The microenvironment determines cell fate by providing both biochemical and biophysical cues that normal and cancerous cells sense and interpret. In turn, cells also modify their ‘niches’ by secreting soluble signaling molecules (e.g., nutrients, growth factors, and hormones) and exerting mechanical forces. Recent advances in bioengineering technology have enabled us to recognize the physiological significances of physical cues, defined here as passive and active forces applied by tumor/stromal cells and extracellular matrix proteins (Broders-Bondon et al. J Cell Biol 2018 PMID: 29467174). Many difficult-to-treat cancers, such as pancreatic ductal adenocarcinoma and gastric cancer, exhibit desmoplasia, a condition characterized by concurrent uncontrolled fibrogenesis and inflammation.

YAP/TAZ are effectors of the Hippo pathway, a master regulator of tissue homeostasis and organ size whose components are frequently mutated in human cancers (Zanconato et al. Cancer Cell 2016 PMID: 27300434). We recently identified a non-canonical Hippo pathway in which Misshapen MAP4Ks and Happyhour MAP4Ks inhibit YAP/TAZ by directly phosphorylating LATS1/2 (Meng et al. Nat Commun 2015 PMID: 26437443), and further discovered that ECM stiffness can regulate this pathway through modulating RAP2 GTPase activities (Meng et al. Nature 2018 PMID: 30135582). For the future research, We would like to focus on (1) Regulation and biological impact of the non-canonical Hippo pathway by identifying new components and signals that are associated with this pathway; and (2) Identifying novel mechanosensing mechanisms, and characterizing integration of mechanical cues and biochemical signals.