Tumor suppressor DAPK1 catalyzes Adhesion Assembly on Rigid but Anoikis on Soft Matrices

Qin, Ruifang; Wolfenson, Haguy; Saxena, Mayur; Sheetz, Michael P.

doi:10.1101/320739

Cited by 7 publications

(7 citation statements)

References 35 publications

(48 reference statements)

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“…A chromatin-remodeling gene CREBBP was found to be overexpressed in breast cancers [29], and is frequently mutated in bladder cancers [30]. DAPK1 is a potential tumor suppressor gene [31,32]. NCOA1 was found to promote angiogenesis in breast cancers [33].…”

Section: Quantitative and Qualitative Assessment Of Quadmutnetex Resultsmentioning

confidence: 99%

QuaDMutNetEx: a method for detecting cancer driver genes with low mutation frequency

2020

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Background: Cancer is caused by genetic mutations, but not all somatic mutations in human DNA drive the emergence or growth of cancers. While many frequently-mutated cancer driver genes have already been identified and are being utilized for diagnostic, prognostic, or therapeutic purposes, identifying driver genes that harbor mutations occurring with low frequency in human cancers is an ongoing endeavor. Typically, mutations that do not confer growth advantage to tumors-passenger mutations-dominate the mutation landscape of tumor cell genome, making identification of low-frequency driver mutations a challenge. The leading approach for discovering new putative driver genes involves analyzing patterns of mutations in large cohorts of patients and using statistical methods to discriminate driver from passenger mutations. Results: We propose a novel cancer driver gene detection method, QuaDMutNetEx. QuaDMutNetEx discovers cancer drivers with low mutation frequency by giving preference to genes encoding proteins that are connected in human protein-protein interaction networks, and that at the same time show low deviation from the mutual exclusivity pattern that characterizes driver mutations occurring in the same pathway or functional gene group across a cohort of cancer samples. Conclusions: Evaluation of QuaDMutNetEx on four different tumor sample datasets show that the proposed method finds biologically-connected sets of low-frequency driver genes, including many genes that are not found if the network connectivity information is not considered. Improved quality and interpretability of the discovered putative driver gene sets compared to existing methods shows that QuaDMutNetEx is a valuable new tool for detecting driver genes. QuaDMutNetEx is available for download from https://github.com/bokhariy/QuaDMutNetEx under the GNU GPLv3 license.

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Section: Quantitative and Qualitative Assessment Of Quadmutnetex Resultsmentioning

confidence: 99%

QuaDMutNetEx: a method for detecting cancer driver genes with low mutation frequency

2020

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“…Another mechanism involves the role of death-associated protein kinase 1 (DAPK1), a central apoptotic regulator that interacts with tropomyosin and talin, and can be recruited to adhesions [ 165 , 166 ]. In normal mouse fibroblasts, when the mechanical feedback forces from a soft ECM are insufficient for the maturation of FAs, DAPK1 dissociates from the adhesion complex and triggers apoptosis [ 167 ]. However, in transformed cells, DAPK1 activity is inhibited, thus preventing the onset of apoptosis in the same non-adhesive conditions [ 168 ].…”

Section: Which Mechanobiological Processes Underlie Anchorage-independent Cancer Cell Growth?mentioning

confidence: 99%

The ‘Yin and Yang’ of Cancer Cell Growth and Mechanosensing

Amer

Shi

Wolfenson

2021

Cancers

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In cancer, two unique and seemingly contradictory behaviors are evident: on the one hand, tumors are typically stiffer than the tissues in which they grow, and this high stiffness promotes their malignant progression; on the other hand, cancer cells are anchorage-independent—namely, they can survive and grow in soft environments that do not support cell attachment. How can these two features be consolidated? Recent findings on the mechanisms by which cells test the mechanical properties of their environment provide insight into the role of aberrant mechanosensing in cancer progression. In this review article, we focus on the role of high stiffness on cancer progression, with particular emphasis on tumor growth; we discuss the mechanisms of mechanosensing and mechanotransduction, and their dysregulation in cancerous cells; and we propose that a ‘yin and yang’ type phenomenon exists in the mechanobiology of cancer, whereby a switch in the type of interaction with the extracellular matrix dictates the outcome of the cancer cells.

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“…Recently, we determined that tumor suppressor Death Associated Protein Kinase1 (DAPK1) causes rigidity-dependent cell apoptosis (anoikis) on soft surfaces but accelerates adhesion assembly on rigid surfaces (Qin et al, 2018). To determine if DAPK1 was involved in stretch-dependent cancer cell apoptosis, we blocked DAPK1 activity with a DAPK1 inhibitor (DAPK1 inhibitor, 100 nM).…”

Section: Cyclic Stretch Mediated-cancer Cell Apoptosis Is Not Driven mentioning

confidence: 99%

“…Adhesion disassembly and eventual cell apoptosis will occur if the surface is soft. Many different tumor suppressors are part of the rigidity sensors including TPM2.1 (formerly known as Tm1), myosin IIA, DAPK1, α-actinin 4 and receptor tyrosine kinases like AXL and ROR2 (Helfman et al, 2008;Qin et al, 2018;Yang et al, 2016;Yang et al, 2018). A common mechanism of the malignant transformation is the depletion of TPM2.1 or the increased expression of Tpm3 (Raval et al, 2003;Stehn et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Mechanical Stretch Kills Transformed Cancer Cells

Tijore

Yao

Wang

et al. 2018

Preprint

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Transformed cancer cells differ from normal cells in several important features like anchorage independence, Warburg effect and mechanosensing. Consequently, transformed cancer cells develop an anaplastic morphology and respond aberrantly to external mechanical forces.Consistent with altered mechano-responsiveness, here we show that transformed cancer cells from many different tissues have reduced growth and become apoptotic upon cyclic stretch as do normal cells after the transformation. When matrix rigidity sensing is restored in transformed cancer cells, they survive and grow faster on soft surface upon cyclic stretch like normal cells but undergo anoikis without stretch by activation of death associated protein kinase1 (DAPK1). In contrast, stretch-dependent apoptosis (mechanoptosis) of transformed cells is driven by stretchmediated calcium influx and calcium-dependent calpain 2 protease activation on both collagen and fibronectin matrices. Further, mechanosensitive calcium channel, Piezo1 is needed for mechanoptosis. Thus, cyclic stretching of transformed cells from different tissues activates apoptosis, whereas similar stretching of normal cells stimulates growth.

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Tumor suppressor DAPK1 catalyzes Adhesion Assembly on Rigid but Anoikis on Soft Matrices

Cited by 7 publications

References 35 publications

QuaDMutNetEx: a method for detecting cancer driver genes with low mutation frequency

QuaDMutNetEx: a method for detecting cancer driver genes with low mutation frequency

The ‘Yin and Yang’ of Cancer Cell Growth and Mechanosensing

Mechanical Stretch Kills Transformed Cancer Cells

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