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Oncogenic Ras, Yki and Notch signals converge to confer clone competitiveness through Upd2

Ying Wang,  Rui Huang,  Minfeng Deng,  Jingjing He,  Mingxi Deng,  Toyotaka Ishibashi,  Cong Yu,  Zongzhao Zhai,  Yan Yan

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文章导航 > Journal of Genetics and Genomics  > 2026 >  53(1): 110-120
Ying Wang, Rui Huang, Minfeng Deng, Jingjing He, Mingxi Deng, Toyotaka Ishibashi, Cong Yu, Zongzhao Zhai, Yan Yan. Oncogenic Ras, Yki and Notch signals converge to confer clone competitiveness through Upd2[J]. 遗传学报, 2026, 53(1): 110-120. doi: 10.1016/j.jgg.2025.04.017
引用本文: Ying Wang, Rui Huang, Minfeng Deng, Jingjing He, Mingxi Deng, Toyotaka Ishibashi, Cong Yu, Zongzhao Zhai, Yan Yan. Oncogenic Ras, Yki and Notch signals converge to confer clone competitiveness through Upd2[J]. 遗传学报, 2026, 53(1): 110-120. doi: 10.1016/j.jgg.2025.04.017
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Ying Wang, Rui Huang, Minfeng Deng, Jingjing He, Mingxi Deng, Toyotaka Ishibashi, Cong Yu, Zongzhao Zhai, Yan Yan. Oncogenic Ras, Yki and Notch signals converge to confer clone competitiveness through Upd2[J]. Journal of Genetics and Genomics, 2026, 53(1): 110-120. doi: 10.1016/j.jgg.2025.04.017
Citation: Ying Wang, Rui Huang, Minfeng Deng, Jingjing He, Mingxi Deng, Toyotaka Ishibashi, Cong Yu, Zongzhao Zhai, Yan Yan. Oncogenic Ras, Yki and Notch signals converge to confer clone competitiveness through Upd2[J]. Journal of Genetics and Genomics, 2026, 53(1): 110-120. doi: 10.1016/j.jgg.2025.04.017
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Oncogenic Ras, Yki and Notch signals converge to confer clone competitiveness through Upd2

doi: 10.1016/j.jgg.2025.04.017

  • a. Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong 999077, China;

  • b. Shenzhen Peking University−Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong 518055, China;

  • c. College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China;

  • d. School of Life Sciences, Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China

基金项目: 

We would like to thank Drs. Mark Van Doren, Jose Pastor-Pareja, Erika Bach, and Aurelio Teleman for kindly sharing fly strains and antibodies. This work was supported by grants to Yan Yan from the Research Grants Council of the Hong Kong Special Administrative Region (GRF16103620, GRF16104324, T13-602/21N) and from Shenzhen Science and Technology Innovation Commission (JCYJ20200109140201722), to Toyotaka Ishibashi from the National Natural Science Foundation of China (32170548), and to Zongzhao Zhai from the National Natural Science Foundation of China (32170509 and 31871469).

详细信息
    通讯作者:

    Zongzhao Zhai,E-mail:zongzhao.zhai@foxmail.com

    Yan Yan,E-mail:yany@ust.hk

Oncogenic Ras, Yki and Notch signals converge to confer clone competitiveness through Upd2

  • a. Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong 999077, China;

  • b. Shenzhen Peking University−Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong 518055, China;

  • c. College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China;

  • d. School of Life Sciences, Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China

Funds: 

We would like to thank Drs. Mark Van Doren, Jose Pastor-Pareja, Erika Bach, and Aurelio Teleman for kindly sharing fly strains and antibodies. This work was supported by grants to Yan Yan from the Research Grants Council of the Hong Kong Special Administrative Region (GRF16103620, GRF16104324, T13-602/21N) and from Shenzhen Science and Technology Innovation Commission (JCYJ20200109140201722), to Toyotaka Ishibashi from the National Natural Science Foundation of China (32170548), and to Zongzhao Zhai from the National Natural Science Foundation of China (32170509 and 31871469).

