title: Accumulation of differentiating intestinal stem cell progenies drives tumorigenesis.
abstract: Stem cell self-renewal and differentiation are coordinated to maintain tissue homeostasis and prevent cancer. Mutations causing stem cell proliferation are traditionally the focus of cancer studies. However, the contribution of the differentiating stem cell progenies in tumorigenesis is poorly characterized. Here we report that loss of the SOX transcription factor, Sox21a, blocks the differentiation programme of enteroblast (EB), the intestinal stem cell progeny in the adult Drosophila midgut. This results in EB accumulation and formation of tumours. Sox21a tumour initiation and growth involve stem cell proliferation induced by the unpaired 2 mitogen released from accumulating EBs generating a feed-forward loop. EBs found in the tumours are heterogeneous and grow towards the intestinal lumen. Sox21a tumours modulate their environment by secreting matrix metalloproteinase and reactive oxygen species. Enterocytes surrounding the tumours are eliminated through delamination allowing tumour progression, a process requiring JNK activation. Our data highlight the tumorigenic properties of transit differentiating cells.
authors.affiliation: Global Health Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Station 19, Lausanne 1015, Switzerland.
authors.forename: Zongzhao
authors.initials: Z
authors.lastname: Zhai
authors.affiliation: Invertebrate Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, Mishima 411-8540, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Kondo
authors.affiliation: Biochemistry Center, University of Heidelberg, Im Neuenheimer Feld 328, Heidelberg 69120, Germany.
authors.forename: Nati
authors.initials: N
authors.lastname: Ha
authors.affiliation: Global Health Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Station 19, Lausanne 1015, Switzerland.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Boquete
authors.affiliation: Biochemistry Center, University of Heidelberg, Im Neuenheimer Feld 328, Heidelberg 69120, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Brunner
authors.affiliation: Invertebrate Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, Mishima 411-8540, Japan.
authors.forename: Ryu
authors.initials: R
authors.lastname: Ueda
authors.affiliation: Global Health Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Station 19, Lausanne 1015, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Lemaitre
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D007422:Intestines / Q000166:cytology*; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D055749:SOXB2 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D055749:SOXB2 Transcription Factors; D050791:STAT Transcription Factors; C000607109:Sox21a protein, Drosophila melanogaster; D014157:Transcription Factors; D053612:Janus Kinases; C085845:hop protein, Drosophila; D020778:Matrix Metalloproteinase 2