
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Affiliation(s)
- Pedro Monteiro
- Actin and Membrane Dynamics Laboratory, Institut Curie-Research Center, CNRS UMR144, PSL Research University, Paris, France.
- Membrane Mechanics and Dynamics of Intracellular Signalling Laboratory, Institut Curie-Research Center, CNRS UMR3666, INSERM U1143, PSL Research University, Paris, France.
| | - David Remy
- Actin and Membrane Dynamics Laboratory, Institut Curie-Research Center, CNRS UMR144, PSL Research University, Paris, France
| | - Eline Lemerle
- Institute of Myology, Sorbonne Université, INSERM UMRS 974, Paris, France
| | - Fiona Routet
- Actin and Membrane Dynamics Laboratory, Institut Curie-Research Center, CNRS UMR144, PSL Research University, Paris, France
| | - Anne-Sophie Macé
- Cell and Tissue Imaging Facility (PICT-IBiSA), Institut Curie, PSL Research University, Paris, France
| | - Chloé Guedj
- Cell and Tissue Imaging Facility (PICT-IBiSA), Institut Curie, PSL Research University, Paris, France
| | - Benoit Ladoux
- Institut Jacques Monod, Université de Paris, CNRS UMR 7592, Paris, France
| | | | - Christophe Lamaze
- Membrane Mechanics and Dynamics of Intracellular Signalling Laboratory, Institut Curie-Research Center, CNRS UMR3666, INSERM U1143, PSL Research University, Paris, France.
| | - Philippe Chavrier
- Actin and Membrane Dynamics Laboratory, Institut Curie-Research Center, CNRS UMR144, PSL Research University, Paris, France.
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Perrin L, Gligorijevic B. Proteolytic and mechanical remodeling of the extracellular matrix by invadopodia in cancer. Phys Biol 2022; 20:10.1088/1478-3975/aca0d8. [PMID: 36343366 PMCID: PMC9942491 DOI: 10.1088/1478-3975/aca0d8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 11/07/2022] [Indexed: 11/09/2022]
Abstract
Cancer invasion and metastasis require remodeling of the adjacent extracellular matrix (ECM). In this mini review, we will cover the mechanisms of proteolytic degradation and the mechanical remodeling of the ECM by cancer cells, with a focus on invadopodia. Invadopodia are membrane protrusions unique to cancer cells, characterized by an actin core and by the focal degradation of ECM via matrix metalloproteases (MMPs). While ECM can also be remodeled, at lower levels, by focal adhesions, or internal collagen digestion, invadopodia are now recognized as the major mechanism for MMP-dependent pericellular ECM degradation by cancer cells. Recent evidence suggests that the completion of epithelial-mesenchymal transition may be dispensable for invadopodia and metastasis, and that invadopodia are required not only for mesenchymal, single cell invasion, but also for collective invasion. During collective invasion, invadopodia was then shown to be located in leader cells, allowing follower cells to move via cooperation. Collectively, this suggests that invadopodia function may be a requirement not only for later steps of metastasis, but also for early invasion of epithelial cells into the stromal tissue. Over the last decade, invadopodia studies have transitioned into in 3D andin vivosettings, leading to the confirmation of their essential role in metastasis in preclinical animal models. In summary, invadopodia may hold a great potential for individual risk assessment as a prognostic marker for metastasis, as well as a therapeutic target.
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Affiliation(s)
- L. Perrin
- Bioengineering Department, Temple University, Philadelphia PA, USA
- Present address, Institut Curie, Paris, France
| | - B. Gligorijevic
- Bioengineering Department, Temple University, Philadelphia PA, USA
- Cancer Signaling and Epigenetics Program, Fox Chase Cancer Center, Philadelphia PA, USA
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9
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Shah L, Latif A, Williams KJ, Tirella A. Role of stiffness and physico-chemical properties of tumour microenvironment on breast cancer cell stemness. Acta Biomater 2022; 152:273-289. [PMID: 36087866 DOI: 10.1016/j.actbio.2022.08.074] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 08/29/2022] [Accepted: 08/30/2022] [Indexed: 01/16/2023]
Abstract
Several physico-chemical properties of the tumour microenvironment (TME) are dysregulated during tumour progression, such as tissue stiffness, extracellular pH and interstitial fluid flow. Traditional preclinical models, although useful to study biological processes, do not provide sufficient control over these physico-chemical properties, hence limiting the understanding of cause-effect relationships between the TME and cancer cells. Breast cancer stem cells (B-CSCs), a dynamic population within the tumour, are known to affect tumour progression, metastasis and therapeutic resistance. With their emerging importance in disease physiology, it is essential to study the interplay between above-mentioned TME physico-chemical variables and B-CSC marker expression. In this work, 3D in vitro models with controlled physico-chemical properties (hydrogel stiffness and composition, perfusion, pH) were used to mimic normal and tumour breast tissue to study changes in proliferation, morphology and B-CSC population in two separate breast cancer cell lines (MCF-7 and MDA-MB 231). Cells encapsulated in alginate-gelatin hydrogels varying in stiffness (2-10 kPa), density and adhesion ligand (gelatin) were perfused (500 µL/min) for up to 14 days. Physiological (pH 7.4) and tumorigenic (pH 6.5) media were used to mimic changes in extracellular pH within the TME. We found that both cell lines have distinct responses to changes in physico-chemical factors in terms of proliferation, cell aggregates size and morphology. Most importantly, stiff and dense hydrogels (10 kPa) and acidic pH (6.5) play a key role in B-CSCs dynamics, increasing both epithelial (E-CSCs) and mesenchymal cancer stem cell (M-CSCs) marker expression, supporting direct impact of the physico-chemical microenvironment on disease onset and progression. STATEMENT OF SIGNIFICANCE: Currently no studies evaluate the impact of physico-chemical properties of the tumour microenvironment on breast cancer stem cell (B-CSC) marker expression in a single in vitro model and at the same time. In this study, 3D in vitro models with varying stiffness, extracellular pH and fluid flow are used to recapitulate the breast tumour microenvironment to evaluate for the first time their direct effect on multiple breast cancer phenotypes: cell proliferation, cell aggregate size and shape, and B-CSC markers. Results suggest these models could open new ways of monitoring disease phenotypes, from the early-onset to progression, as well as being used as testing platforms for effective identification of specific phenotypes in the presence of relevant tumour physico-chemical microenvironment.
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Affiliation(s)
- Lekha Shah
- Division of Pharmacy and Optometry, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, M13 9PL, Manchester, United Kingdom
| | - Ayşe Latif
- Division of Pharmacy and Optometry, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, M13 9PL, Manchester, United Kingdom
| | - Kaye J Williams
- Division of Pharmacy and Optometry, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, M13 9PL, Manchester, United Kingdom
| | - Annalisa Tirella
- Division of Pharmacy and Optometry, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, M13 9PL, Manchester, United Kingdom; BIOtech - Center for Biomedical Technologies, Department of Industrial Engineering, University of Trento, Via delle Regole 101, Trento 38123, Italy.
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10
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Yoon HY, Maron BY, Girald-Berlingeri S, Gasilina A, Gollin JC, Jian X, Akpan I, Yohe ME, Randazzo PA, Chen PW. ERK phosphorylation is dependent on cell adhesion in a subset of pediatric sarcoma cell lines. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2022; 1869:119264. [PMID: 35381293 DOI: 10.1016/j.bbamcr.2022.119264] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 03/15/2022] [Accepted: 03/28/2022] [Indexed: 06/14/2023]
Abstract
Osteosarcoma (OS) and Pax-Foxo1 fusion negative rhabdomyosarcoma (FN-RMS) are pediatric sarcomas with poor prognoses in patients with advanced disease. In both malignancies, an actin binding protein has been linked to poor prognosis. Integrin adhesion complexes (IACs) are closely coupled to actin networks and IAC-mediated signaling has been implicated in the progression of carcinomas. However, the relationship of IACs and actin cytoskeleton remodeling with cell signaling is understudied in pediatric sarcomas. Here, we tested the hypothesis that IAC dynamics affect ERK activation in OS and FN-RMS cell lines. Adhesion dependence of ERK activation differed among the OS and FN-RMS cells examined. In the OS cell lines, adhesion did not have a consistent effect on phospho-ERK (pERK). ERK phosphorylation in response to fetal calf serum or 1 ng/ml EGF was nearly as efficient in OS cell lines and one FN-RMS cell line in suspension as cells adherent to poly-l-lysine (PL) or fibronectin (FN). By contrast, adhesion to plastic, PL or FN increased ERK phosphorylation and was greater than additive with a 15 min exposure to 1 ng/ml EGF in three FN-RMS cell lines. Increases in pERK were partly dependent on FAK and PAK1/2 but independent of IAC maturation. As far as we are aware, this examination of adhesion-dependent signaling is the first in pediatric sarcomas and has led to the discovery of differences from the prevailing paradigms and differences in the degree of coupling between components in the signaling pathways among the cell lines.
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Affiliation(s)
- Hye-Young Yoon
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States of America
| | - Ben Y Maron
- Department of Biology, Williams College, Williamstown, MA, United States of America
| | - Sofia Girald-Berlingeri
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States of America
| | - Anjelika Gasilina
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States of America
| | - Josephine C Gollin
- Department of Biology, Williams College, Williamstown, MA, United States of America
| | - Xiaoying Jian
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States of America
| | - Itoro Akpan
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States of America
| | - Marielle E Yohe
- Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD, United States of America
| | - Paul A Randazzo
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States of America.
| | - Pei-Wen Chen
- Department of Biology, Williams College, Williamstown, MA, United States of America
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11
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Li J, Peng L, Chen Q, Ye Z, Zhao T, Hou S, Gu J, Hang Q. Integrin β1 in Pancreatic Cancer: Expressions, Functions, and Clinical Implications. Cancers (Basel) 2022; 14:cancers14143377. [PMID: 35884437 PMCID: PMC9318555 DOI: 10.3390/cancers14143377] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/02/2022] [Accepted: 07/07/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Pancreatic cancer (PC) is a highly aggressive malignant tumor with an extremely poor prognosis. Early diagnosis and treatment are key to improving the survival rate of PC patients. Emerging studies show that integrins might contribute to the pathogenesis of PC. This review presents the various signaling pathways that are mediated by integrins in PC and emphasizes the multiple functions of integrin β1 in malignant behaviors of PC. It also discusses the clinical significance of integrin β1 as well as integrin β1-based therapy in PC patients. Abstract Pancreatic cancer (PC) is characterized by rapid progression and a high mortality rate. The current treatment is still based on surgical treatment, supplemented by radiotherapy and chemotherapy, and new methods of combining immune and molecular biological treatments are being explored. Despite this, the survival rate of PC patients is still very disappointing. Therefore, clarifying the molecular mechanism of PC pathogenesis and developing precisely targeted drugs are key to improving PC prognosis. As the most common β subunit of the integrin family, integrin β1 has been proved to be closely related to the vascular invasion, distant metastasis, and survival of PC patients, and treatment targeting integrin β1 in PC has gained initial success in animal models. In this review, we summarize the various signaling pathways by which integrins are involved in PC, focusing on the roles of integrin β1 in the malignant behaviors of PC. Additionally, recent studies regarding the feasibility of integrin β1 as a diagnostic and prognostic biomarker in PC are also discussed. Finally, we present the progress of several integrin β1-based clinical trials to highlight the potential of integrin β1 as a target for personalized therapy in PC.