    摘要
  • 摘要: Cell competition is an evolutionarily ancient mechanism that functions to remove unfit or dangerous clonal cells in a multicellular community. A classical model is the removal of polarity-deficient clones, such as the precancerous scribble (scrib) mutant clones, in Drosophila imaginal discs. The activation of Ras, Yki, or Notch signaling robustly reverses the scrib mutant clonal fate from elimination to tumorous growth. Whether these signals converge to adopt a common mechanism to overcome the elimination pressure posed by cell competition remains unclear. Using single-cell transcriptomics, we find that a critical converging point downstream of Ras, Yki, and Notch signals is the upregulation of Upd2, an IL-6 family cytokine. Overexpression of Upd2 is sufficient to rescue the scrib mutant clones from elimination. Depletion of Upd2 blocks the growth of the scrib mutant clones with active Ras, Yki, and Notch signals. Moreover, Upd2 overexpression promotes robust intestinal stem cell (ISC) proliferation, while Upd2 is intrinsically required in ISCs for the growth of the adult intestine. Together, these results identify Upd2 as a crucial cell fitness factor that sustains tissue growth but can potentiate tumorigenesis when deregulated.
    Abstract: Cell competition is an evolutionarily ancient mechanism that functions to remove unfit or dangerous clonal cells in a multicellular community. A classical model is the removal of polarity-deficient clones, such as the precancerous scribble (scrib) mutant clones, in Drosophila imaginal discs. The activation of Ras, Yki, or Notch signaling robustly reverses the scrib mutant clonal fate from elimination to tumorous growth. Whether these signals converge to adopt a common mechanism to overcome the elimination pressure posed by cell competition remains unclear. Using single-cell transcriptomics, we find that a critical converging point downstream of Ras, Yki, and Notch signals is the upregulation of Upd2, an IL-6 family cytokine. Overexpression of Upd2 is sufficient to rescue the scrib mutant clones from elimination. Depletion of Upd2 blocks the growth of the scrib mutant clones with active Ras, Yki, and Notch signals. Moreover, Upd2 overexpression promotes robust intestinal stem cell (ISC) proliferation, while Upd2 is intrinsically required in ISCs for the growth of the adult intestine. Together, these results identify Upd2 as a crucial cell fitness factor that sustains tissue growth but can potentiate tumorigenesis when deregulated.
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    • 参考文献(53)
  • Atkins, M., Potier, D., Romanelli, L., Jacobs, J., Mach, J., Hamaratoglu, F., Aerts, S.,Haider, G., 2016. An ectopic network of transcription factors regulated by Hippo signaling drives growth and invasion of a Malignant tumor model. Curr. Biol. 26, 2101-2113.
    Bach, E.A., Ekas, L.A., Ayala-Camargo, A., Flaherty, M.S., Lee, H., Perrimon, N.,Baeg, G.H., 2007. GFP reporters detect the activation of the Drosophila JAK/STAT pathway in vivo. Gene Expr. Patterns 7, 323-331.
    Baker, N.E., 2020. Emerging mechanisms of cell competition. Nat. Rev. Genet. 21, 683-697.
    Bilder, D., Li, M.,Perrimon, N., 2000. Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science 289, 113-116.
    Bilder, D.,Perrimon, N., 2000. Localization of apical epithelial determinants by the basolateral PDZ protein Scribble. Nature 403, 676-680.
