Cancer Cells Resist Mechanical Destruction in Circulation via RhoA/Actomyosin-Dependent Mechano-Adaptation

Abstract

Highlights d Cancer cells from primary tumors are resistant to fluid shear stress (FSS) d Resistance to FSS is a physiological, mechano-adaptive response in cancer cells d Cancer cells respond to FSS by activating the RhoA-myosin II axis and formins d Myosin II activity protects CTCs from hemodynamic forces in in vivo assays Authors

Survival of the resilient: Mechano-adaptation of circulating tumor cells to fluid shear stress

“…In our recent study we demonstrated that exposure to FSS in vitro results in the activation of ras homolog family member A (RHOA) in cancer cells (Figure 1). 10 FSS exposure also led to both a formin-dependent increase in cortical F-actin levels and an increase in activation of myosin, consistent with the activation of these cytoskeletal master regulators, that prevents damage to the plasma membrane induced by FSS (Figure 1). 10 Inhibiting the mechano-adaptive response through the RHOA-actomyosin network led to an increase in the fraction of cells destroyed by both in vitro applied FSS and hemodynamic FSS, a decrease in the CTC burden of orthotopically injected mice, and a delay in the onset of metastatic disease using an experimental metastasis model.…”

“…10 FSS exposure also led to both a formin-dependent increase in cortical F-actin levels and an increase in activation of myosin, consistent with the activation of these cytoskeletal master regulators, that prevents damage to the plasma membrane induced by FSS (Figure 1). 10 Inhibiting the mechano-adaptive response through the RHOA-actomyosin network led to an increase in the fraction of cells destroyed by both in vitro applied FSS and hemodynamic FSS, a decrease in the CTC burden of orthotopically injected mice, and a delay in the onset of metastatic disease using an experimental metastasis model. 10 Importantly, we also showed that FSS resistance is a property of cancer cells directly isolated from genetically-engineered mouse primary tumors and patient-derived xenografts, demonstrating that FSS resistance observed in cancer cells is not a product of in vitro culture or metastatic selection.…”

“…10 Inhibiting the mechano-adaptive response through the RHOA-actomyosin network led to an increase in the fraction of cells destroyed by both in vitro applied FSS and hemodynamic FSS, a decrease in the CTC burden of orthotopically injected mice, and a delay in the onset of metastatic disease using an experimental metastasis model. 10 Importantly, we also showed that FSS resistance is a property of cancer cells directly isolated from genetically-engineered mouse primary tumors and patient-derived xenografts, demonstrating that FSS resistance observed in cancer cells is not a product of in vitro culture or metastatic selection. Collectively these data demonstrate the importance of mechano-adaptive FSS resistance for the survival of CTCs.…”

“…Interestingly, non-transformed cells do not undergo these mechano-adaptive responses when exposed to FSS while in suspension. 9,10 Moreover, cellular transformation by deletion of tumor suppressor genes or expression of oncogenes confers FSS resistance. 7,10 Whether transformation enables FSS resistance via altering the regulation of cellular mechanics or upregulation of mechanosensitive proteins is unknown.…”

“…9,10 Moreover, cellular transformation by deletion of tumor suppressor genes or expression of oncogenes confers FSS resistance. 7,10 Whether transformation enables FSS resistance via altering the regulation of cellular mechanics or upregulation of mechanosensitive proteins is unknown. It is also unclear how cancer cells sense FSS while in suspension, whether this involves mechanoreceptors or if membrane stretching acts on the cortical F-actin network to enable cancer cells to sense FSS (Figure 1).…”