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Affiliation(s)
- Jiajia Li
- Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou 225009, China; (J.L.); (S.H.)
| | - Liyao Peng
- Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210000, China;
| | - Qun Chen
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, China;
| | - Ziping Ye
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China;
| | - Tiantian Zhao
- Department of Clinical Medicine, Medical College, Yangzhou University, Yangzhou 225001, China;
| | - Sicong Hou
- Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou 225009, China; (J.L.); (S.H.)
- Department of Clinical Medicine, Medical College, Yangzhou University, Yangzhou 225001, China;
| | - Jianguo Gu
- Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai 81-8558, Japan
- Correspondence: (J.G.); (Q.H.); Tel.: +86-13-8145-8885 (Q.H.)
| | - Qinglei Hang
- Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai 81-8558, Japan
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Correspondence: (J.G.); (Q.H.); Tel.: +86-13-8145-8885 (Q.H.)
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12
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Parveen S, Khamari A, Raju J, Coppolino MG, Datta S. Syntaxin 7 contributes to breast cancer cell invasion by promoting invadopodia formation. J Cell Sci 2022; 135:275829. [PMID: 35762511 DOI: 10.1242/jcs.259576] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 05/12/2022] [Indexed: 12/15/2022] Open
Abstract
Invasion in various cancer cells requires coordinated delivery of signaling proteins, adhesion proteins, actin-remodeling proteins and proteases to matrix-degrading structures called invadopodia. Vesicular trafficking involving SNAREs plays a crucial role in the delivery of cargo to the target membrane. Screening of 13 SNAREs from the endocytic and recycling route using a gene silencing approach coupled with functional assays identified syntaxin 7 (STX7) as an important player in MDA-MB-231 cell invasion. Total internal reflection fluorescence microscopy (TIRF-M) studies revealed that STX7 resides near invadopodia and co-traffics with MT1-MMP (also known as MMP14), indicating a possible role for this SNARE in protease trafficking. STX7 depletion reduced the number of invadopodia and their associated degradative activity. Immunoprecipitation studies revealed that STX7 forms distinct SNARE complexes with VAMP2, VAMP3, VAMP7, STX4 and SNAP23. Depletion of VAMP2, VAMP3 or STX4 abrogated invadopodia formation, phenocopying what was seen upon lack of STX7. Whereas depletion of STX4 reduced MT1-MMP level at the cell surfaces, STX7 silencing significantly reduced the invadopodia-associated MT1-MMP pool and increased the non-invadosomal pool. This study highlights STX7 as a major contributor towards the invadopodia formation during cancer cell invasion. This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Sameena Parveen
- Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, Bhopal 462066, India
| | - Amrita Khamari
- Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, Bhopal 462066, India
| | - Jyothikamala Raju
- Thazhathemalayil House, Thodupuzha East PO, Keerikode, Kerala 685585, India
| | - Marc G Coppolino
- Department of Molecular and Cellular Biology, University of Guelph, Ontario N1G 2W1, Canada
| | - Sunando Datta
- Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, Bhopal 462066, India
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13
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Saji T, Nishita M, Ikeda K, Endo M, Okada Y, Minami Y. c-Src-mediated phosphorylation and activation of kinesin KIF1C promotes elongation of invadopodia in cancer cells. J Biol Chem 2022; 298:102090. [PMID: 35654143 PMCID: PMC9234240 DOI: 10.1016/j.jbc.2022.102090] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 05/21/2022] [Accepted: 05/24/2022] [Indexed: 10/25/2022] Open
Abstract
Invadopodia on cancer cells play crucial roles in tumor invasion and metastasis by degrading and remodeling the surrounding extracellular matrices (ECM) and driving cell migration in complex three-dimensional environments. Previous studies have indicated that microtubules (MTs) play a crucial role in elongation of invadopodia, but not their formation, probably by regulating delivery of membrane and secretory proteins within invadopodia. However, the identity of the responsible MT-based molecular motors and their regulation has been elusive. Here, we show that KIF1C, a member of kinesin-3 family, is localized to the tips of invadopodia and is required for their elongation and the invasion of cancer cells. We also found that c-Src phosphorylates tyrosine residues within the stalk domain of KIF1C, thereby enhancing its association with tyrosine phosphatase PTPD1, that in turn activates MT-binding ability of KIF1C, probably by relieving the autoinhibitory interaction between its motor and stalk domains. These findings shed new insights into how c-Src signaling is coupled to the MT-dependent dynamic nature of invadopodia, and also advance our understanding of the mechanism of KIF1C activation through release of its autoinhibition.
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Affiliation(s)
- Takeshi Saji
- Department of Biochemistry, Fukushima Medical University School of Medicine, Fukushima, Japan; Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan
| | - Michiru Nishita
- Department of Biochemistry, Fukushima Medical University School of Medicine, Fukushima, Japan; Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan.
| | - Kazuho Ikeda
- Department of Cell Biology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mitsuharu Endo
- Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan
| | - Yasushi Okada
- Department of Cell Biology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Laboratory for Cell Polarity Regulation, RIKEN Center for Biosystems Dynamics Research (BDR), Osaka, Japan; Department of Physics, Graduate School of Science, The University of Tokyo, Tokyo, Japan; Universal Biology Institute (UBI) and International Research Center for Neurointelligence (WPI-IRCN), The University of Tokyo, Tokyo, Japan
| | - Yasuhiro Minami
- Division of Cell Physiology, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe, Japan.
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14
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Jakubik CT, Weckerly CC, Hammond GR, Bresnick AR, Backer JM. PIP 3 abundance overcomes PI3K signaling selectivity in invadopodia. FEBS Lett 2022; 596:417-426. [PMID: 34990021 PMCID: PMC8885911 DOI: 10.1002/1873-3468.14273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/07/2021] [Accepted: 12/16/2021] [Indexed: 02/03/2023]
Abstract
PI3Kβ is required for invadopodia-mediated matrix degradation by breast cancer cells. Invadopodia maturation requires GPCR activation of PI3Kβ and its coupling to SHIP2 to produce PI(3,4)P2 . We now test whether selectivity for PI3Kβ is preserved under conditions of mutational increases in PI3K activity. In breast cancer cells where PI3Kβ is inhibited, short-chain diC8-PIP3 rescues gelatin degradation in a SHIP2-dependent manner; rescue by diC8-PI(3,4)P2 is SHIP2-independent. Surprisingly, the expression of either activated PI3Kβ or PI3Kα mutants rescued the effects of PI3Kβ inhibition. In both cases, gelatin degradation was SHIP2-dependent. These data confirm the requirement for PIP3 conversion to PI(3,4)P2 for invadopodia function and suggest that selectivity for distinct PI3K isotypes may be obviated by mutational activation of the PI3K pathway.
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Affiliation(s)
- Charles T. Jakubik
- Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue Bronx, NY
| | - Claire C. Weckerly
- Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Gerald R.V. Hammond
- Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Anne R. Bresnick
- Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue Bronx, NY
| | - Jonathan M. Backer
- Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue Bronx, NY
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY
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15
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Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression. Int J Mol Sci 2021; 23:ijms23010146. [PMID: 35008569 PMCID: PMC8745566 DOI: 10.3390/ijms23010146] [Citation(s) in RCA: 212] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer progression with uncontrolled tumor growth, local invasion, and metastasis depends largely on the proteolytic activity of numerous matrix metalloproteinases (MMPs), which affect tissue integrity, immune cell recruitment, and tissue turnover by degrading extracellular matrix (ECM) components and by releasing matrikines, cell surface-bound cytokines, growth factors, or their receptors. Among the MMPs, MMP-14 is the driving force behind extracellular matrix and tissue destruction during cancer invasion and metastasis. MMP-14 also influences both intercellular as well as cell-matrix communication by regulating the activity of many plasma membrane-anchored and extracellular proteins. Cancer cells and other cells of the tumor stroma, embedded in a common extracellular matrix, interact with their matrix by means of various adhesive structures, of which particularly invadopodia are capable to remodel the matrix through spatially and temporally finely tuned proteolysis. As a deeper understanding of the underlying functional mechanisms is beneficial for the development of new prognostic and predictive markers and for targeted therapies, this review examined the current knowledge of the interplay of the various MMPs in the cancer context on the protein, subcellular, and cellular level with a focus on MMP14.
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16
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Liang L, Sui R, Song Y, Zhao Y. Acidic microenvironment enhances MT1-MMP-mediated cancer cell motility through integrin β1/cofilin/F-actin axis. Acta Biochim Biophys Sin (Shanghai) 2021; 53:1558-1566. [PMID: 34568889 DOI: 10.1093/abbs/gmab130] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Indexed: 12/22/2022] Open
Abstract
Tumor acidic microenvironment is the main feature of many solid tumors. As a part of the tumor microenvironment, it has a profound impact on the occurrence and development of tumors. However, the research on how tumor cells sense the changes of the external microenvironment and how the intracellular subcellular structures transmit the signals from extracellular to intracellular is unclear. In this study, we identify that the acidic microenvironment enhances cancer cell motility, and the expression of membrane-anchored membrane type 1-matrix metalloproteinase is also associated with cell motility, which indicates more degradation of the ECM under the acidic microenvironment. Moreover, the expression of cofilin is low in the acidic microenvironment, and the F-actin filaments are distributed more along the cells. The cytoskeletal F-actin changes are consistent with the potential of a high-invasive phenotype. Further study reveals the upstream control of the signal transductions from extracellular to intracellular, that is, the integrin β1 functions to trigger the biological responses under the acidic microenvironment. Our results demonstrate that the acidic microenvironment enhances cancer cell motility through the integrin β1/cofilin/F-actin signal axis. This study clearly shows the scheme of the signal transmissions from extracellular to intracellular and further reveals the cytoskeletal roles for the contributions of cancer cell motility under acidic microenvironment, which provides new targets for cancer intervention from the biochemical and biophysical perspectives.
