This report describes a tumor model using an activated form of Dmel\yki expressed in adult intestinal stem cells (ISC) and the use of this model to investigate the phenomenon of cachexia. Dmel\yki is orthologous to human YAP1 and is a core component of the Hippo Signaling Pathway (FBgg0000913); see the human disease model report 'cancer, multiple, Hippo signaling pathway' (FBhh0000764).
When an activated form of Dmel\yki is specifically expressed in adult intestinal stem cells of the midgut, sequential steps of tumor development are observed, each lasting approximately 2 days: proliferation state; tumorigenesis state, during which tumors expand to the whole midgut; ascites state, during which the abdomen expands and muscle dysfunction is observed; wasting or bloating state, with further abdomen expansion, severe TAG decrease, carbohydrate increase, and muscle dysfunction.
MEK/ERK (MAPK/ERK) signaling is observed to increase during this progression, in both tumors and non-tumorous host tissues. Tumor MEK/ERK activation is required for tumor growth. Non-autonomous activation of MEK/ERK in host tissues results in muscle wasting and lipid loss. This system has allowed characterization and comparison of molecular mechanisms involved in ISC tumor development and resulting changes in non-tumorous tissues. In an assessment of the contribution of various candidate ligand genes, it was determined that Pvf1 and its receptor Pvr play a key role in this process. One of the conclusions of these studies is that Pvf1 and ImpL2 are independent regulators of the non-autonomous tissue wasting observed with yki-induced ISC tumors; see the human disease model report 'cachexia, IGFBP-related' (FBhh0000535).
Several MEK pharmaceutical inhibitors were shown to ameliorate the wasting phenotypes.
The Warburg effect (preferential use of aerobic glycolysis by cancer cells) may be one of the contributing factors in the development of cachexia. See human disease model reports 'cancer, aerobic glycolysis (Warburg effect), larval growth ' (FBhh0000502) and 'cancer, epithelial, glycolytic tumor model' (FBhh0000959).
[updated Apr. 2021 by FlyBase; FBrf0222196]
Cachexia is characterized by a dramatic loss of skeletal muscle mass and adipose tissue, resulting in substantial weight loss. It is also known as "wasting syndrome", causing disproportionate muscle wasting, weakness, fatigue, and loss of appetite in affected individuals. Cachexia occurs in many cancers, usually at the advanced stages of disease. [ http://www.news-medical.net/health/Cachexia-Wasting-Syndrome-.aspx ] [ https://www.cancer.gov/about-cancer/treatment/research/cachexia ]
Moderate-scoring ortholog of human YAP1; lower-scoring ortholog of WWTR1 (1 Drosophila to 2 human). Dmel\yki shares 31% identity and 45% similarity with YAP1; it shares 25% identity and 34% similarity with WWTR1.