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Review
. 2019 May 24;7:85.
doi: 10.3389/fcell.2019.00085. eCollection 2019.

Hippo Signaling in Cancer: Lessons From Drosophila Models

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Free PMC article
Review

Hippo Signaling in Cancer: Lessons From Drosophila Models

Kirti Snigdha et al. Front Cell Dev Biol. .
Free PMC article

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.

Keywords: Drosophila; cancer; cell death; cell proliferation; cell-polarity; hippo pathway.

Figures

FIGURE 1
FIGURE 1
The Drosophila Hippo pathway Network. (A,A′) Compared to Wild type (A), loss of function of Hippo pathway genes wtsX1 (eyFLP; FRT82B cl w+/FRT82B wtsX1) causes significant overgrowth of the Drosophila head. (A,B) Schematic diagram of the Hippo pathway in Drosophila. Cells are shown with Sub-apical region and basolateral junctions. Hippo pathway components in Drosophila are shown in different colors, with pointed and blunt arrowheads indicating activating and inhibitory interactions, respectively. Continuous lines indicate known interactions, whereas dashed lines indicate unknown mechanisms. See text for further details. Crb, Crumbs; Dco, Disks overgrown; Dlg, Disks large; Ds, Dachsous; Ex, Expanded; Hth, Homothorax; Jub, Ajuba; Lgl, Lethal giant larvae; Mer, Merlin; Mats, Mob as a tumor suppressor; Rassf, Ras-associated factor; Sav, Salvador; Scrib, Scribble; Sd, Scalloped; TEA domain protein; Tsh, Teashirt; Yki, Yorkie; hpo, Hippo; wts, warts; aPKC, atypical protein kinase C; Wbp2, WW domain binding protein 2; Mop, Myopic; Zyx, Zyxin; STRIPAK, striatin-interacting phosphatase and kinase; Mad, Mothers against Decapentaplegic; Tgi, Tondu-domain containing growth inhibitor; Ft, Fat; Lft, Lowfat.
FIGURE 2
FIGURE 2
Domain structure of Hippo pathway proteins. The domain structure of Hippo pathway components is shown along with the length of each protein (indicated in parentheses). FERM, Kinase, WW, TEAD, PPXY. PPAY, SARAH, and C2-domains are the prominent domains through which major protein-protein interactions occur in the Hippo pathway.
FIGURE 3
FIGURE 3
Drosophila cancer models. (A) Cartoon showing various larval organs/cells in which Drosophila cancer models have been developed. The many tissue specific manipulations possible in Drosophila have generated tissue specific tumor models like epithelial tumors, glioma, hematopoietic tumors, intestinal tumors, and germ-cell tumors. Examples of some models are shown in (B–D). (B,B′) show confocal images of GFP marked glial cells in normal versus a glioma brain model. Note the enlarged brain lobes and increased number of GFP expressing glial cells. (C–D′) Epithelial tumors modeled in imaginal disks are shown. Panels show a comparison of a normal eye disk (C) with a disk carrying GFP labeled tumors (C′) caused by overexpression of oncogenic Ras in polarity deficient scribble mutant cells (RasV 12, scrib-/-) induced by MARCM technique. (D,D′) Wild type wing imaginal disk showing a stripe of GFP expression in the patched-GAL4 domain (ptcGAL4>UASGFP) is compared to overgrowths caused by overexpression of the activated form of Hippo pathway effector Yki (ptcGAL4>UASGFP, UASYki3SA).

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