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Affiliation(s)
- Lubiao Liang
- Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Ran Sui
- College of Bioengineering, Chongqing University, Chongqing 400030, China
| | - Yongxiang Song
- Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Yajin Zhao
- School of Stomatology, Zunyi Medical University, Zunyi 563000, China
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17
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Hülsemann M, Sanchez C, Verkhusha PV, Des Marais V, Mao SPH, Donnelly SK, Segall JE, Hodgson L. TC10 regulates breast cancer invasion and metastasis by controlling membrane type-1 matrix metalloproteinase at invadopodia. Commun Biol 2021; 4:1091. [PMID: 34531530 PMCID: PMC8445963 DOI: 10.1038/s42003-021-02583-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 08/23/2021] [Indexed: 01/12/2023] Open
Abstract
During breast cancer metastasis, cancer cell invasion is driven by actin-rich protrusions called invadopodia, which mediate the extracellular matrix degradation required for the success of the invasive cascade. In this study, we demonstrate that TC10, a member of a Cdc42 subfamily of p21 small GTPases, regulates the membrane type 1 matrix metalloproteinase (MT1-MMP)-driven extracellular matrix degradation at invadopodia. We show that TC10 is required for the plasma membrane surface exposure of MT1-MMP at these structures. By utilizing our Förster resonance energy transfer (FRET) biosensor, we demonstrate the p190RhoGAP-dependent regulation of spatiotemporal TC10 activity at invadopodia. We identified a pathway that regulates invadopodia-associated TC10 activity and function through the activation of p190RhoGAP and the downstream interacting effector Exo70. Our findings reveal the role of a previously unknown regulator of vesicular fusion at invadopodia, TC10 GTPase, in breast cancer invasion and metastasis.
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Affiliation(s)
- Maren Hülsemann
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Colline Sanchez
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Polina V Verkhusha
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Vera Des Marais
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Analytical Imaging Facility, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Serena P H Mao
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Sara K Donnelly
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Jeffrey E Segall
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Louis Hodgson
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
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18
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Dissecting the Inorganic Nanoparticle-Driven Interferences on Adhesome Dynamics. JOURNAL OF NANOTHERANOSTICS 2021. [DOI: 10.3390/jnt2030011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Inorganic nanoparticles have emerged as an attractive theranostic tool applied to different pathologies such as cancer. However, the increment in inorganic nanoparticle application in biomedicine has prompted the scientific community to assess their potential toxicities, often preventing them from entering clinical settings. Cytoskeleton network and the related adhesomes nest are present in most cellular processes such as proliferation, migration, and cell death. The nanoparticle treatment can interfere with the cytoskeleton and adhesome dynamics, thus inflicting cellular damage. Therefore, it is crucial dissecting the molecular mechanisms involved in nanoparticle cytotoxicity. This review will briefly address the main characteristics of different adhesion structures and focus on the most relevant effects of inorganic nanoparticles with biomedical potential on cellular adhesome dynamics. Besides, the review put into perspective the use of inorganic nanoparticles for cytoskeleton targeting or study as a versatile tool. The dissection of the molecular mechanisms involved in the nanoparticle-driven interference of adhesome dynamics will facilitate the future development of nanotheranostics targeting cytoskeleton and adhesomes to tackle several diseases, such as cancer.
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19
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Saha T, Gil-Henn H. Invadopodia, a Kingdom of Non-Receptor Tyrosine Kinases. Cells 2021; 10:cells10082037. [PMID: 34440806 PMCID: PMC8391121 DOI: 10.3390/cells10082037] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/05/2021] [Accepted: 08/06/2021] [Indexed: 01/01/2023] Open
Abstract
Non-receptor tyrosine kinases (NRTKs) are crucial mediators of intracellular signaling and control a wide variety of processes such as cell division, morphogenesis, and motility. Aberrant NRTK-mediated tyrosine phosphorylation has been linked to various human disorders and diseases, among them cancer metastasis, to which no treatment presently exists. Invasive cancer cells leaving the primary tumor use invadopodia, feet-like structures which facilitate extracellular matrix (ECM) degradation and intravasation, to escape the primary tumor and disseminate into distant tissues and organs during metastasis. A major challenge in metastasis research is to elucidate the molecular mechanisms and signaling pathways underlying invadopodia regulation, as the general belief is that targeting these structures can potentially lead to the eradication of cancer metastasis. Non-receptor tyrosine kinases (NRTKs) play a central role in regulating invadopodia formation and function, but how they coordinate the signaling leading to these processes was not clear until recently. Here, we describe the major NRTKs that rule invadopodia and how they work in concert while keeping an accurate hierarchy to control tumor cell invasiveness and dissemination.
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20
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Wu K, Wu H, Lyu W, Kim Y, Furdui CM, Anderson KS, Koleske AJ. Platelet-derived growth factor receptor beta activates Abl2 via direct binding and phosphorylation. J Biol Chem 2021; 297:100883. [PMID: 34144039 PMCID: PMC8259415 DOI: 10.1016/j.jbc.2021.100883] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/07/2021] [Accepted: 06/14/2021] [Indexed: 11/27/2022] Open
Abstract
Abl family kinases are nonreceptor tyrosine kinases activated by diverse cellular stimuli that regulate cytoskeleton organization, morphogenesis, and adhesion. The catalytic activity of Abl family kinases is tightly regulated in cells by a complex set of intramolecular and intermolecular interactions and post-translational modifications. For example, the platelet-derived growth factor receptor beta (PDGFRβ), important for cell proliferation and chemotaxis, is a potent activator of Abl family kinases. However, the molecular mechanism by which PDGFRβ engages and activates Abl family kinases is not known. We show here that the Abl2 Src homology 2 domain directly binds to phosphotyrosine Y771 in the PDGFRβ cytoplasmic domain. PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain. Y116, Y161, Y272, and Y310 are all located at or near the Src homology 3/Src homology 2-kinase linker interface, which helps maintain Abl family kinases in an autoinhibited conformation. We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. These findings reveal how PDGFRβ engages and phosphorylates Abl2 leading to activation of the kinase, providing a framework to understand how growth factor receptors engage and activate Abl family kinases.
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Affiliation(s)
- Kuanlin Wu
- Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA
| | - Hanzhi Wu
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Wanqing Lyu
- Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA
| | - Youngjoo Kim
- Department of Pharmacology, Yale University, New Haven, Connecticut, USA
| | - Cristina M Furdui
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Karen S Anderson
- Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA; Department of Pharmacology, Yale University, New Haven, Connecticut, USA
| | - Anthony J Koleske
- Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA; Department of Neuroscience, Yale University, New Haven, Connecticut, USA.
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21
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Store-operated Ca 2+ entry as a key oncogenic Ca 2+ signaling driving tumor invasion-metastasis cascade and its translational potential. Cancer Lett 2021; 516:64-72. [PMID: 34089807 DOI: 10.1016/j.canlet.2021.05.036] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/12/2021] [Accepted: 05/26/2021] [Indexed: 12/25/2022]
Abstract
Tumor metastasis is the primary cause of treatment failure and cancer-related deaths. Store-operated Ca2+ entry (SOCE), which is mediated by stromal interaction molecules (STIM) and ORAI proteins, has been implicated in the tumor invasion-metastasis cascade. Epithelial-mesenchymal transition (EMT) is a cellular program that enables tumor cells to acquire the capacities needed for migration and invasion and the formation of distal metastases. Tumor-associated angiogenesis contributes to metastasis because aberrantly developed vessels offer a path for tumor cell dissemination as well as supply sufficient nutrients for the metastatic colony to develop into metastasis. Recently, increasing evidence has indicated that SOCE alterations actively participate in the multi-step process of tumor metastasis. In addition, the dysregulated expression of STIM/ORAI has been reported to be a predictor of poor prognosis. Herein, we review the latest advances about the critical role of SOCE in the tumor metastasis cascade and the underlying regulatory mechanisms. We emphasize the contributions of SOCE to the EMT program, tumor cell migration and invasion, and angiogenesis. We further discuss the possibility of modulating SOCE or intervening in the downstream signaling pathways as a feasible targeting therapy for cancer treatment.
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22
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Luttman JH, Colemon A, Mayro B, Pendergast AM. Role of the ABL tyrosine kinases in the epithelial-mesenchymal transition and the metastatic cascade. Cell Commun Signal 2021; 19:59. [PMID: 34022881 PMCID: PMC8140471 DOI: 10.1186/s12964-021-00739-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 04/16/2021] [Indexed: 12/20/2022] Open
Abstract
The ABL kinases, ABL1 and ABL2, promote tumor progression and metastasis in various solid tumors. Recent reports have shown that ABL kinases have increased expression and/or activity in solid tumors and that ABL inactivation impairs metastasis. The therapeutic effects of ABL inactivation are due in part to ABL-dependent regulation of diverse cellular processes related to the epithelial to mesenchymal transition and subsequent steps in the metastatic cascade. ABL kinases target multiple signaling pathways required for promoting one or more steps in the metastatic cascade. These findings highlight the potential utility of specific ABL kinase inhibitors as a novel treatment paradigm for patients with advanced metastatic disease. Video abstract.
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Affiliation(s)
- Jillian Hattaway Luttman
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, 308 Research Drive, C-233A LSRC Bldg., P.O. Box 3813, Durham, NC 27710 USA
| | - Ashley Colemon
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, 308 Research Drive, C-233A LSRC Bldg., P.O. Box 3813, Durham, NC 27710 USA
| | - Benjamin Mayro
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, 308 Research Drive, C-233A LSRC Bldg., P.O. Box 3813, Durham, NC 27710 USA
| | - Ann Marie Pendergast
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, 308 Research Drive, C-233A LSRC Bldg., P.O. Box 3813, Durham, NC 27710 USA
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23
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Mishra YG, Manavathi B. Focal adhesion dynamics in cellular function and disease. Cell Signal 2021; 85:110046. [PMID: 34004332 DOI: 10.1016/j.cellsig.2021.110046] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 05/13/2021] [Indexed: 02/06/2023]
Abstract
Acting as a bridge between the cytoskeleton of the cell and the extra cellular matrix (ECM), the cell-ECM adhesions with integrins at their core, play a major role in cell signalling to direct mechanotransduction, cell migration, cell cycle progression, proliferation, differentiation, growth and repair. Biochemically, these adhesions are composed of diverse, yet an organised group of structural proteins, receptors, adaptors, various enzymes including protein kinases, phosphatases, GTPases, proteases, etc. as well as scaffolding molecules. The major integrin adhesion complexes (IACs) characterised are focal adhesions (FAs), invadosomes (podosomes and invadopodia), hemidesmosomes (HDs) and reticular adhesions (RAs). The varied composition and regulation of the IACs and their signalling, apart from being an integral part of normal cell survival, has been shown to be of paramount importance in various developmental and pathological processes. This review per-illustrates the recent advancements in the research of IACs, their crucial roles in normal as well as diseased states. We have also touched on few of the various methods that have been developed over the years to visualise IACs, measure the forces they exert and study their signalling and molecular composition. Having such pertinent roles in the context of various pathologies, these IACs need to be understood and studied to develop therapeutical targets. We have given an update to the studies done in recent years and described various techniques which have been applied to study these structures, thereby, providing context in furthering research with respect to IAC targeted therapeutics.
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Affiliation(s)
- Yasaswi Gayatri Mishra
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India
| | - Bramanandam Manavathi
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India.