    Brumby, A.M., Richardson, H.E., 2003. scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J. 22, 5769-5779.
    Buchon, N., Osman, D., David, F.P., Fang, H.Y., Boquete, J.P., Deplancke, B.,Lemaitre, B., 2013. Morphological and molecular characterization of adult midgut compartmentalization in Drosophila. Cell Rep. 3, 1725-1738.
    Bunker, B.D., Nellimoottil, T.T., Boileau, R.M., Classen, A.K.,Bilder, D., 2015. The transcriptional response to tumorigenic polarity loss in Drosophila. Elife 4, e03189.
    Chatterjee, D., Cong, F., Wang, X.F., Machado Costa, C.A., Huang, Y.C., Deng, W.M., 2023. Cell polarity opposes Jak/STAT-mediated Escargot activation that drives intratumor heterogeneity in a Drosophila tumor model. Cell Rep. 42, 112061.
    Chen, C.L., Schroeder, M.C., Kango-Singh, M., Tao, C.,Halder, G., 2012. Tumor suppression by cell competition through regulation of the Hippo pathway. Proc. Natl. Acad. Sci. U. S. A. 109, 484-489.
    Chen, T., Chen, X., Zhang, S., Zhu, J., Tang, B., Wang, A., Dong, L., Zhang, Z., Yu, C., Sun, Y., et al., 2021. The genome sequence archive family: Toward explosive data growth and diverse data types. Genomics Proteomics Bioinformatics 19, 578-583.
    Choi, H.M.T., Schwarzkopf, M., Fornace, M.E., Acharya, A., Artavanis, G., Stegmaier, J., Cunha, A., Pierce, N.A., 2018. Third-generation in situ hybridization chain reaction: multiplexed, quantitative, sensitive, versatile, robust. Development 145, dev165753.
    Cong, B.,Cagan, R.L., 2024. Cell competition and cancer from Drosophila to mammals. Oncogenesis 13, 1.
    Cordero, J.B., Macagno, J.P., Stefanatos, R.K., Strathdee, K.E., Cagan, R.L.,Vidal, M., 2010. Oncogenic Ras diverts a host TNF tumor suppressor activity into tumor promoter. Dev. Cell 18, 999-1011.
    de Vreede, G., Gerlach, S.U.,Bilder, D., 2022. Epithelial monitoring through ligand-receptor segregation ensures malignant cell elimination. Science 376, 297-301.
    Delidakis, C.,Artavanis-Tsakonas, S., 1992. The Enhancer of split [E(spl)] locus of Drosophila encodes seven independent helix-loop-helix proteins. Proc. Natl. Acad. Sci. U. S. A. 89, 8731-8735.
    Deng, M., Wang, Y., Zhang, L., Yang, Y., Huang, S., Wang, J., Ge, H., Ishibashi, T.,Yan, Y., 2019. Single cell transcriptomic landscapes of pattern formation, proliferation and growth in Drosophila wing imaginal discs. Development 146, dev179754.
    Ekas, L.A., Cardozo, T.J., Flaherty, M.S., McMillan, E.A., Gonsalves, F.C.,Bach, E.A., 2010. Characterization of a dominant-active STAT that promotes tumorigenesis in Drosophila. Dev. Biol. 344, 621-636.
    Everetts, N.J., Worley, M.I., Yasutomi, R., Yosef, N., Hariharan, I.K., 2021. Single-cell transcriptomics of the Drosophila wing disc reveals instructive epithelium-to-myoblast interactions. Elife 10, e61276.
    Feng, S., Thomas, S.,Wang, J., 2012. Diverse tumor pathology due to distinctive patterns of JAK/STAT pathway activation caused by different Drosophila polyhomeotic alleles. Genetics 190, 279-282.
    Ferguson, S.B., Blundon, M.A., Klovstad, M.S.,Schupbach, T., 2012. Modulation of gurken translation by insulin and TOR signaling in Drosophila. J. Cell Sci. 125, 1407-1419.
    Flaherty, M.S., Salis, P., Evans, C.J., Ekas, L.A., Marouf, A., Zavadil, J., Banerjee, U.,Bach, E.A., 2010. chinmo is a functional effector of the JAK/STAT pathway that regulates eye development, tumor formation, and stem cell self-renewal in Drosophila. Dev. Cell 18, 556-568.
