Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • stat3 inhibitor br Prostaglandins meet Hippo The

    2022-07-26


    Prostaglandins meet Hippo The prostaglandins lie at the crossroads between inflammation, regeneration and tumorigenesis (Figure 3). Prostaglandins are synthesized from archidonic stat3 inhibitor by Cox1 and Cox2 enzymes [40, 41] and in the gut, prostaglandin E2 (PGE2) protects against DSS-induced colitis, but also promotes tumorigenesis [42, 43]. Kim et al. recently demonstrated that PGE2 signals through the Gαs-coupled receptor, EP4, to stimulate Yap activity that in turn induces Cox2 and EP4 []. Yap also synergized with PGE2 signalling to induce colon tumorigenesis in mice. In addition, studies on types IIA and X phospholipase A2 (PLA2), the former being a well-established modifier of tumorigenicity in the gut, showed another pathway regulating Yap []. Secreted forms of PLA2 boost PGE2 production by hydrolyzing phospholipids to generate archidonic acid, whereas the cytoplasmic forms induced Yap expression and phosphorylation. This impaired Wnt-driven maturation of Paneth cells with defects in ISC maintenance and regeneration. The prostaglandin pathway is thus an important modulator of Hippo during gut regeneration and tumorigenesis.
    Hippo signalling, mechanotransduction and the tumour microenvironment In the last 5 years, numerous studies have documented how cell shape and stiffness affect cytoskeletal networks and modulate Hippo signalling (Figure 3) [46, 47, 48, 49, 50]. In gut organoid cultures, modular synthetic hydrogels with high matrix stiffness promote Yap-dependent ISC cell survival [], indicating that mechanical stimulation of Yap is likely important in colorectal cancer progression. During adenoma formation the earliest morphological lesions are aberrant crypt foci (ACF), which are enlarged, abnormally-shaped crypts [52]. In mice, Apc-mutant ACFs have high nuclear Yap, whereas earlier lesions with relatively normal morphology showed limited nuclear Yap. In Drosophila, differential cell growth within the wing imaginal disc generates mechanical stress that alters Hippo signalling to control tissue expansion [53]. It is thus intriguing to speculate that Yap activation in ACF may be driven by altered shape and stiffness in growing lesions. Recent technological breakthroughs enabling precise mechanical stimulation of tissues, such as mouse colon, should now provide the tools to test this [54••, 55]. At later stages, cancer-associated fibroblasts (CAFs) can critically modulate the stiffness of the tumour microenvironment extracellular matrix (ECM) and release various growth factors [56, 57, 58, 59, 60••]. In particular, collagen deposition promotes the invasive properties of colon cancer cells [61, 62] and together with increased tissue stiffness may modulate Hippo signalling to promote progression. Finally, it should be noted that Hippo signalling not only senses, but also shapes the tumour microenvironment both directly and indirectly. For instance Yap signalling in CAFs promotes matrix stiffening, cancer cell invasion and angiogenesis [63]. Moreover Hippo signalling intersects with the Tgfβ pathway [64, 65, 66] to influence fibrotic responses in myofibroblasts that is likely to also function during cancer progression [67, 68, 69]. Yap regulation of a range of secreted factors may thus broadly function in regenerating crypts and adenomas []. For example the Yap target, Il33, has attracted attention for its role in stimulating immune cells and tumour-associated myofibroblasts in the gut [70, 71, 72]. Altogether these studies highlight the important role for Hippo signalling in modulating the rich interplay between the tumour microenvironment and cancer cells.
    Concluding remarks The discovery and characterization of the Hippo pathway over a decade ago has generated enormous insight into the mechanisms underlying regeneration and cancer in numerous tissues types. Although originally viewed as a potent regulator of cell proliferation and survival, various other functions have now been ascribed to Hippo signalling. In particular, the capacity of Yap/Taz to reprogram cell fate in various tissues besides the gut is now well recognized [73••, 74•, 75, 76, 77]. In the gut epithelium, the main effectors of the Hippo pathway, Yap and Taz, are effectively shut off by the upstream Mst/Lats kinase cassette and other related kinases. Upon injury or following an oncogenic event, Yap/Taz subcellular localization is subject to dynamic regulation that in the gut is important for ISC maintenance and the formation of intestinal adenomas during tumour initiation. In this context, Yap acts to buffer the prodifferentiation effects of excessive Wnt signalling and also induce expression of proregenerative genes.