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Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster

Abstract

Loss of cell polarity and cancer are tightly correlated1, but proof for a causative relationship has remained elusive. In stem cells, loss of polarity and impairment of asymmetric cell division could alter cell fates and thereby render daughter cells unable to respond to the mechanisms that control proliferation2. To test this hypothesis, we generated Drosophila melanogaster larval neuroblasts containing mutations in various genes that control asymmetric cell division and then assayed their proliferative potential after transplantation into adult hosts. We found that larval brain tissue carrying neuroblasts with mutations in raps (also called pins), mira, numb or pros grew to more than 100 times their initial size, invading other tissues and killing the hosts in 2 weeks. These tumors became immortal and could be retransplanted into new hosts for years. Six weeks after the first implantation, genome instability and centrosome alterations, two traits of malignant carcinomas3,4, appeared in these tumors. Increasing evidence suggests that some tumors may be of stem cell origin5,6. Our results show that loss of function of any of several genes that control the fate of a stem cell's daughters may result in hyperproliferation, triggering a chain of events that subverts cell homeostasis in a general sense and leads to cancer.

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Figure 1: Overgrowth of mutant brain tissue implanted into adult hosts.
Figure 2: Cell types found in implanted tumors.
Figure 3: Genome and centrosome instability in implanted tumors.

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Acknowledgements

We thank Y.N. Jan, F. Matsuzaki, A. Ephrussi, A. Wodarz, J. Knoblich, the Developmental Studies Hybridoma Bank and the Bloomington Drosophila Stock Center for providing fly stocks and antibodies; E. Gateff, A. Wodarz, J. Casanova, E. Battlle, G. Morata, P. Askjaer, P. Dominguez and members of our laboratory for discussions; G. Bouche for his guidance to E.C. during the course of his doctoral thesis; M. Llamazares for proofreading; and I. Vernos and the people in her laboratory who hosted E.C. for their contribution. C.G. is indebted to J. Szabad for demonstrating the tissue transplantation technique. Work in our laboratory is supported by grants from the European Union, the Spanish MEC and Fundación Médica MMA.

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Correspondence to Cayetano Gonzalez.

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Caussinus, E., Gonzalez, C. Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster. Nat Genet 37, 1125–1129 (2005). https://doi.org/10.1038/ng1632

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