In a recent study, researchers at TIFR Hyderabad show how the elasticity of extracellular matrix (ECM) of epithelial tissue affects their fundamental defence against oncogenic insults. ECM forms the gel containing proteins and minerals in which our tissues are embedded. Diseases like obesity, fibrosis etc. are known to cause pathological stiffening of this matrix. Patients with such conditions show heightened susceptibility to cancer but little is known as to what could be the cause.
Shilpa P. Pothapragada (Ph.D. student at Tamal Das’ lab in TIFR Hyderabad) and colleagues decipher how ECM elasticity plays a decisive role in determining the outcome of this defence, also known as Epithelial Defence against Cancer (EDAC). They use Ras oncogenic mutation to create precancerous cells which when come in contact with their normal counterparts, are forced to move out of the tissue only when the ECM is soft. When they used an ECM which is stiff instead, non-cancerous epithelial cells could now no longer remove these precancerous cells. A result of this, the precancerous cells can freely expand and grow without restriction.
The scientists look at molecular players to understand what leads to this failure in precancerous cell removal. When the ECM is soft, an actin crosslinking protein called Filamin comes to the interface between normal and precancerous cells in order to help push out the precancerous cells. On a stiff ECM, however, Filamin gets scavenged around the nucleus of the normal cell. Thus, there is not enough Filamin available to help extrude precancerous cells. The observations of this study explains the link between ECM stiffness and higher incidence of cancer which may pave way for therapeutic interventions in cancer prevention.
Matrix mechanics regulates epithelial defence against cancer by tuning dynamic localization of filamin