The activation of the HIPPO pathway is implicated in cancer development and disease progression in terms of treatment resistance and metastasis. The HIPPO pathway is a highly conserved signalling mechanism regulating key cellular processes including proliferation, differentiation, determination of cell fate, organ size, and tissue homeostasis. One of the main activators of the HIPPO pathway is Yes-associated protein 1 (YAP1), a coactivator of the TEA domain transcription factors, and its transcriptional regulation of numerous target genes promote tumor development. Mechanisms of YAP1 activation in cancer also occur via dysregulated signalling of Src family kinases, growth factors and cytokines. Specifically, glycoprotein 130 (gp130 or CD130) dependent cytokine signalling has been previously linked to upregulation of YAP1 expression and activity, associated with Apc-driven colon cancer progression, mediated by gp130-driven cytokines, interleukins 6 and 11 (IL-6, IL-11) and Leukemia Inhibitor Factor 1 (LIF-1). Our previous studies have demonstrated that amplified gp130-dependent IL-6, and to a greater extent, IL-11 signalling cause spontaneous neoplastic transformation of gastric tissue in the gp130Y757F mouse, comprising of a knock-in mutation of the SHP2/SOCS3 binding site in the gp130 intracellular domain.
The current study demonstrates the importance of the HIPPO pathway in the gp130Y757F model of intestinal-type gastric adenocarcinoma demonstrating a direct, functional relationship of exacerbated gp130-dependent cytokine signalling with STAT3 and YAP1 activation. Conditional, Tff1-Cre-mediatedYap1 gene knockout in the gastric epithelium of gp130Y757F mouse reduced gastric tumor incidence. In animals with established disease, ablation of YAP1 activity significantly reduced tumor size to inhibit cancer progression. Transcriptomics profiling of gastric epithelial cells using RNASeq identified novel YAP1-dependent cellular effects that contribute to gastric cancer development and progression. For the first time, we demonstrate the involvement of YAP1 in regulating innate and adaptive immune responses, primarily via alteration of cell signatures in gastric mucosal epithelial cells to drive tumorigenesis. Our findings highlight the importance of the crosstalk between the gastric mucosa and systemic immune responses that drive tumour development in a proinflammatory environment. Further, our data support the idea that the inhibition of YAP1 activity provides a clear opportunity as the development of targeted treatments for gastric cancer patients.