• cancer

Work in a number of systems and species supports the role of the Hippo signaling pathway in regulation of organ size and tissue homeostasis through its control of proliferation and apoptosis. Experiments in Drosophila identified the first known gene in this pathway, Warts (wts, a serine/threonine protein kinase, orthologous to human LATS2 and LATS1); clonal loss of wts in imaginal discs was shown to result in tissue overgrowth and dysregulated morphogenesis. Two additional genes with similar clonal overproliferation phenotypes were quickly identified: sav (regulator of hpo, orthologous to human sav1) and hippo (hpo, pro-apoptotic kinase, orthologous to human STK3 and STK4). Genetic interactions between wts, hpo, and sav supported the hypothesis that these three genes are part of a common pathway. Adding to these original observations, a large body of work in multiple species supports the role of the Hippo signaling pathway as a tumor suppressor. However, in some systems, the activation of Hippo signaling appears to be associated with tumor progression.

Experiments in Drosophila have continued to contribute to understanding of the Hippo pathway, including identification of additional members of the pathway, and its role in development and progression of cancer. See the pathway report 'Hippo Signaling Pathway' (FBgg0000917) for a listing of genes encoding core components and regulators of this pathway in flies. Multiple experiments support the model that the Hippo pathway regulates cell invasion by activating JNK signaling. Since loss-of-function mutations of most of the genes involved are homozygous lethals, experimental design in this system frequently makes use of somatic clones or GAL4-UAS targeted expression.

In a model of cell invasion in the wing epithelium, overexpression of hpo or wts or knockdown of yki (transcriptional regulator, orthologous to human YAP1) results in overproliferation phenotypes and cells with molecular characteristics of epithelial-mesenchymal transition. This system has been used to assess the role of downstream genes in cancer progression via Hippo signaling, including that of the microRNAs bantam (mir-ban) and mir-8. Dmel\yki has been used in a model in combination with Dmel\l(2)gl, a Scribble complex gene (see FBhh0000590). Using the eye phenotype produced by overexpression of yki, the Drosophila gene Prosap was identified as a regulator of the Hippo pathway; one of the three human orthologs of Prosap, SHANK2, is amplified and/or overexpressed in a number of human cancers. RNAi-mediated knockdown of Tao, a regulator of the Hippo pathway, in the eye results in overgrowth of posterior ommatidial cells; double knockdown of Tao and hpo or wts results in an extreme posterior ommatidial overgrowth phenotype.

Beyond imaginal discs, it has been demonstrated that loss of sav in Malpighian tubule stem cells results in overproliferation phenotypes and expansion of the stem cell population; loss-of-function clones of wts in the fly ovarian follicular epithelium results in tumor formation; over-expression of a phosphorylation-resistant form of yki in the ovary results in overproliferation and loss of epithelial architecture. Many physical and genetic interactions have been described for these Drosophila genes (including with each other); see below and in the relevant gene reports.

A number of the human genes associated with the human Hippo signaling pathway have been introduced into flies: Hsap\LATS2, Hsap\LATS1, Hsap\STK3, Hsap\STK4, Hsap\YAP1. LATS1 and YAP1 have been associated with specific cancers in GWAS studies (see GWAS Catalog, below in 'External links'). Expression of either Hsap\LATS1 or Hsap\LATS2 results in heterologous rescue (functional complementation) of the lethal phenotype of wts mutations. Variants of LATS1 and LATS2 predicted to result in loss of function have been characterized in flies for capacity to regulate growth in the larval wing epithelium. Heterologous rescue (functional complementation) of the hpo clonal overgrowth phenotype by Hsap\STK3 is observed. Partial functional complementation of Hsap\YAP1 for Dmel\yki has been observed: overexpression of hpo in the developing eye results in pupal lethality; co-expression of yki rescues the lethal phenotype, co-expression of Hsap\YAP1 partially rescues the lethal phenotype (FBrf0187228).

[updated Apr. 2022 by FlyBase; FBrf0222196]