Active contractility at E-cadherin junctions and its implications for cell extrusion in cancer

Wu, Selwin K.; Lagendijk, Anne Karine; Hogan, Benjamin M.; Gómez, Guillermo A.; Yap, Alpha S.

doi:10.4161/15384101.2014.989127

Cited by 42 publications

(55 citation statements)

References 57 publications

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“…Studies of cells changing their growth behavior under RPM exposure, revealed again to be a very suitable model to promote research on the metastatic activity of cancer cells in Earth‐bound patients. It allows to combine biological and biochemical experiments to address questions on the mechanisms that enable the cells to leave a monolayer and to survive a possible anchorage free period . As demonstrated in this study, the application of immunological or chemical agents will be of great help for future investigations on these questions.…”

Section: Discussionmentioning

confidence: 89%

Decreased E‐Cadherin in MCF7 Human Breast Cancer Cells Forming Multicellular Spheroids Exposed to Simulated Microgravity

et al. 2018

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MCF7 human breast cancer cells were cultured under normal gravity (1 g) and on a random positioning machine (RPM) preventing sedimentation. After 2 weeks, adherent 1 g-control and adherent RPM cells (AD) as well as multicellular spheroids (MCS) were harvested. AD and MCS had been exposed to the RPM in the same culture flask. In a subsequent proteome analysis, the majority of the proteins detected showed similar label-free quantification (LFQ) scores in each of the respective subpopulations, but in both AD or MCS cultures, proteins were also found whose LFQs deviated at least twofold from their counterparts in the 1 g-control cells. They included the cell junction protein E-cadherin, which was diminished in MCS cells, where proteins of the E-cadherin autodegradation pathway were enhanced and c-Src (proto-oncogene tyrosine-protein kinase c-Src) was detected. Spheroid formation was prevented by inhibition of c-Src but promoted by antibodies blocking E-cadherin activity. An interaction analysis of the detected proteins that are involved in forming and regulating junctions or adhesion complexes and in E-cadherin autodegradation indicated connections between the two protein groups. This suggests that the balance of proteins that up- or downregulate E-cadherin mediates the tendency of MCF7 cells to form MCS during RPM exposure.

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Section: Discussionmentioning

confidence: 89%

Decreased E‐Cadherin in MCF7 Human Breast Cancer Cells Forming Multicellular Spheroids Exposed to Simulated Microgravity

et al. 2018

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“…The early events of basal extrusion require remodeling of the actin cytoskeleton (reviewed in Wu et al, 2015). When we examined clones in the wing expressing miR-8 for 48h, we noted that F-actin levels appeared reduced apically.…”

Section: Resultsmentioning

confidence: 99%

miR-8 modulates cytoskeletal regulators to influence cell survival and epithelial organization in Drosophila wings

Bolin

Rachmaninoff

Moncada

et al. 2016

Developmental Biology

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Summary The miR-200 microRNA family plays important tumor suppressive roles. The sole Drosophila miR-200 ortholog, miR-8 plays conserved roles in Wingless, Notch and Insulin signaling pathways linked to tumorigenesis, yet homozygous null animals are viable and often appear morphologically normal. We observed that wing tissues mosaic for miR-8 levels by genetic loss or gain of function exhibited patterns of cell death consistent with a role for miR-8 in modulating cell survival in vivo. Here we show that miR-8 levels impact several actin cytoskeletal regulators that can affect cell survival and epithelial organization. We show that loss of miR-8 can confer resistance to apoptosis independent of an epithelial to mesenchymal transition while the persistence of cells expressing high levels of miR-8 in the wing epithelium leads to increased JNK signaling, aberrant expression of extracellular matrix remodeling proteins and disruption of proper wing epithelial organization. Altogether our results suggest that very low as well as very high levels of miR-8 can contribute to hallmarks associated with cancer, suggesting approaches to increase miR-200 microRNAs in cancer treatment should be moderate.