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The multiple roles of actin-binding proteins at invadopodia. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021. [PMID: 33962752 DOI: 10.1016/bs.ircmb.2021.03.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2024]
Abstract
Invadopodia are actin-rich membrane protrusions that facilitate cancer cell dissemination by focusing on proteolytic activity and clearing paths for migration through physical barriers, such as basement membranes, dense extracellular matrices, and endothelial cell junctions. Invadopodium formation and activity require spatially and temporally regulated changes in actin filament organization and dynamics. About three decades of research have led to a remarkable understanding of how these changes are orchestrated by sequential recruitment and coordinated activity of different sets of actin-binding proteins. In this chapter, we provide an update on the roles of the actin cytoskeleton during the main stages of invadopodium development with a particular focus on actin polymerization machineries and production of pushing forces driving extracellular matrix remodeling.
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Masi I, Caprara V, Spadaro F, Chellini L, Sestito R, Zancla A, Rainer A, Bagnato A, Rosanò L. Endothelin-1 drives invadopodia and interaction with mesothelial cells through ILK. Cell Rep 2021; 34:108800. [PMID: 33657382 DOI: 10.1016/j.celrep.2021.108800] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 01/02/2021] [Accepted: 02/05/2021] [Indexed: 01/09/2023] Open
Abstract
Cancer cells use actin-based membrane protrusions, invadopodia, to degrade stroma and invade. In serous ovarian cancer (SOC), the endothelin A receptor (ETAR) drives invadopodia by a not fully explored coordinated function of β-arrestin1 (β-arr1). Here, we report that β-arr1 links the integrin-linked kinase (ILK)/βPIX complex to activate Rac3 GTPase, acting as a central node in the adhesion-based extracellular matrix (ECM) sensing and degradation. Downstream, Rac3 phosphorylates PAK1 and cofilin and promotes invadopodium-dependent ECM proteolysis and invasion. Furthermore, ETAR/ILK/Rac3 signaling supports the communication between cancer and mesothelial cells, favoring SOC cell adhesion and transmigration. In vivo, ambrisentan, an ETAR antagonist, inhibits the adhesion and spreading of tumor cells to intraperitoneal organs, and invadopodium marker expression. As prognostic factors, high EDNRA/ILK expression correlates with poor SOC clinical outcome. These findings provide a framework for the ET-1R/β-arr1 pathway as an integrator of ILK/Rac3-dependent adhesive and proteolytic signaling to invadopodia, favoring cancer/stroma interactions and metastatic behavior.
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Affiliation(s)
- Ilenia Masi
- Unit of Preclinical Models and New Therapeutic Agents, IRCCS - Regina Elena National Cancer Institute, Rome 00128, Italy
| | - Valentina Caprara
- Unit of Preclinical Models and New Therapeutic Agents, IRCCS - Regina Elena National Cancer Institute, Rome 00128, Italy
| | - Francesca Spadaro
- Confocal Microscopy Unit, Core Facilities, Istituto Superiore di Sanità, Rome 00161, Italy
| | - Lidia Chellini
- Unit of Preclinical Models and New Therapeutic Agents, IRCCS - Regina Elena National Cancer Institute, Rome 00128, Italy
| | - Rosanna Sestito
- Unit of Preclinical Models and New Therapeutic Agents, IRCCS - Regina Elena National Cancer Institute, Rome 00128, Italy
| | - Andrea Zancla
- Department of Engineering, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, Rome 00128, Italy; Department of Engineering, Università degli Studi Roma Tre, via Vito Volterra 62, Rome 00146, Italy
| | - Alberto Rainer
- Department of Engineering, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, Rome 00128, Italy; Institute of Nanotechnology (NANOTEC), National Research Council (CNR), c/o Campus Ecotekne, via Monteroni, Lecce 73100, Italy
| | - Anna Bagnato
- Unit of Preclinical Models and New Therapeutic Agents, IRCCS - Regina Elena National Cancer Institute, Rome 00128, Italy
| | - Laura Rosanò
- Unit of Preclinical Models and New Therapeutic Agents, IRCCS - Regina Elena National Cancer Institute, Rome 00128, Italy; Institute of Molecular Biology and Pathology, National Research Council (CNR), Rome 00185, Italy.
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26
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Integrin-Linked Kinase Links Integrin Activation to Invadopodia Function and Invasion via the p(T567)-Ezrin/NHERF1/NHE1 Pathway. Int J Mol Sci 2021; 22:ijms22042162. [PMID: 33671549 PMCID: PMC7926356 DOI: 10.3390/ijms22042162] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/10/2021] [Accepted: 02/18/2021] [Indexed: 12/16/2022] Open
Abstract
Tumor cell invasion depends largely on degradation of the extracellular matrix (ECM) by protease-rich structures called invadopodia, whose formation and activity requires the convergence of signaling pathways engaged in cell adhesion, actin assembly, membrane regulation and ECM proteolysis. It is known that β1-integrin stimulates invadopodia function through an invadopodial p(T567)-ezrin/NHERF1/NHE1 signal complex that regulates NHE1-driven invadopodia proteolytic activity and invasion. However, the link between β1-integrin and this signaling complex is unknown. In this study, in metastatic breast (MDA-MB-231) and prostate (PC-3) cancer cells, we report that integrin-linked kinase (ILK) integrates β1-integrin with this signaling complex to regulate invadopodia activity and invasion. Proximity ligation assay experiments demonstrate that, in invadopodia, ILK associates with β1-integrin, NHE1 and the scaffold proteins p(T567)-ezrin and NHERF1. Activation of β1-integrin increased both invasion and invadopodia activity, which were specifically blocked by inhibition of either NHE1 or ILK. We conclude that ILK integrates β1-integrin with the ECM proteolytic/invasion signal module to induce NHE1-driven invadopodial ECM proteolysis and cell invasion.
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Luo Y, Hu J, Liu Y, Li L, Li Y, Sun B, Kong R. Invadopodia: A potential target for pancreatic cancer therapy. Crit Rev Oncol Hematol 2021; 159:103236. [PMID: 33482351 DOI: 10.1016/j.critrevonc.2021.103236] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 01/05/2021] [Accepted: 01/16/2021] [Indexed: 02/08/2023] Open
Abstract
Dissemination of cancer cells is an intricate multistep process that represents the most deadly aspect of cancer. Cancer cells form F-actin-rich protrusions known as invadopodia to invade surrounding tissues, blood vessels and lymphatics. A number of studies have demonstrated the significant roles of invadopodia in cancer. Therefore, the specific cells and molecules involved in invadopodia activity can provide as therapeutic targets. In this review, we included a thorough overview of studies in invadopodia and discussed their functions in cancer metastasis. We then presented the specific cells and molecules involved in invadopodia activity in pancreatic cancer and analyzed their suitability to be effective therapeutic targets. Currently, drugs targeting invadopodia and relevant clinical trials are negligible. Here, we highlighted the significance of potential drugs and discussed future obstacles in implementing clinical trials. This review presents a new perspective on invadopodia-induced pancreatic cancer metastasis and may prosper the development of targeted therapeutics against pancreatic cancer.
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Affiliation(s)
- Yan Luo
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jisheng Hu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yong Liu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Le Li
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yilong Li
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Rui Kong
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
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Yuan Z, Wei W. RAB5A promotes the formation of filopodia in pancreatic cancer cells via the activation of cdc42 and β1-integrin. Biochem Biophys Res Commun 2021; 535:54-59. [PMID: 33341673 DOI: 10.1016/j.bbrc.2020.12.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/10/2020] [Indexed: 01/27/2023]
Abstract
Filopodia are slender actin-rich plasma membrane protrusions that function to drive cell migration and invasion. Despite the observation of defective filopodia formation in many malignant tumors, the regulation mechanism remained unknown to date. In the present study, for the first time, we demonstrate that RAB5A, a Rab GTPase family protein, is a potent regulator of filopodia formation in pancreatic cancer cells. High expression of RAB5A was associated with filopodia formation and migration in pancreatic cancer cells. Overexpression of RAB5A promoted filopodia formation and migration in CF Pac-1 cells. In contrast, down-regulation of RAB5A expression in SW1990 cells with a high endogenous RAB5A expression level impeded the formation of filopodia. Further analysis indicated that RAB5A was required for cdc42 activation in CF Pac-1 and SW1990 cells. Moreover, to investigate the underlying mechanism by which the activation of cdc42 mediates RAB5A-induced filopodia formation, the active state of β1-integrin was examined in cells with different expression levels of RAB5A. We observed that RAB5A regulated the accumulation of the active β1-integrin. We demonstrated that down-regulation of the expression of β1-integrin strongly suppressed filopodia formation and cdc42 activation mediated by RAB5A. These results indicate the important role of RAB5A in the regulation of filopodia formation in pancreatic cancer cells, which is dependent on the activation of cdc42 and β1-integrin.
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Affiliation(s)
- Ziyan Yuan
- Experimental Animal Center, Naval Medical University, Shanghai, People's Republic of China
| | - Wei Wei
- Clinical Research Center, Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China.
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29
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Vellino S, Oddou C, Rivier P, Boyault C, Hiriart-Bryant E, Kraut A, Martin R, Coute Y, Knölker HJ, Valverde MA, Albigès-Rizo C, Destaing O. Cross-talk between the calcium channel TRPV4 and reactive oxygen species interlocks adhesive and degradative functions of invadosomes. J Cell Biol 2021; 220:211651. [PMID: 33399853 PMCID: PMC7788461 DOI: 10.1083/jcb.201910079] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 07/23/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023] Open
Abstract
Invadosomes support cell invasion by coupling both acto-adhesive and extracellular matrix degradative functions, which are apparently antagonistic. β1-integrin dynamics regulate this coupling, but the actual sensing mechanism and effectors involved have not yet been elucidated. Using genetic and reverse genetic approaches combined with biochemical and imaging techniques, we now show that the calcium channel TRPV4 colocalizes with β1-integrins at the invadosome periphery and regulates its activation and the coupling of acto-adhesive and degradative functions. TRPV4-mediated regulation of podosome function depends on its ability to sense reactive oxygen species (ROS) in invadosomes' microenvironment and involves activation of the ROS/calcium-sensitive kinase Ask1 and binding of the motor MYO1C. Furthermore, disease-associated TRPV4 gain-of-function mutations that modulate ECM degradation are also implicated in the ROS response, which provides new perspectives in our understanding of the pathophysiology of TRPV4 channelopathies.
