YAP/TAZ are Activated by Mechanical and Hormonal Stimuli in Myometrium and Exhibit Increased Baseline Activation in Uterine Fibroids

Cross-talk between Janus kinase-signal transducer and activator of transcription pathway and transforming growth factor beta pathways and increased collagen1A1 production in uterine leiomyoma cells

“…The viscoelastic properties of the ECM may contribute to the stiffness and attenuated response to mechanical signaling. Furthermore, the increased presence of integrin proteins (93,129) and stiffness-dependent Yap translocation (130) support the variation in mechanotransductive property of leiomyomas compared to myometrium. Mechanical stretch is known to activate both the JAK/STAT and TGFb pathways in many instances such as bone and cartilage pathobiology, cardiomyocytes, and vascular diseases (131,132).…”

“…It can also interact directly with pSMAD complex, inhibiting its action (129). Activated STAT3 is also known to interact with the proteins that are involved in the noncanonical TGFb pathway such as the ERKs (130,131), enhancing or repressing their action. On the other hand, SMAD3 can repress the expression as well as the activation of STAT3 (99,101) the extracellular matrix production including the collagens; this requires further analysis as we introduce involvement of JAK/STAT3 pathway in the physiopathology of the tumor growth.…”

Summary of the proceedings of the Basic Science of Uterine Fibroids meeting: new developments (February 28, 2020)

“…In such settings, matrices of pathologic stiffness promote profibrotic signaling and enhanced deposition and remodeling of ECM, leading to feedback loops that promote progressive fibrosis (6). There is growing evidence of mechanosensing being involved in fibroid growth (7). Work to identify the mechanically activated pathways that promote ECM deposition and diseaserelated changes in ECM composition and mechanics that regulate cell function in mesenchymal cells is ongoing.…”

Physiomimetic Models of Adenomyosis

“…These adaptations occur through a compendium of mechanical signaling pathways that are integrated in part by the intracellular translocation of transcriptional regulators YAP and TAZ to the nucleus, allowing differences in mechanical signaling between two different tissue environments in vivo to be inferred from immunohistochemistry. 162 An elegant in vivo-in vitro mechanical signaling study involving the myometrium first demonstrated links between the mechanical properties of uterine leiomyomas (fibroids) relative to surrounding myometrium and the corresponding relative amounts of nuclear YAP/ TAZ (via immunohistochemistry), and then showed that isolated myometrial SMCs or fibroid cells cultured in 2D on a set of synthetic hydrogel substrates with systematically varied mechanical stiffness recapitulated the trends in nuclear YAP/TAZ seen for each cell type in vivo, along with enhanced ECM deposition by fibroid cells as seen in vivo. 162 This in vivo-in vitro correspondence suggests that the in vitro model may be a useful proxy for analyzing potential therapeutic interventions into mechanical signaling pathways.…”

“…162 An elegant in vivo-in vitro mechanical signaling study involving the myometrium first demonstrated links between the mechanical properties of uterine leiomyomas (fibroids) relative to surrounding myometrium and the corresponding relative amounts of nuclear YAP/ TAZ (via immunohistochemistry), and then showed that isolated myometrial SMCs or fibroid cells cultured in 2D on a set of synthetic hydrogel substrates with systematically varied mechanical stiffness recapitulated the trends in nuclear YAP/TAZ seen for each cell type in vivo, along with enhanced ECM deposition by fibroid cells as seen in vivo. 162 This in vivo-in vitro correspondence suggests that the in vitro model may be a useful proxy for analyzing potential therapeutic interventions into mechanical signaling pathways. Other behaviors, such as invasion/survival, may require a 3D environment to capture these in vivo behaviors.…”