Force Talk - Professor Adam J Engler

Join Professor Adam J Engler from UC San Diego for a Force Talk entitled "Understanding and exploiting cancer mechanobiology".

Mammary epithelial cells (MECs) are classically known to respond to differences in extracellular matrix (ECM) stiffness by transitioning to a malignant, non-polarized state on stiffer ECM, i.e. Epithelial-Mesenchymal Transition (EMT). While this is akin to stiff mammary tumors that one can detect with manual palpation, breast cancer fibrosis is dynamic and stiffening occurs over months to years. I will describe our efforts to mimic the onset of tumor-associated fibrosis using dynamic methacrylated-hyaluronic acid (MeHA) hydrogels, whose stiffness that can be modulated from normal 100 Pa to malignant 5000 Pa. Contrary to previous observations, we find that collective decisions by MECs in 3D aggregates–called acini–indicate partial protection from the stiffened niche. To interpret MEC mechano-signaling that result in this protection, I will also present our new understanding of the molecular mechanisms used by MECs to interpret stiffness, i.e., Hippo/YAP/TAZ/LETS and Twist-Lyn/EPH2A signaling. After cells leave this niche, however, mechanical changes can be exploited to improve metastatic detection. I will conclude my presentation with new data showing that we can use differences in cell-ECM adhesion strength to mark metastatic cells even in mixed or lineage committed populations, and that these cells undergo adurotactic migration down stiffness gradients as shown in computational and experimental models. These data suggest potential improvements to our prognostic capacity when diagnosing and treating epithelial tumors.