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Affiliation(s)
- Sanela Vellino
- Dynamique des systèmes d'adhérence, Institut for Advanced Biosciences, Centre de Recherche University Grenoble Alpes/INSERM U1209/Centre National de la Recherche Scientifique Unité mixte de recherche 5309, La Tronche, France
| | - Christiane Oddou
- Dynamique des systèmes d'adhérence, Institut for Advanced Biosciences, Centre de Recherche University Grenoble Alpes/INSERM U1209/Centre National de la Recherche Scientifique Unité mixte de recherche 5309, La Tronche, France
| | - Paul Rivier
- Dynamique des systèmes d'adhérence, Institut for Advanced Biosciences, Centre de Recherche University Grenoble Alpes/INSERM U1209/Centre National de la Recherche Scientifique Unité mixte de recherche 5309, La Tronche, France
| | - Cyril Boyault
- Dynamique des systèmes d'adhérence, Institut for Advanced Biosciences, Centre de Recherche University Grenoble Alpes/INSERM U1209/Centre National de la Recherche Scientifique Unité mixte de recherche 5309, La Tronche, France
| | - Edwige Hiriart-Bryant
- Dynamique des systèmes d'adhérence, Institut for Advanced Biosciences, Centre de Recherche University Grenoble Alpes/INSERM U1209/Centre National de la Recherche Scientifique Unité mixte de recherche 5309, La Tronche, France
| | - Alexandra Kraut
- Laboratoire EDyP, Institute of Biosciences and Biotechnologies of Grenoble-Biologie à Grande Echelle, Commissariat à l'Énergie Atomique Grenoble, Grenoble, France
| | - René Martin
- Faculty of Chemistry, Technische Universität Dresden, Dresden, Germany
| | - Yohann Coute
- Laboratoire EDyP, Institute of Biosciences and Biotechnologies of Grenoble-Biologie à Grande Echelle, Commissariat à l'Énergie Atomique Grenoble, Grenoble, France
| | | | - Miguel A. Valverde
- Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Corinne Albigès-Rizo
- Dynamique des systèmes d'adhérence, Institut for Advanced Biosciences, Centre de Recherche University Grenoble Alpes/INSERM U1209/Centre National de la Recherche Scientifique Unité mixte de recherche 5309, La Tronche, France
| | - Olivier Destaing
- Dynamique des systèmes d'adhérence, Institut for Advanced Biosciences, Centre de Recherche University Grenoble Alpes/INSERM U1209/Centre National de la Recherche Scientifique Unité mixte de recherche 5309, La Tronche, France,Correspondence to Olivier Destaing:
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30
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Creeden JF, Alganem K, Imami AS, Henkel ND, Brunicardi FC, Liu SH, Shukla R, Tomar T, Naji F, McCullumsmith RE. Emerging Kinase Therapeutic Targets in Pancreatic Ductal Adenocarcinoma and Pancreatic Cancer Desmoplasia. Int J Mol Sci 2020; 21:ijms21228823. [PMID: 33233470 PMCID: PMC7700673 DOI: 10.3390/ijms21228823] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/16/2020] [Accepted: 11/19/2020] [Indexed: 02/08/2023] Open
Abstract
Kinase drug discovery represents an active area of therapeutic research, with previous pharmaceutical success improving patient outcomes across a wide variety of human diseases. In pancreatic ductal adenocarcinoma (PDAC), innovative pharmaceutical strategies such as kinase targeting have been unable to appreciably increase patient survival. This may be due, in part, to unchecked desmoplastic reactions to pancreatic tumors. Desmoplastic stroma enhances tumor development and progression while simultaneously restricting drug delivery to the tumor cells it protects. Emerging evidence indicates that many of the pathologic fibrotic processes directly or indirectly supporting desmoplasia may be driven by targetable protein tyrosine kinases such as Fyn-related kinase (FRK); B lymphoid kinase (BLK); hemopoietic cell kinase (HCK); ABL proto-oncogene 2 kinase (ABL2); discoidin domain receptor 1 kinase (DDR1); Lck/Yes-related novel kinase (LYN); ephrin receptor A8 kinase (EPHA8); FYN proto-oncogene kinase (FYN); lymphocyte cell-specific kinase (LCK); tec protein kinase (TEC). Herein, we review literature related to these kinases and posit signaling networks, mechanisms, and biochemical relationships by which this group may contribute to PDAC tumor growth and desmoplasia.
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Affiliation(s)
- Justin F. Creeden
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (N.D.H.); (R.S.); (R.E.M.)
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (F.C.B.); (S.-H.L.)
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 6038, USA
- Correspondence: ; Tel.: +1-419-383-6474
| | - Khaled Alganem
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (N.D.H.); (R.S.); (R.E.M.)
| | - Ali S. Imami
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (N.D.H.); (R.S.); (R.E.M.)
| | - Nicholas D. Henkel
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (N.D.H.); (R.S.); (R.E.M.)
| | - F. Charles Brunicardi
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (F.C.B.); (S.-H.L.)
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 6038, USA
| | - Shi-He Liu
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (F.C.B.); (S.-H.L.)
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 6038, USA
| | - Rammohan Shukla
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (N.D.H.); (R.S.); (R.E.M.)
| | - Tushar Tomar
- PamGene International BV, 5200 BJ’s-Hertogenbosch, The Netherlands; (T.T.); (F.N.)
| | - Faris Naji
- PamGene International BV, 5200 BJ’s-Hertogenbosch, The Netherlands; (T.T.); (F.N.)
| | - Robert E. McCullumsmith
- Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA; (K.A.); (A.S.I.); (N.D.H.); (R.S.); (R.E.M.)
- Neurosciences Institute, ProMedica, Toledo, OH 6038, USA
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Daisy Precilla S, Kuduvalli SS, Thirugnanasambandhar Sivasubramanian A. Disentangling the therapeutic tactics in GBM: From bench to bedside and beyond. Cell Biol Int 2020; 45:18-53. [PMID: 33049091 DOI: 10.1002/cbin.11484] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 10/04/2020] [Accepted: 10/11/2020] [Indexed: 12/15/2022]
Abstract
Glioblastoma multiforme (GBM) is one of the most common and malignant form of adult brain tumor with a high mortality rate and dismal prognosis. The present standard treatment comprising surgical resection followed by radiation and chemotherapy using temozolomide can broaden patient's survival to some extent. However, the advantages are not palliative due to the development of resistance to the drug and tumor recurrence following the multimodal treatment approaches due to both intra- and intertumoral heterogeneity of GBM. One of the major contributors to temozolomide resistance is O6 -methylguanine-DNA methyltransferase. Furthermore, deficiency of mismatch repair, base excision repair, and cytoprotective autophagy adds to temozolomide obstruction. Rising proof additionally showed that a small population of cells displaying certain stem cell markers, known as glioma stem cells, adds on to the resistance and tumor progression. Collectively, these findings necessitate the discovery of novel therapeutic avenues for treating glioblastoma. As of late, after understanding the pathophysiology and biology of GBM, some novel therapeutic discoveries, such as drug repurposing, targeted molecules, immunotherapies, antimitotic therapies, and microRNAs, have been developed as new potential treatments for glioblastoma. To help illustrate, "what are the mechanisms of resistance to temozolomide" and "what kind of alternative therapeutics can be suggested" with this fatal disease, a detailed history of these has been discussed in this review article, all with a hope to develop an effective treatment strategy for GBM.
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Affiliation(s)
- S Daisy Precilla
- Central Inter-Disciplinary Research Facility, Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India
| | - Shreyas S Kuduvalli
- Central Inter-Disciplinary Research Facility, Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India
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Revach OY, Grosheva I, Geiger B. Biomechanical regulation of focal adhesion and invadopodia formation. J Cell Sci 2020; 133:133/20/jcs244848. [DOI: 10.1242/jcs.244848] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
ABSTRACT
Integrin adhesions are a structurally and functionally diverse family of transmembrane, multi-protein complexes that link the intracellular cytoskeleton to the extracellular matrix (ECM). The different members of this family, including focal adhesions (FAs), focal complexes, fibrillar adhesions, podosomes and invadopodia, contain many shared scaffolding and signaling ‘adhesome’ components, as well as distinct molecules that perform specific functions, unique to each adhesion form. In this Hypothesis, we address the pivotal roles of mechanical forces, generated by local actin polymerization or actomyosin-based contractility, in the formation, maturation and functionality of two members of the integrin adhesions family, namely FAs and invadopodia, which display distinct structures and functional properties. FAs are robust and stable ECM contacts, associated with contractile stress fibers, while invadopodia are invasive adhesions that degrade the underlying matrix and penetrate into it. We discuss here the mechanisms, whereby these two types of adhesion utilize a similar molecular machinery to drive very different – often opposing cellular activities, and hypothesize that early stages of FAs and invadopodia assembly use similar biomechanical principles, whereas maturation of the two structures, and their ‘adhesive’ and ‘invasive’ functionalities require distinct sources of biomechanical reinforcement.
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Affiliation(s)
- Or-Yam Revach
- Departments of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Inna Grosheva
- Departments of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
- Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Benjamin Geiger
- Departments of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
- Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
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Ji R, Zhu XJ, Wang ZR, Huang LQ. Cortactin in Epithelial-Mesenchymal Transition. Front Cell Dev Biol 2020; 8:585619. [PMID: 33195233 PMCID: PMC7606982 DOI: 10.3389/fcell.2020.585619] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 09/24/2020] [Indexed: 12/15/2022] Open
Abstract
Cortactin, a member of the actin-binding protein family, plays an important role in cell movement involving the cytoskeleton, as cell movement mediated by cortactin may induce the epithelial–mesenchymal transition. Cortactin participates in tumor proliferation, migration, and invasion and other related disease processes by binding to different proteins and participating in different pathways and mechanisms that induce the occurrence of these disease processes. Therefore, this article reviews the correlations between cortactin, the actin cytoskeleton, and the epithelial–mesenchymal transition and discusses its clinical importance in tumor therapy.
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Affiliation(s)
- Rong Ji
- Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
| | - Xiao-Juan Zhu
- Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
| | - Zhi-Rong Wang
- Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
| | - Li-Qiang Huang
- Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
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Masi I, Caprara V, Bagnato A, Rosanò L. Tumor Cellular and Microenvironmental Cues Controlling Invadopodia Formation. Front Cell Dev Biol 2020; 8:584181. [PMID: 33178698 PMCID: PMC7593604 DOI: 10.3389/fcell.2020.584181] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 09/09/2020] [Indexed: 12/11/2022] Open
Abstract
During the metastatic progression, invading cells might achieve degradation and subsequent invasion into the extracellular matrix (ECM) and the underlying vasculature using invadopodia, F-actin-based and force-supporting protrusive membrane structures, operating focalized proteolysis. Their formation is a dynamic process requiring the combined and synergistic activity of ECM-modifying proteins with cellular receptors, and the interplay with factors from the tumor microenvironment (TME). Significant advances have been made in understanding how invadopodia are assembled and how they progress in degradative protrusions, as well as their disassembly, and the cooperation between cellular signals and ECM conditions governing invadopodia formation and activity, holding promise to translation into the identification of molecular targets for therapeutic interventions. These findings have revealed the existence of biochemical and mechanical interactions not only between the actin cores of invadopodia and specific intracellular structures, including the cell nucleus, the microtubular network, and vesicular trafficking players, but also with elements of the TME, such as stromal cells, ECM components, mechanical forces, and metabolic conditions. These interactions reflect the complexity and intricate regulation of invadopodia and suggest that many aspects of their formation and function remain to be determined. In this review, we will provide a brief description of invadopodia and tackle the most recent findings on their regulation by cellular signaling as well as by inputs from the TME. The identification and interplay between these inputs will offer a deeper mechanistic understanding of cell invasion during the metastatic process and will help the development of more effective therapeutic strategies.
