Abstract
Epithelial cancer tissues often possess polyploid giant cells, which are thought to be highly oncogenic. However, the mechanisms by which polyploid giant cells are generated in tumor tissues and how such cells contribute to tumor progression remain elusive. We previously noticed in Drosophila imaginal epithelium that cells mutant for the endocytic gene rab5 exhibit enlarged nuclei. Here we find that mutations in endocytic ‘neoplastic tumor-suppressor’ genes, such as rab5, vps25, erupted, or avalanche result in generation of polyploid giant cells. Genetic analyses on rab5-defective cells reveal that cooperative activation of JNK and Yorkie generates polyploid giant cells via endoreplication. Mechanistically, Yorkie-mediated upregulation of Diap1 cooperates with JNK to downregulate the G2/M cyclin CycB, thereby inducing endoreplication. Interestingly, malignant tumors induced by Ras activation and cell polarity defect also consist of polyploid giant cells, which are generated by JNK and Yorkie-mediated downregulation of CycB. Strikingly, elimination of polyploid giant cells from such malignant tumors by blocking endoreplication strongly suppressed tumor growth and metastatic behavior. Our observations suggest that JNK and Yorkie, two oncogenic proteins activated in many types of human cancers, cooperatively drive tumor progression by generating oncogenic polyploid giant cells.
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Acknowledgements
We thank Masato Enomoto, Yukari Sando, Yuya Sanaki, Kiichiro Taniguchi, and Masatoshi Yamamoto for discussions, and K. Sawada, K. Baba and Y. Senda for technical assistance. We also thank Leonie Quinn, Masayuki Miura, Takashi Adachi-Yamada, the Bloomington Stock Center, the Drosophila Genomics and Genetic Resources (DGGR), and the FlyORF for fly stocks. This work was supported in part by grants from the MEXT/JSPS KAKENHI (Grant Number 26114002, 16K14606, 16H02505, 15H05862, 26711013, and 17H03673) to S.O. and T.I., the Naito Foundation to T.I., the Takeda Science Foundation to S.O. and T.I., the Japan Foundation for Applied Enzymology to S.O., and Japan Agency for Medical Research and Development (Project for Elucidating and Controlling Mechanisms of Aging and Longevity) to T.I. B.C. was supported in part by Ichikawa International Scholarship Foundation.
This work was supported in part by grants from the MEXT/JSPS KAKENHI (Grant Numbers 26114002, 16K14606, 16H02505, 15H05862, 26711013, and 17H03673), the Naito Foundation, the Takeda Science Foundation, the Japan Foundation for Applied Enzymology, and Japan Agency for Medical Research and Development (Project for Elucidating and Controlling Mechanisms of Aging and Longevity) to T.I. B.C. was supported in part by Ichikawa International Scholarship Foundation.
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Cong, B., Ohsawa, S. & Igaki, T. JNK and Yorkie drive tumor progression by generating polyploid giant cells in Drosophila. Oncogene 37, 3088–3097 (2018). https://doi.org/10.1038/s41388-018-0201-8
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DOI: https://doi.org/10.1038/s41388-018-0201-8
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