Understanding the LATS1 pro-apoptotic signaling network in melanoma.

The tumor suppressor LATS1 is a core kinase of the MST2 pathway that regulates many cellular processes such as proliferation, cell growth, differentiation, and apoptosis. The MST2 pathway has been reported to interact with the MAPK pathway at the level of MST2 through RAF1, blocking MTS2 signaling. Our group has reported that, upon a proapoptotic signal, the tumor suppressor RASSF1A disrupts RAF1-MST2 complexes, leading to activation of MST2 and further LATS1-mediated phosphorylation of YAP, which triggers YAP translocation to the nucleus together with p73, leading to apoptosis. Apart from this mechanism, our group has found evidence showing that LATS1 could act as a signaling hub integrating proliferative and apoptotic signals and thus deciding cell fate. Several lines of evidence have shown that LATS1 crosstalks with several proteins of the apoptotic pathways including Mdm2, Omi, and p53. To get a better knowledge of the signaling network mediating LATS1 proapoptotic signaling, we have performed a proteomics screening. In this screening we have identified a cluster of proteins that are part of the intrinsic apoptotic pathway. Here we present validation experiments of these novel interactions and characterize the molecular mechanisms mediated by LATS1 proapoptotic network. We focus in melanoma cells, a cancer type where loss of function of the RASSF1A/MST2/LATS1 seems to be common. Thus, the main driving mutation of melanoma mutant BRAF has been shown to inhibit MST2; loss of expression of RASSF1A by promotor methylation is rather frequent and our analysis show that LAST1 is also downregulated. Our results indicate that the silencing of LATS1 crosstalk with the intrinsic pathway results in the evasion of apoptotic signals in melanocytes and can lead to cell transformation. Citation Format: Lucia Garcia-Gutierrez, Stephanie McKenna, Andrew Badrock, Adam Hurlstone, David Matallanas. Understanding the LATS1 pro-apoptotic signaling network in melanoma [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B01.