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Affiliation(s)
- Ilenia Masi
- Unit of Preclinical Models and New Therapeutic Agents, IRCCS - Regina Elena National Cancer Institute, Rome, Italy
| | - Valentina Caprara
- Unit of Preclinical Models and New Therapeutic Agents, IRCCS - Regina Elena National Cancer Institute, Rome, Italy
| | - Anna Bagnato
- Unit of Preclinical Models and New Therapeutic Agents, IRCCS - Regina Elena National Cancer Institute, Rome, Italy
| | - Laura Rosanò
- Unit of Preclinical Models and New Therapeutic Agents, IRCCS - Regina Elena National Cancer Institute, Rome, Italy.,Institute of Molecular Biology and Pathology, CNR, Rome, Italy
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35
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Increased Stiffness Inhibits Invadopodia Formation and Cell Migration in 3D. Biophys J 2020; 119:726-736. [PMID: 32697977 DOI: 10.1016/j.bpj.2020.07.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 06/04/2020] [Accepted: 07/06/2020] [Indexed: 12/16/2022] Open
Abstract
Cancer cells typically invade through basement membranes (BMs) at key points during metastasis, including primary tumor invasion, intravasation, and extravasation. Cells extend invadopodia protrusions to create channels in the nanoporous BM through which they can invade, either via proteolytic degradation or mechanical force. Increased matrix stiffness can promote cancer progression, and two-dimensional (2D) culture studies indicate that increased stiffness promotes invadopodia degradation activity. However, invadopodia can function mechanically, independent of their degradative activity, and cells do not form fully matured invadopodia or migrate in the direction of the invadopodia in 2D environments. Here, we elucidated the impact of matrix stiffness on the mechanical mode of invadopodia activity of cancer cells cultured in three-dimensional BM-like matrices. Invadopodia formation and cell migration assays were performed for invasive breast cancer cells cultured in mechanically plastic, nanoporous, and minimally degradable interpenetrating networks of reconstituted BM matrix and alginate, which presented a range of elastic moduli from 0.4 to 9.3 kPa. Across this entire range of stiffness, we find that cells form mature invadopodia that often precede migration in the direction of the protrusion. However, at higher stiffness, cells form shorter and more transient invadopodia and are less likely to extend invadopodia overall, contrasting with results from 2D studies. Subsequently, cell migration is diminished in stiff environments. Thus, although previous studies indicate that increased stiffness may promote malignant phenotypes and the degradative activity of invadopodia, our findings show that increased stiffness physically restricts invadopodia extension and cell migration in three-dimensional, BM-like environments.
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36
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Grafinger OR, Gorshtein G, Stirling T, Brasher MI, Coppolino MG. β1 integrin-mediated signaling regulates MT1-MMP phosphorylation to promote tumor cell invasion. J Cell Sci 2020; 133:jcs239152. [PMID: 32205364 DOI: 10.1242/jcs.239152] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 03/12/2020] [Indexed: 12/15/2022] Open
Abstract
Malignant cancer cells can invade extracellular matrix (ECM) through the formation of F-actin-rich subcellular structures termed invadopodia. ECM degradation at invadopodia is mediated by matrix metalloproteinases (MMPs), and recent findings indicate that membrane-anchored membrane type 1-matrix metalloproteinase (MT1-MMP, also known as MMP14) has a primary role in this process. Maintenance of an invasive phenotype is dependent on internalization of MT1-MMP from the plasma membrane and its recycling to sites of ECM remodeling. Internalization of MT1-MMP is dependent on its phosphorylation, and here we examine the role of β1 integrin-mediated signaling in this process. Activation of β1 integrin using the antibody P4G11 induced phosphorylation and internalization of MT1-MMP and resulted in increased cellular invasiveness and invadopodium formation in vitro We also observed phosphorylation of Src and epidermal growth factor receptor (EGFR) and an increase in their association in response to β1 integrin activation, and determined that Src and EGFR promote phosphorylation of MT1-MMP on Thr567 These results suggest that MT1-MMP phosphorylation is regulated by a β1 integrin-Src-EGFR signaling pathway that promotes recycling of MT1-MMP to sites of invadopodia formation during cancer cell invasion.This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Olivia R Grafinger
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Genya Gorshtein
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Tyler Stirling
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Megan I Brasher
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Marc G Coppolino
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, N1G 2W1, Canada
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Chen L, Zhu M, Yu S, Hai L, Zhang L, Zhang C, Zhao P, Zhou H, Wang S, Yang X. Arg kinase mediates CXCL12/CXCR4-induced invadopodia formation and invasion of glioma cells. Exp Cell Res 2020; 389:111893. [PMID: 32035133 DOI: 10.1016/j.yexcr.2020.111893] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 01/29/2020] [Accepted: 02/04/2020] [Indexed: 01/01/2023]
Abstract
Compared with noninvasive tumor cells, glioma cells overexpress chemokine receptor type 4 (CXCR4), which exhibits significantly greater expression in invasive tumor cells than in noninvasive tumor cells. C-X-C motif chemokine ligand 12 (CXCL12, also known as stromal derived factor-1, SDF-1) and its cell surface receptor CXCR4 activate a signaling axis that induces the expression of membrane type-2 matrix metalloproteinase (MT2-MMP), which plays a pivotal role in the invasion and migration of various cancer cells; however, the specific mechanism involved in this is unclear. Recently, studies have shown that invadopodia can recruit and secrete related enzymes, such as matrix metalloproteinases (MMPs), to degrade the surrounding extracellular matrix (ECM), promoting the invasion and migration of tumor cells. Phosphorylated cortactin (pY421-cortactin) is required for the formation and maturation of invadopodia, but the upstream regulatory factors and kinases involved in phosphorylation have not been elucidated. In this study, we found that CXCL12/CXCR4 was capable of inducing glioma cell invadopodia formation, probably by regulating cortactin phosphorylation. The interaction of cortactin and Arg (also known as Abl-related nonreceptor tyrosine kinase, ABL2) in glioma cells was demonstrated. The silencing of Arg inhibited glioma cell invadopodia formation and invasion by blocking cortactin phosphorylation. Moreover, CXCL12 could not induce glioma cell invasion in Arg-knockdown glioma cells. Based on these results, it can be concluded that Arg mediates CXCL12/CXCR4-induced glioma cell invasion, and CXCL12/CXCR4 regulates invadopodia maturation through the Arg-cortactin pathway, which indicates that Arg could be a candidate therapeutic target to inhibit glioma cell invasion.
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Affiliation(s)
- Lei Chen
- Department of Neurosurgery, Tianjin First Central Hospital, Tianjin, 300192, PR China
| | - Meng Zhu
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, PR China
| | - Shengping Yu
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, PR China
| | - Long Hai
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, PR China
| | - Liang Zhang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, PR China
| | - Chen Zhang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, PR China
| | - Pengfei Zhao
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, PR China
| | - Hua Zhou
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, PR China
| | - Song Wang
- Department of Neurosurgery, Tianjin First Central Hospital, Tianjin, 300192, PR China
| | - Xuejun Yang
- Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, PR China.
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Guégan JP, Ginestier C, Charafe-Jauffret E, Ducret T, Quignard JF, Vacher P, Legembre P. CD95/Fas and metastatic disease: What does not kill you makes you stronger. Semin Cancer Biol 2020; 60:121-131. [PMID: 31176682 DOI: 10.1016/j.semcancer.2019.06.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 06/05/2019] [Accepted: 06/05/2019] [Indexed: 12/14/2022]
Abstract
CD95 (also known as Fas) is the prototype of death receptors; however, evidence suggests that this receptor mainly implements non-apoptotic signaling pathways such as NF-κB, MAPK, and PI3K that are involved in cell migration, differentiation, survival, and cytokine secretion. At least two different forms of CD95 L exist. The multi-aggregated transmembrane ligand (m-CD95 L) is cleaved by metalloproteases to release a homotrimeric soluble ligand (s-CD95 L). Unlike m-CD95 L, the interaction between s-CD95 L and its receptor CD95 fails to trigger apoptosis, but instead promotes calcium-dependent cell migration, which contributes to the accumulation of inflammatory Th17 cells in damaged organs of lupus patients and favors cancer cell invasiveness. Novel inhibitors targeting the pro-inflammatory roles of CD95/CD95 L may provide attractive therapeutic options for patients with chronic inflammatory disorders or cancer. This review discusses the roles of the CD95/CD95 L pair in cell migration and metastasis.
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Affiliation(s)
- Jean Philippe Guégan
- CLCC Eugène Marquis, Équipe Ligue Contre Le Cancer, Rennes, France; Université Rennes, INSERM U1242, Rennes, France
| | - Christophe Ginestier
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, Marseille, France
| | - Emmanuelle Charafe-Jauffret
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, Marseille, France
| | - Thomas Ducret
- Université de Bordeaux, Bordeaux, France; Centre de Recherche Cardio Thoracique de Bordeaux, INSERM U1045, Bordeaux, France
| | - Jean-François Quignard
- Université de Bordeaux, Bordeaux, France; Centre de Recherche Cardio Thoracique de Bordeaux, INSERM U1045, Bordeaux, France
| | - Pierre Vacher
- Université de Bordeaux, Bordeaux, France; INSERM U1218, Bordeaux, France
| | - Patrick Legembre
- CLCC Eugène Marquis, Équipe Ligue Contre Le Cancer, Rennes, France; Université Rennes, INSERM U1242, Rennes, France.
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39
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Liu G, Bao Y, Liu C, Zhu Q, Zhao L, Lu X, Zhu Q, Lv Y, Bai F, Wen H, Sun Y, Zhu WG. IKKε phosphorylates kindlin-2 to induce invadopodia formation and promote colorectal cancer metastasis. Theranostics 2020; 10:2358-2373. [PMID: 32104508 PMCID: PMC7019159 DOI: 10.7150/thno.40397] [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: 09/17/2019] [Accepted: 12/30/2019] [Indexed: 12/24/2022] Open
Abstract
Invadopodia formation is a key driver of cancer metastasis. The noncanonical IkB-related kinase IKKε has been implicated in cancer metastasis, but its roles in invadopodia formation and colorectal cancer (CRC) metastasis are unclear. Methods: Immunofluorescence, gelatin-degradation assay, wound healing assay and transwell invasion assay were used to determine the influence of IKKε over-expression, knockdown and pharmacological inhibition on invadopodia formation and the migratory and invasive capacity of CRC cells in vitro. Effects of IKKε knockdown or pharmacological inhibition on CRC metastasis were examined in mice. Immunohistochemistry staining was used to detect expression levels of IKKε in CRC patient tissues, and its association with prognosis in CRC patients was also analyzed. Immunoprecipitation, western blotting and in vitro kinase assay were constructed to investigate the molecular mechanisms. Results: IKKε co-localizes with F-actin and the invadopodia marker Tks5 at the gelatin-degrading sites of CRC cells. Genetic over-expression/knockdown or pharmacological inhibition of IKKε altered invadopodia formation and the migratory and invasive capacity of CRC cells in vitro. In vivo, knockdown or pharmacological inhibition of IKKε significantly suppressed metastasis of CRC cells in mice. IKKε knockdown also inhibited invadopodia formation in vivo. Clinical investigation of tumor specimens from 191 patients with CRC revealed that high IKKε expression correlates with metastasis and poor prognosis of CRC. Mechanistically, IKKε directly binds to and phosphorylates kindlin-2 at serine 159; this effect mediates the IKKε-induced invadopodia formation and promotion of CRC metastasis. Conclusions: We identify IKKε as a novel regulator of invadopodia formation and a unique mechanism by which IKKε promotes the metastasis of CRC. Our study suggests that IKKε is a potential target to suppress CRC metastasis.
