**5.4 Gut-cancer model**

*Drosophila* is an important tool in medicine to explore the details of cancer. There are a wide range of cancers where *Drosophila* is taken into consideration – from brain, gut to thyroid and lung. The loss of Adenomatous polyposis coli gene (*APC,* tumor suppressor gene) in flies leads to an increase in ISC proliferation in the gut [300]. This resembles the condition seen in intestinal adenomas (benign tumor of epithelial tissue). JNK-Wg signaling controls the number of ISCs found in the gut. Injured or damaged ECs lead to an increase in JNK signaling and increase in Wg ligands in (EB). This in turn activates JAK STAT ligands - Upd2 and Upd3, which further increase ISCs' non-autonomous over proliferation [301]. Loss of *Apc* in ISCs increases JAK–STAT pathway as well, which in turn affects ISCs proliferation. This helps in establishing the conservation of pathways that regulate ISC proliferation and gut homeostasis [302]. In some studies, it is also shown that *Apc* and RAS control growth of cells in gut by interacting with one another. Non-receptor tyrosine kinase c-Src is associated to quite a few forms of cancer including colorectal cancer (CRC). In wildtype *Drosophila*, orthologous forms of c-Src act exactly how they would in mammals. Activation in c-Src leads to ISC proliferation and decrease or inactivation in c-Src inhibits further ISC proliferation [303]. These results show beyond doubt how ISC proliferation is directly involved with cancer formation and these genes and mechanisms are conserved from flies to mammals. Few studies have looked into hindgut (equivalent of mammalian colon) as a model for cancer. Oncogenes in the hindgut synergize with innate immunity system to stimulate tumor cell invasion. After bacterial infection, ISCs proliferate but less in hindgut as

opposed to midgut. RAS oncogene, RASv12 induces cell invasion and dissemination of ECs into the abdominal cavity. Upon RASv12expression, hindgut shows cancerlike phenotype. It activates JNK signaling pathway which in turn increases ISC proliferation and hence, tumor growth [304].
