RT Journal Article
SR Electronic
T1 Mechanotransduction of strain regulates an invasive phenotype in newly transformed epithelial cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 770487
DO 10.1101/770487
A1 Sophie Chagnon-Lessard
A1 Hubert Jean-Ruel
A1 Michel Godin
A1 Andrew E. Pelling
YR 2019
UL http://biorxiv.org/content/early/2019/09/15/770487.abstract
AB 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 RasV12-transformed MDCK cells by impeding their apical extrusion. Concurrently, they prevent the formation of strong circumferential belts of actin in RasV12 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 RasV12 protrusions. We show that RasV12 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.