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40
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Optogenetic control of cofilin and αTAT in living cells using Z-lock. Nat Chem Biol 2019; 15:1183-1190. [PMID: 31740825 PMCID: PMC6873228 DOI: 10.1038/s41589-019-0405-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 10/09/2019] [Indexed: 11/29/2022]
Abstract
Here we introduce Z-lock, an optogenetic approach for reversible, light-controlled steric inhibition of protein active sites. The LOV domain and Zdk, a small protein that binds LOV selectively in the dark, are appended to the protein of interest where they sterically block the active site. Irradiation causes LOV to change conformation and release Zdk, exposing the active site. Computer-assisted protein design was used to optimize linkers and Zdk-LOV affinity, for both effective binding in the dark, and effective light-induced release of the intramolecular interaction. Z-lock cofilin was shown to have actin severing ability in vitro, and in living cancer cells it produced protrusions and invadopodia. An active fragment of the tubulin acetylase αTAT was similarly modified and shown to acetylate tubulin upon irradiation.
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41
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Bayarmagnai B, Perrin L, Esmaeili Pourfarhangi K, Graña X, Tüzel E, Gligorijevic B. Invadopodia-mediated ECM degradation is enhanced in the G1 phase of the cell cycle. J Cell Sci 2019; 132:jcs.227116. [PMID: 31533971 DOI: 10.1242/jcs.227116] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 09/10/2019] [Indexed: 12/16/2022] Open
Abstract
The process of tumor cell invasion and metastasis includes assembly of invadopodia, protrusions capable of degrading the extracellular matrix (ECM). The effect of cell cycle progression on invadopodia has not been elucidated. In this study, by using invadopodia and cell cycle fluorescent markers, we show in 2D and 3D cultures, as well as in vivo, that breast carcinoma cells assemble invadopodia and invade into the surrounding ECM preferentially during the G1 phase. The expression (MT1-MMP, also known as MMP14, and cortactin) and localization (Tks5; also known as SH3PXD2A) of invadopodia components are elevated in G1 phase, and cells synchronized in G1 phase exhibit significantly higher ECM degradation compared to the cells synchronized in S phase. The cyclin-dependent kinase inhibitor (CKI) p27kip1 (also known as CDKN1B) localizes to the sites of invadopodia assembly. Overexpression and stable knockdown of p27kip1 lead to contrasting effects on invadopodia turnover and ECM degradation. Taken together, these findings suggest that expression of invadopodia components, as well as invadopodia function, are linked to cell cycle progression, and that invadopodia are controlled by cell cycle regulators. Our results caution that this coordination between invasion and cell cycle must be considered when designing effective chemotherapies.
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Affiliation(s)
- Battuya Bayarmagnai
- Department of Bioengineering, Temple University, Philadelphia, PA 19122, USA
| | - Louisiane Perrin
- Department of Bioengineering, Temple University, Philadelphia, PA 19122, USA
| | | | - Xavier Graña
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.,Fels Research Institute for Cancer Biology and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - Erkan Tüzel
- Department of Bioengineering, Temple University, Philadelphia, PA 19122, USA
| | - Bojana Gligorijevic
- Department of Bioengineering, Temple University, Philadelphia, PA 19122, USA .,Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
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Hypoxia Downregulates LPP3 and Promotes the Spatial Segregation of ATX and LPP1 During Cancer Cell Invasion. Cancers (Basel) 2019; 11:cancers11091403. [PMID: 31546971 PMCID: PMC6769543 DOI: 10.3390/cancers11091403] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 09/07/2019] [Accepted: 09/12/2019] [Indexed: 12/16/2022] Open
Abstract
Hypoxia is a common characteristic of advanced solid tumors and a potent driver of tumor invasion and metastasis. Recent evidence suggests the involvement of autotaxin (ATX) and lysophosphatidic acid receptors (LPARs) in cancer cell invasion promoted by the hypoxic tumor microenvironment; however, the transcriptional and/or spatiotemporal control of this process remain unexplored. Herein, we investigated whether hypoxia promotes cell invasion by affecting the main enzymes involved in its production (ATX) and degradation (lipid phosphate phosphatases, LPP1 and LPP3). We report that hypoxia not only modulates the expression levels of lysophosphatidic acid (LPA) regulatory enzymes but also induces their significant spatial segregation in a variety of cancers. While LPP3 expression was downregulated by hypoxia, ATX and LPP1 were asymmetrically redistributed to the leading edge and to the trailing edge, respectively. This was associated with the opposing roles of ATX and LPPs in cell invasion. The regulated expression and compartmentalization of these enzymes of opposing function can provide an effective way to control the generation of an LPA gradient that drives cellular invasion and migration in the hypoxic zones of tumors.
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43
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Erami Z, Heitz S, Bresnick AR, Backer JM. PI3Kβ links integrin activation and PI(3,4)P 2 production during invadopodial maturation. Mol Biol Cell 2019; 30:2367-2376. [PMID: 31318314 PMCID: PMC6741064 DOI: 10.1091/mbc.e19-03-0182] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 06/17/2019] [Accepted: 07/01/2019] [Indexed: 11/17/2022] Open
Abstract
The invasion of tumor cells from the primary tumor is mediated by invadopodia, actin-rich protrusive organelles that secrete matrix metalloproteases and degrade the extracellular matrix. This coupling between protrusive activity and matrix degradation facilitates tumor invasion. We previously reported that the PI3Kβ isoform of PI 3-kinase, which is regulated by both receptor tyrosine kinases and G protein-coupled receptors, is required for invasion and gelatin degradation in breast cancer cells. We have now defined the mechanism by which PI3Kβ regulates invadopodia. We find that PI3Kβ is specifically activated downstream from integrins, and is required for integrin-stimulated spreading and haptotaxis as well as integrin-stimulated invadopodia formation. Surprisingly, these integrin-stimulated and PI3Kβ-dependent responses require the production of PI(3,4)P2 by the phosphoinositide 5'-phosphatase SHIP2. Thus, integrin activation of PI3Kβ is coupled to the SHIP2-dependent production of PI(3,4)P2, which regulates the recruitment of PH domain-containing scaffolds such as lamellipodin to invadopodia. These findings provide novel mechanistic insight into the role of PI3Kβ in the regulation of invadopodia in breast cancer cells.
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Affiliation(s)
- Zahra Erami
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461
| | - Samantha Heitz
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461
| | - Anne R. Bresnick
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461
| | - Jonathan M. Backer
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461
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Septin 9 isoforms promote tumorigenesis in mammary epithelial cells by increasing migration and ECM degradation through metalloproteinase secretion at focal adhesions. Oncogene 2019; 38:5839-5859. [PMID: 31285548 PMCID: PMC6859949 DOI: 10.1038/s41388-019-0844-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 05/09/2019] [Accepted: 05/10/2019] [Indexed: 02/07/2023]
Abstract
The cytoskeletal interacting protein Septin 9 (SEPT9), a member of the septin gene family, has been proposed to have oncogenic functions. It is a known hot spot of retroviral tagging insertion and a fusion partner of both de novo and therapy-induced mixed lineage leukemia (MLL). Of all septins, SEPT9 holds the strongest link to cancer, especially breast cancer. Murine models of breast cancer frequently exhibit Sept9 amplification in the form of double minute chromosomes, and about 20% of human breast cancer display genomic amplification and protein over expression at the SEPT9 locus. Yet, a clear mechanism by which SEPT9 elicits tumor-promoting functions is lacking. To obtain unbiased insights on molecular signatures of SEPT9 upregulation in breast tumors, we overexpressed several of its isoforms in breast cancer cell lines. Global transcriptomic profiling supports a role of SEPT9 in invasion. Functional studies reveal that SEPT9 upregulation is sufficient to increase degradation of the extracellular matrix, while SEPT9 downregulation inhibits this process. The degradation pattern is peripheral and associated with focal adhesions (FA), where it is coupled with increased expression of matrix metalloproteinases. SEPT9 overexpression induces MMP upregulation in human tumors and in culture models and promotes MMP3 secretion to the media at FAs. Downregulation of SEPT9 or chemical inhibition of septin filament assembly impairs recruitment of MMP3 to FAs. Our results indicate that SEPT9 promotes upregulation and both trafficking and secretion of MMPs near FAs, thus enhancing migration and invasion of breast cancer cells.
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45
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Zhang X, Xing XX, Cui JF. Invadopodia formation: An important step in matrix stiffness-regulated tumor invasion and metastasis. Shijie Huaren Xiaohua Zazhi 2019; 27:589-597. [DOI: 10.11569/wcjd.v27.i9.589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Highly motile and invasive abilities are symbolic features of metastatic tumor cells. Being a critical molecular event for maintaining the highly migratory and invasive capabilities of tumor cells, invadopodia formation undoubtedly determines the progression of tumor invasion and metastasis. Growing numbers of studies suggest that increased matrix stiffness, as a notable property of physical mechanics in solid tumors, participates in the regulation of tumor invasion and metastasis via different molecular mechanisms. However, to date the relevant mechanisms of matrix stiffness-induced invadopodia formation and activity in tumor cells remain largely unclear. This paper is to make a review on the structure and function of invadopodia, the stages and inductive factors of invadopodia formation, the regulatory mechanisms of matrix stiffness-induced invadopodia formation and so on, with an aim to reveal the important roles of invadopodia in matrix stiffness-regulated tumor invasion and metastasis.
