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.