Hippo Signaling in Cancer: Lessons From Drosophila Models

Abstract

Hippo pathway was initially identified through genetic screens for genes regulating organ size in fruitflies. Recent studies have highlighted the role of Hippo signaling as a key regulator of homeostasis, and in tumorigenesis. Hippo pathway is comprised of genes that act as tumor suppressor genes like hippo ( hpo ) and warts ( wts ), and oncogenes like yorkie ( yki ). YAP and TAZ are two related mammalian homologs of Drosophila Yki that act as effectors of the Hippo pathway. Hippo signaling deficiency can cause YAP- or TAZ-dependent oncogene addiction for cancer cells. YAP and TAZ are often activated in human malignant cancers. These transcriptional regulators may initiate tumorigenic changes in solid tumors by inducing cancer stem cells and proliferation, culminating in metastasis and chemo-resistance. Given the complex mechanisms (e.g., of the cancer microenvironment, and the extrinsic and intrinsic cues) that overpower YAP/TAZ inhibition, the molecular roles of the Hippo pathway in tumor growth and progression remain poorly defined. Here we review recent findings from studies in whole animal model organism like Drosophila on the role of Hippo signaling regarding its connection to inflammation, tumor microenvironment, and other oncogenic signaling in cancer growth and progression.

Mob Family Proteins: Regulatory Partners in Hippo and Hippo-Like Intracellular Signaling Pathways

“…Since the seminal identification of the Hippo pathway, multiple upstream regulators and downstream targets have been identified that implicate the core Hippo signaling pathway, comprised of Hippo kinase, Warts kinase, Mats (Mob1), and Salvador, as a key regulator for a diverse set of cellular and physiological functions, including stem cell maintenance, cellular differentiation, epithelial cell mechano-transduction, cytoskeletal dynamics, cell migration, organogenesis, tissue homeostasis, and pathology (reviewed in Staley and Irvine, 2012;Matsui and Lai, 2013;Yu and Guan, 2013;Irvine and Harvey, 2015;Fallahi et al, 2016;Chen et al, 2019;Sahu and Mondal, 2019;Snigdha et al, 2019). In this section, we focus only on the specific studies that identified the genes and illuminated our understanding of the signaling pathways.…”

MicroRNA-103a curtails the stemness of non-small cell lung cancer cells by binding to OTUB1 through the Hippo signaling pathway

“…While in the current work, we clari ed the miR-103a mimic lowered the extent of YAP phosphorylation in NSCLC cells, indicating a correlation between miR-103a and the Hippo signaling pathway. YAP, a related mammalian homolog of Drosophila yorkie that acts as an effector of the Hippo signaling pathway, is often induced in malignancies and may exerted tumor-promoting properties by activating CSCs [22].…”

Hippo Signaling-Mediated Mechanotransduction in Cell Movement and Cancer Metastasis

“…The first mutant component of the Hpo pathway, wts, was retrieved from a forward genetic screen seeking tumor suppressors, with hpo, sav and mats being later identified based on the same phenotype of tissue overgrowth in mosaic mutant clones (Justice et al, 1995;Xu et al, 1995;Kango-Singh et al, 2002;Tapon et al, 2002;Harvey et al, 2003;Jia et al, 2003;Pantalacci et al, 2003;Lai et al, 2005;Zheng and Pan, 2019). Two of these components, hpo and wts, encode a serine/threonine kinase that belongs to the Ste-20 kinases and Nuclear Dbf2-related (NDR) family of proteins, respectively (Snigdha et al, 2019). Further studies have shown that the Hpo and Wts proteins both bind to the WW domain adaptor protein, Sav.…”