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A genome-wide Drosophila epithelial tumorigenesis screen identifies Tetraspanin 29Fb as an evolutionarily conserved suppressor of Ras-driven cancer

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posted on 23.03.2022, 22:27 authored by T Zoranovic, Jan Manent, L Willoughby, R Matos de Simoes, John La-MarcaJohn La-Marca, Sofya Golenkina, X Cuiping, S Gruber, B Angjeli, EE Kanitz, SJF Cronin, GG Neely, A Wernitznig, Patrick HumbertPatrick Humbert, KJ Simpson, CS Mitsiades, Helena RichardsonHelena Richardson, JM Penninger
Oncogenic mutations in the small GTPase Ras contribute to ~30% of human cancers. However, Ras mutations alone are insufficient for tumorigenesis, therefore it is paramount to identify cooperating cancer-relevant signaling pathways. We devised an in vivo near genome-wide, functional screen in Drosophila and discovered multiple novel, evolutionarily-conserved pathways controlling Ras-driven epithelial tumorigenesis. Human gene orthologs of the fly hits were significantly downregulated in thousands of primary tumors, revealing novel prognostic markers for human epithelial tumors. Of the top 100 candidate tumor suppressor genes, 80 were validated in secondary Drosophila assays, identifying many known cancer genes and multiple novel candidate genes that cooperate with Ras-driven tumorigenesis. Low expression of the confirmed hits significantly correlated with the KRASG12 mutation status and poor prognosis in pancreatic cancer. Among the novel top 80 candidate cancer genes, we mechanistically characterized the function of the top hit, the Tetraspanin family member Tsp29Fb, revealing that Tsp29Fb regulates EGFR signaling, epithelial architecture and restrains tumor growth and invasion. Our functional Drosophila screen uncovers multiple novel and evolutionarily conserved epithelial cancer genes, and experimentally confirmed Tsp29Fb as a key regulator of EGFR/Ras induced epithelial tumor growth and invasion.

Funding

JMP is supported by IMBA, the Austrian Ministry of Science, ERC Advanced Investigator grant and an Innovator Award from Era of Hope. TZ was supported by a Marie Curie Excellence grant. RdMS is supported by a grant from Invest NI RD0412515. HER and POH were supported by fellowships from the National Health & Medical Research Council (NHMRC). HER was also supported by a La Trobe University bridging fellowship and La Trobe funds. LW, JM, JELM, and SG were supported by a NHMRC grant #1020525 and a PeterMac Foundation grant to HER, JMP, KJS and POH, a Cancer Council Victoria grant #1122083 to HER, POH and JMP and funds from La Trobe Institute of Molecular Science and La Trobe University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

History

Publication Date

16/10/2018

Journal

PLoS Genetics

Volume

14

Issue

10

Article Number

e1007688

Pagination

36p.

Publisher

Public Library of Science (PLOS)

ISSN

1553-7404

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