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Affiliation(s)
- Xi Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xiao-Xia Xing
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jie-Feng Cui
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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46
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Peláez R, Pariente A, Pérez-Sala Á, Larrayoz IM. Integrins: Moonlighting Proteins in Invadosome Formation. Cancers (Basel) 2019; 11:cancers11050615. [PMID: 31052560 PMCID: PMC6562994 DOI: 10.3390/cancers11050615] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 04/26/2019] [Accepted: 04/28/2019] [Indexed: 12/24/2022] Open
Abstract
Invadopodia are actin-rich protrusions developed by transformed cells in 2D/3D environments that are implicated in extracellular matrix (ECM) remodeling and degradation. These structures have an undoubted association with cancer invasion and metastasis because invadopodium formation in vivo is a key step for intra/extravasation of tumor cells. Invadopodia are closely related to other actin-rich structures known as podosomes, which are typical structures of normal cells necessary for different physiological processes during development and organogenesis. Invadopodia and podosomes are included in the general term 'invadosomes,' as they both appear as actin puncta on plasma membranes next to extracellular matrix metalloproteinases, although organization, regulation, and function are slightly different. Integrins are transmembrane proteins implicated in cell-cell and cell-matrix interactions and other important processes such as molecular signaling, mechano-transduction, and cell functions, e.g., adhesion, migration, or invasion. It is noteworthy that integrin expression is altered in many tumors, and other pathologies such as cardiovascular or immune dysfunctions. Over the last few years, growing evidence has suggested a role of integrins in the formation of invadopodia. However, their implication in invadopodia formation and adhesion to the ECM is still not well known. This review focuses on the role of integrins in invadopodium formation and provides a general overview of the involvement of these proteins in the mechanisms of metastasis, taking into account classic research through to the latest and most advanced work in the field.
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Affiliation(s)
- Rafael Peláez
- Biomarkers and Molecular Signaling Group, Neurodegenerative Diseases Area Center for Biomedical Research of La Rioja, CIBIR, c.p., 26006. Logroño, Spain.
| | - Ana Pariente
- Biomarkers and Molecular Signaling Group, Neurodegenerative Diseases Area Center for Biomedical Research of La Rioja, CIBIR, c.p., 26006. Logroño, Spain.
| | - Álvaro Pérez-Sala
- Biomarkers and Molecular Signaling Group, Neurodegenerative Diseases Area Center for Biomedical Research of La Rioja, CIBIR, c.p., 26006. Logroño, Spain.
| | - Ignacio M Larrayoz
- Biomarkers and Molecular Signaling Group, Neurodegenerative Diseases Area Center for Biomedical Research of La Rioja, CIBIR, c.p., 26006. Logroño, Spain.
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Valenzuela-Iglesias A, Burks HE, Arnette CR, Yalamanchili A, Nekrasova O, Godsel LM, Green KJ. Desmoglein 1 Regulates Invadopodia by Suppressing EGFR/Erk Signaling in an Erbin-Dependent Manner. Mol Cancer Res 2019; 17:1195-1206. [PMID: 30655320 PMCID: PMC6581214 DOI: 10.1158/1541-7786.mcr-18-0048] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 12/07/2018] [Accepted: 01/08/2019] [Indexed: 12/14/2022]
Abstract
Loss of the desmosomal cell-cell adhesion molecule, Desmoglein 1 (Dsg1), has been reported as an indicator of poor prognosis in head and neck squamous cell carcinomas (HNSCC) overexpressing epidermal growth factor receptor (EGFR). It has been well established that EGFR signaling promotes the formation of invadopodia, actin-based protrusions formed by cancer cells to facilitate invasion and metastasis, by activating pathways leading to actin polymerization and ultimately matrix degradation. We previously showed that Dsg1 downregulates EGFR/Erk signaling by interacting with the ErbB2-binding protein Erbin (ErbB2 Interacting Protein) to promote keratinocyte differentiation. Here, we provide evidence that restoring Dsg1 expression in cells derived from HNSCC suppresses invasion by decreasing the number of invadopodia and matrix degradation. Moreover, Dsg1 requires Erbin to downregulate EGFR/Erk signaling and to fully suppress invadopodia formation. Our findings indicate a novel role for Dsg1 in the regulation of invadopodia signaling and provide potential new targets for development of therapies to prevent invadopodia formation and therefore cancer invasion and metastasis. IMPLICATIONS: Our work exposes a new pathway by which a desmosomal cadherin called Dsg1, which is lost early in head and neck cancer progression, suppresses cancer cell invadopodia formation by scaffolding ErbB2 Interacting Protein and consequent attenuation of EGF/Erk signaling.
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Affiliation(s)
| | - Hope E Burks
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Christopher R Arnette
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Amulya Yalamanchili
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Oxana Nekrasova
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Lisa M Godsel
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Kathleen J Green
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
- Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago and Evanston, IL
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Pourfarhangi KE, Bergman A, Gligorijevic B. ECM Cross-Linking Regulates Invadopodia Dynamics. Biophys J 2019; 114:1455-1466. [PMID: 29590602 DOI: 10.1016/j.bpj.2018.01.027] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 12/22/2017] [Accepted: 01/22/2018] [Indexed: 12/26/2022] Open
Abstract
Invadopodia are membrane protrusions dynamically assembled by invasive cancer cells in contact with the extracellular matrix (ECM). Invadopodia are enriched by the structural proteins actin and cortactin as well as metalloproteases such as MT1-MMP, whose function is to degrade the surrounding ECM. During metastasis, invadopodia are necessary for cancer cell intravasation and extravasation. Although signaling pathways involved in the assembly and function of invadopodia are well studied, few studies address invadopodia dynamics and how the cell-ECM interactions contribute to cell invasion. Using iterative analysis based on time-lapse microscopy and mathematical modeling of invasive cancer cells, we found that cells oscillate between invadopodia presence and cell stasis-termed the "invadopodia state"-and invadopodia absence during cell translocation-termed the "migration state." Our data suggest that β1-integrin-ECM binding and ECM cross-linking control the duration of each of the two states. By changing the concentration of cross-linkers in two-dimensional and three-dimensional cultures, we generate an ECM in which 0-0.92 of total lysine residues are cross-linked. Using an ECM with a range of cross-linking degrees, we demonstrate that the dynamics of invadopodia-related functions have a biphasic relationship to ECM cross-linking. At intermediate levels of ECM cross-linking (0.39), cells exhibit rapid invadopodia protrusion-retraction cycles and rapid calcium spikes, which lead to more frequent MT1-MMP delivery, causing maximal invadopodia-mediated ECM degradation. In contrast, both extremely high or low levels of cross-linking lead to slower invadopodia-related dynamics and lower ECM degradation. Additionally, β1-integrin inhibition modifies the dynamics of invadopodia-related functions as well as the length of time cells spend in either of the states. Collectively, these data suggest that β1-integrin-ECM binding nonlinearly translates small physical differences in the extracellular environment to differences in the dynamics of cancer cell behaviors. Understanding the conditions under which invadopodia can be reduced by subtle environment-targeting treatments may lead to combination therapies for preventing metastatic spread.
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Affiliation(s)
| | - Aviv Bergman
- Systems & Computational Biology Department, Albert Einstein College of Medicine, New York, New York; Santa Fe Institute, Santa Fe, New Mexico
| | - Bojana Gligorijevic
- Bioengineering Department, College of Engineering, Temple University, Philadelphia, Pennsylvania; Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
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Kumar S, Das A, Barai A, Sen S. MMP Secretion Rate and Inter-invadopodia Spacing Collectively Govern Cancer Invasiveness. Biophys J 2019; 114:650-662. [PMID: 29414711 DOI: 10.1016/j.bpj.2017.11.3777] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 11/11/2017] [Accepted: 11/20/2017] [Indexed: 01/10/2023] Open
Abstract
Invadopodia are micron-sized invasive structures that mediate extracellular matrix (ECM) degradation through a combination of membrane-bound and soluble matrix metalloproteinases (MMPs). However, how such localized degradation is converted into pores big enough for cancer cells to invade, and the relative contributions of membrane-bound versus soluble MMPs to this process remain unclear. In this article, we address these questions by combining experiments and simulations. We show that in MDA-MB-231 cells, an increase in ECM density enhances invadopodia-mediated ECM degradation and decreases inter-invadopodia spacing. ECM degradation is mostly mediated by soluble MMPs, which are activated by membrane-bound MT1-MMP. We present a computational model of invadopodia-mediated ECM degradation, which recapitulates the above observations and identifies MMP secretion rate as an important regulator of invadopodia stability. Simulations with multiple invadopodia suggest that inter-invadopodia spacing and MMP secretion rate collectively dictate the size of the degraded zones. Taken together, our results suggest that for creating pores conducive for cancer invasion, cells must tune inter-invadopodia spacing and MMP secretion rate in an ECM density-dependent manner, thereby striking a balance between invadopodia penetration and ECM degradation.
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Affiliation(s)
- Sandeep Kumar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
| | - Alakesh Das
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
| | - Amlan Barai
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
| | - Shamik Sen
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India.
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Mah EJ, Lefebvre AEYT, McGahey GE, Yee AF, Digman MA. Collagen density modulates triple-negative breast cancer cell metabolism through adhesion-mediated contractility. Sci Rep 2018; 8:17094. [PMID: 30459440 DOI: 10.2139/ssrn.3188427] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 10/30/2018] [Indexed: 05/21/2023] Open
Abstract
Extracellular matrix (ECM) mechanical properties upregulate cancer invasion, cell contractility, and focal adhesion formation. Alteration in energy metabolism is a known characteristic of cancer cells (i.e., Warburg effect) and modulates cell invasion. There is little evidence to show if collagen density can alter cancer cell metabolism. We investigated changes in energy metabolism due to collagen density in five breast cell lines by measuring the fluorescence lifetime of NADH. We found that only triple-negative breast cancer cells, MDA-MB231 and MDA-MB468 cells, had an increased population of bound NADH, indicating an oxidative phosphorylation (OXPHOS) signature, as collagen density decreased. When inhibiting ROCK and cell contractility, MDA-MB231 cells on glass shifted from glycolysis (GLY) to OXPHOS, confirming the intricate relationship between mechanosensing and metabolism. MCF10A cells showed less significant changes in metabolism, shifting towards GLY as collagen density decreased. The MCF-7 and T-47D, less invasive breast cancer cells, compared to the MDA-MB231 and MDA-MB468 cells, showed no changes regardless of substrate. In addition, OXPHOS or GLY inhibitors in MDA-MB231 cells showed dramatic shifts from OXPHOS to GLY or vice versa. These results provide an important link between cellular metabolism, contractility, and collagen density in human breast cancer.
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Affiliation(s)
- Emma J Mah
- Department of Chemical Engineering and Materials Science, University of California, Irvine, Irvine, California, USA
- Laboratory for Fluorescence Dynamics, University of California, Irvine, Irvine, USA
| | - Austin E Y T Lefebvre
- Department of Biomedical Engineering, University of California, Irvine, Irvine, California, USA
- Laboratory for Fluorescence Dynamics, University of California, Irvine, Irvine, USA
| | - Gabrielle E McGahey
- Department of Biomedical Engineering, University of California, Irvine, Irvine, California, USA
- Laboratory for Fluorescence Dynamics, University of California, Irvine, Irvine, USA
| | - Albert F Yee
- Department of Chemical Engineering and Materials Science, University of California, Irvine, Irvine, California, USA
- Department of Biomedical Engineering, University of California, Irvine, Irvine, California, USA
| | - Michelle A Digman
- Department of Chemical Engineering and Materials Science, University of California, Irvine, Irvine, California, USA.
- Department of Biomedical Engineering, University of California, Irvine, Irvine, California, USA.
- Laboratory for Fluorescence Dynamics, University of California, Irvine, Irvine, USA.
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