120. MRC lecture series #2. Understanding and Exploiting Cancer Mechanobiology

Speaker : Adam J. Engler, (University of California, San Diego,)

Location : Room 512 Dental building, Dankook University 

Date: 2022-1-20

Understanding and Exploiting Cancer Mechanobiology

Abstract

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 more accurately 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, utilizing a two step polymerization process. Contrary to previous observations, we find that collective decisions by MECs in 3D aggregates–called acini–indicate partial protection from the stiffened niche (PNAS 2019). 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 (Nature 2018) and Twist signaling (Nature Cell Bio 2015). 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 (Cancer Res 2020), and that these cells undergo adurotactic migration down stiffness gradients as shown in computational and experimental models (Cell Reports 2021). These data suggest potential improvements to our prognostic capacity when diagnosing and treating epithelial tumors.