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

Tamara Zoranovic, Jan Manent, Lee Willoughby, Ricardo Matos de Simoes, John E. La Marca, Sofya Golenkina, Xia Cuiping, Susanne Gruber, Belinda Angjeli, Elisabeth Eva Kanitz, Shane J.F. Cronin, G. Gregory Neely, Andreas Wernitznig, Patrick O. Humbert, Kaylene J. Simpson, Constantine S. Mitsiades, Helena E. Richardson, Josef M. Penninger

Research output: Contribution to journalArticleResearchpeer-review

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Abstract

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.

Original languageEnglish
Article numbere1007688
Number of pages36
JournalPLoS Genetics
Volume14
Issue number10
DOIs
Publication statusPublished - 16 Oct 2018

Keywords

  • Drosophila melanogaster
  • eyes
  • gene ontologies
  • genetic screens
  • carcinogenesis
  • tumor suppressor genes
  • RNA interference
  • gene expression

Cite this

Zoranovic, Tamara ; Manent, Jan ; Willoughby, Lee ; Matos de Simoes, Ricardo ; La Marca, John E. ; Golenkina, Sofya ; Cuiping, Xia ; Gruber, Susanne ; Angjeli, Belinda ; Kanitz, Elisabeth Eva ; Cronin, Shane J.F. ; Neely, G. Gregory ; Wernitznig, Andreas ; Humbert, Patrick O. ; Simpson, Kaylene J. ; Mitsiades, Constantine S. ; Richardson, Helena E. ; Penninger, Josef M. / A genome-wide Drosophila epithelial tumorigenesis screen identifies Tetraspanin 29Fb as an evolutionarily conserved suppressor of Ras-driven cancer. In: PLoS Genetics. 2018 ; Vol. 14, No. 10.
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title = "A genome-wide Drosophila epithelial tumorigenesis screen identifies Tetraspanin 29Fb as an evolutionarily conserved suppressor of Ras-driven cancer",
abstract = "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.",
keywords = "Drosophila melanogaster, eyes, gene ontologies, genetic screens, carcinogenesis, tumor suppressor genes, RNA interference, gene expression",
author = "Tamara Zoranovic and Jan Manent and Lee Willoughby and {Matos de Simoes}, Ricardo and {La Marca}, {John E.} and Sofya Golenkina and Xia Cuiping and Susanne Gruber and Belinda Angjeli and Kanitz, {Elisabeth Eva} and Cronin, {Shane J.F.} and Neely, {G. Gregory} and Andreas Wernitznig and Humbert, {Patrick O.} and Simpson, {Kaylene J.} and Mitsiades, {Constantine S.} and Richardson, {Helena E.} and Penninger, {Josef M.}",
year = "2018",
month = "10",
day = "16",
doi = "10.1371/journal.pgen.1007688",
language = "English",
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Zoranovic, T, Manent, J, Willoughby, L, Matos de Simoes, R, La Marca, JE, Golenkina, S, Cuiping, X, Gruber, S, Angjeli, B, Kanitz, EE, Cronin, SJF, Neely, GG, Wernitznig, A, Humbert, PO, Simpson, KJ, Mitsiades, CS, Richardson, HE & Penninger, JM 2018, 'A genome-wide Drosophila epithelial tumorigenesis screen identifies Tetraspanin 29Fb as an evolutionarily conserved suppressor of Ras-driven cancer', PLoS Genetics, vol. 14, no. 10, e1007688. https://doi.org/10.1371/journal.pgen.1007688

A genome-wide Drosophila epithelial tumorigenesis screen identifies Tetraspanin 29Fb as an evolutionarily conserved suppressor of Ras-driven cancer. / Zoranovic, Tamara; Manent, Jan; Willoughby, Lee; Matos de Simoes, Ricardo; La Marca, John E.; Golenkina, Sofya; Cuiping, Xia; Gruber, Susanne; Angjeli, Belinda; Kanitz, Elisabeth Eva; Cronin, Shane J.F.; Neely, G. Gregory; Wernitznig, Andreas; Humbert, Patrick O.; Simpson, Kaylene J.; Mitsiades, Constantine S.; Richardson, Helena E.; Penninger, Josef M.

In: PLoS Genetics, Vol. 14, No. 10, e1007688, 16.10.2018.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - A genome-wide Drosophila epithelial tumorigenesis screen identifies Tetraspanin 29Fb as an evolutionarily conserved suppressor of Ras-driven cancer

AU - Zoranovic, Tamara

AU - Manent, Jan

AU - Willoughby, Lee

AU - Matos de Simoes, Ricardo

AU - La Marca, John E.

AU - Golenkina, Sofya

AU - Cuiping, Xia

AU - Gruber, Susanne

AU - Angjeli, Belinda

AU - Kanitz, Elisabeth Eva

AU - Cronin, Shane J.F.

AU - Neely, G. Gregory

AU - Wernitznig, Andreas

AU - Humbert, Patrick O.

AU - Simpson, Kaylene J.

AU - Mitsiades, Constantine S.

AU - Richardson, Helena E.

AU - Penninger, Josef M.

PY - 2018/10/16

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N2 - 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.

AB - 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.

KW - Drosophila melanogaster

KW - eyes

KW - gene ontologies

KW - genetic screens

KW - carcinogenesis

KW - tumor suppressor genes

KW - RNA interference

KW - gene expression

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DO - 10.1371/journal.pgen.1007688

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JO - PLoS Genetics

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