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“…Specific patterns of intercellular tension are controlled in part by the cortical F-actin network. Dysregulation of this pattern of contractility at the cell-cell junctions has been shown to drive oncogenic extrusion [24], [25]. An increase in cortical contractile F-actin within the Ras V12 cells was also found to be actively implicated in their extrusion by the surrounding WT cells [24], [25].…”

Section: Cortical Actin Belts Around Ras V12 Cells Diminish Under Strainmentioning

confidence: 99%

“…Dysregulation of this pattern of contractility at the cell-cell junctions has been shown to drive oncogenic extrusion [24], [25]. An increase in cortical contractile F-actin within the Ras V12 cells was also found to be actively implicated in their extrusion by the surrounding WT cells [24], [25]. Since these previous results indicate that cortical actin is critical in determining the fate of Ras V12 cells, we investigated the effects of strain on the remodeling of cortical actin throughout the co-culture.…”

Section: Cortical Actin Belts Around Ras V12 Cells Diminish Under Strainmentioning

confidence: 99%

“…Many studies investigate how the ECM stiffness impacts tumor progression [23], but mechanically dynamic microenvironments are considered less often. For the recognition and elimination of transformed cells, epithelial defense relies on many cytoskeletal proteins and cell-generated contractile forces in both WT [14] and transformed cells [24], [25]. Given that external forces can remodel the cytoskeleton architecture, we hypothesize that external forces have a profound impact on the behavior of Ras V12 cells within the epithelial monolayer.…”

Section: Introductionmentioning

confidence: 99%

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Mechanotransduction of strain regulates an invasive phenotype in newly transformed epithelial cells

Chagnon-Lessard

Jean-Ruel

Godin

et al. 2019

Preprint

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Carcinoma, the most common type of cancer, develops in the sheets of cells forming the epithelium and lining our organs and cavities. It usually begins with the transformation of a single cell via the activation of oncogenes such as Ras. The capacity of epithelia to eliminate newly transformed cells via apical extrusion is believed to be a critical defense mechanism to eradicate initial stages of carcinoma. Our organs and tissues are in constant motion, exposing epithelial cells to mechanical stretch. How these external forces impact the onset and progression of tumor growth is thus of primary interest, but little is known currently. Here we show that mechanical strains jeopardize the epithelial defense mechanisms against Ras V12 -transformed MDCK cells by impeding their apical extrusion. Concurrently, they prevent the formation of strong circumferential belts of actin in Ras V12 cells, previously established as a primary step of apical extrusion under static conditions. Cyclic stretching also changes the metastatic phenotype of newly transformed cells by greatly promoting the formation of Ras V12 protrusions. We show that Ras V12 and wild type MDCK cells possess distinct sensitivity to strain. External forces remodel their actin cytoskeletons and adhesion complexes differently, resulting in a more invasive system dynamic. Our work also shows that the Rho-ROCK mechanotransduction pathway is involved in regulating the mechanically-induced switch to a more aggressive phenotype. Such insight may lead to the targeting of mechanotransduction pathways in innovative future therapies. Significance statement:Cancer progression is increasingly viewed as a complex journey in which the mechanical properties of the microenvironment play a key role. The entire human body is in constant motion, yet the initial stage of cancer development at the cellular level is commonly studied in static petri dishes. Here we demonstrate that in a mechanically dynamic microenvironment, oncogenic Ras-transformed cells exhibit drastically different cellular dynamics and movements when compared to static conditions. They grow larger invasive protrusions, and they are much less likely to be eliminated from the healthy tissues. A deeper understanding of how external physical cues regulate early stage microtumor growth can reveal potentially new and unexplored avenues for cancer therapies.

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Active contractility at E-cadherin junctions and its implications for cell extrusion in cancer

Cited by 42 publications

References 57 publications

Decreased E‐Cadherin in MCF7 Human Breast Cancer Cells Forming Multicellular Spheroids Exposed to Simulated Microgravity

Decreased E‐Cadherin in MCF7 Human Breast Cancer Cells Forming Multicellular Spheroids Exposed to Simulated Microgravity

miR-8 modulates cytoskeletal regulators to influence cell survival and epithelial organization in Drosophila wings

Mechanotransduction of strain regulates an invasive phenotype in newly transformed epithelial cells

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