Tissue Force Programs Cell Fate and Tumor Aggression

Northey, Jason J.; Przybyla, Laralynne; Weaver, Valerie M.

doi:10.1158/2159-8290.cd-16-0733

Cited by 191 publications

(184 citation statements)

References 140 publications

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“…Tumor mechanics have a profound effect on fibroblasts and cancer cells and can promote tumor progression and metastasis (56). Stiffening of ECM creates a feed-forward self-reinforcing loop that contributes to the activation state of the fibroblast (57).…”

Section: Discussionmentioning

confidence: 99%

Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers

et al. 2018

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We have profiled, for the first time, an evolving human metastatic microenvironment, measuring gene expression, matrisome proteomics, cytokine and chemokine levels, cellularity, ECM organization and biomechanical properties, all on the same sample. Using biopsies of high-grade serous ovarian cancer (HGSOC) metastases that ranged from minimal to extensive disease, we show how non-malignant cell densities and cytokine networks evolve with disease progression. Multivariate integration of the different components allowed us to define for the first time, gene and protein profiles that predict extent of disease and tissue stiffness, whilst also revealing the complexity and dynamic nature of matrisome remodeling during development of metastases. Although we studied a single metastatic site from one human malignancy, a pattern of expression of 22 matrisome genes distinguished patients with a shorter overall survival in ovarian and twelve other primary solid cancers, suggesting that there may be a common matrix response to human cancer.

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Section: Discussionmentioning

confidence: 99%

Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers

et al. 2018

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“…Blindly depleting the stroma would decrease tissue tension and in turn reduce tumour aggressivity,78 but would also risk to remove components of the ECM and subtypes of CAFs with tumour-inhibiting properties. Results from this approach could therefore give effects opposite to the intended.…”

Section: Introductionmentioning

confidence: 99%

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

Neeße

Bauer

Öhlund

et al. 2018

Gut

268

222

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Pancreatic ductal adenocarcinoma (PDA) is notoriously aggressive and hard to treat. The tumour microenvironment (TME) in PDA is highly dynamic and has been found to promote tumour progression, metastasis niche formation and therapeutic resistance. Intensive research of recent years has revealed an incredible heterogeneity and complexity of the different components of the TME, including cancer-associated fibroblasts, immune cells, extracellular matrix components, tumour vessels and nerves. It has been hypothesised that paracrine interactions between neoplastic epithelial cells and TME compartments may result in either tumour-promoting or tumour-restraining consequences. A better preclinical understanding of such complex and dynamic network systems is required to develop more powerful treatment strategies for patients. Scientific activity and the number of compelling findings has virtually exploded during recent years. Here, we provide an update of the most recent findings in this area and discuss their translational and clinical implications for basic scientists and clinicians alike.

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“…7), providing, to our knowledge, the first direct link between upstream forces transmitted through the cytoskeleton and downstream nuclear localization of a transcriptional co-activator. Tissue stiffening is associated with tumorigenesis 38 and cancer progression 39 , suggesting that aberrant cytoskeletal mechanotransduction through FHL2 may contribute to FHL2's role in this disease. We report a strategy for generating point mutants specifically deficient in tensed F-actin binding that is applicable to all mechanoresponsive LIMprotein families we identified.…”

Section: Discussionmentioning

confidence: 99%

Mechanosensing through direct binding of tensed F-actin by LIM domains

Sun

Phua

Axiotakis

et al. 2020

Preprint

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Mechanical signals transmitted through the cytoplasmic actin cytoskeleton must be relayed to the nucleus to control gene expression. LIM domains are protein-protein interaction modules found in cytoskeletal proteins and transcriptional regulators; however, it is unclear if there is a direct link between these two functions. Here we identify three LIM protein families (zyxin, paxillin, and FHL) whose members preferentially localize to the actin cytoskeleton in mechanically-stimulated cells through their tandem LIM domains. A minimal actin-myosin reconstitution system reveals that representatives of all three families directly bind F-actin only in the presence of mechanical force. Point mutations at a site conserved in each LIM domain of these proteins selectively disrupt tensed F-actin binding in vitro and cytoskeletal localization in cells, demonstrating a common, avidity-based mechanism. Finally, we find that binding to tensed F-actin in the cytoplasm excludes the cancer-associated transcriptional co-activator FHL2 from the nucleus in stiff microenvironments. This establishes direct force-activated F-actin binding by FHL2 as a mechanosensing mechanism. Our studies suggest that force-dependent sequestration of LIM proteins on the actin cytoskeleton could be a general mechanism for controlling nuclear localization to effect mechanical signaling.

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Tissue Force Programs Cell Fate and Tumor Aggression

Cited by 191 publications

References 140 publications

Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers

Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

Mechanosensing through direct binding of tensed F-actin by LIM domains

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