    Fortini, M.E., Rebay, I., Caron, L.A.,Artavanis-Tsakonas, S., 1993. An activated Notch receptor blocks cell-fate commitment in the developing Drosophila eye. Nature 365, 555-557.
    Gilbert, M.M., Weaver, B.K., Gergen, J.P.,Reich, N.C., 2005. A novel functional activator of the Drosophila JAK/STAT pathway, unpaired2, is revealed by an in vivo reporter of pathway activation. Mech. Dev. 122, 939-948.
    Harrison, D.A., McCoon, P.E., Binari, R., Gilman, M.,Perrimon, N., 1998. Drosophila unpaired encodes a secreted protein that activates the JAK signaling pathway. Genes Dev. 12, 3252-3263.
    Hombria, J.C., Brown, S., Hader, S.,Zeidler, M.P., 2005. Characterisation of Upd2, a Drosophila JAK/STAT pathway ligand. Dev. Biol. 288, 420-433.
    Ji, T., Zhang, L., Deng, M., Huang, S., Wang, Y., Pham, T.T., Smith, A.A., Sridhar, V., Cabernard, C., Wang, J., et al., 2019. Dynamic MAPK signaling activity underlies a transition from growth arrest to proliferation in Drosophila scribble mutant tumors. Dis. Model Mech. 12, dmm040147.
    Johnson, D.E., O'Keefe, R.A.,Grandis, J.R., 2018. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol. 15, 234-248.
    Kang, S., Narazaki, M., Metwally, H.,Kishimoto, T., 2020. Historical overview of the interleukin-6 family cytokine. J. Exp. Med. 217, e20190347.
    Karsten, P., Hader, S.,Zeidler, M.P., 2002. Cloning and expression of Drosophila SOCS36E and its potential regulation by the JAK/STAT pathway. Mech. Dev. 117, 343-346.
    Kim, W., Jang, Y.G., Yang, J.,Chung, J., 2017. Spatial activation of TORC1 is regulated by Hedgehog and E2F1 signaling in the Drosophila eye. Dev. Cell 42, 363-375.
    Kowalczyk, W., Romanelli, L., Atkins, M., Hillen, H., Bravo Gonzalez-Blas, C., Jacobs, J., Xie, J., Soheily, S., Verboven, E., Moya, I.M., et al., 2022. Hippo signaling instructs ectopic but not normal organ growth. Science 378, eabg3679.
    Kulshammer, E., Mundorf, J., Kilinc, M., Frommolt, P., Wagle, P.,Uhlirova, M., 2015. Interplay among Drosophila transcription factors Ets21c, Fos and Ftz-F1 drives JNK-mediated tumor malignancy. Dis. Model Mech. 8, 1279-1293.
    McGuire, S.E., Mao, Z.,Davis, R.L., 2004. Spatiotemporal gene expression targeting with the TARGET and gene-switch systems in Drosophila. Sci. STKE 2004, pl6.
    Miguel-Aliaga, I., Jasper, H.,Lemaitre, B., 2018. Anatomy and physiology of the digestive tract of Drosophila melanogaster. Genetics 210, 357-396.
    Morata, G., 2021. Cell competition: A historical perspective. Dev. Biol. 476, 33-40.
    Morata, G.,Ripoll, P., 1975. Minutes: mutants of Drosophila autonomously affecting cell division rate. Dev. Biol. 42, 211-221.
    Neufeld, T.P., de la Cruz, A.F., Johnston, L.A.,Edgar, B.A., 1998. Coordination of growth and cell division in the Drosophila wing. Cell 93, 1183-1193.
    Orange, S.T., Leslie, J., Ross, M., Mann, D.A.,Wackerhage, H., 2023. The exercise IL-6 enigma in cancer. Trends Endocrinol. Metab. 34, 749-763.
    Pagliarini, R.A.,Xu, T., 2003. A genetic screen in Drosophila for metastatic behavior. Science 302, 1227-1231.
    Rajan, A.,Perrimon, N., 2012. Drosophila cytokine unpaired 2 regulates physiological homeostasis by remotely controlling insulin secretion. Cell 151, 123-137.
    Recasens-Alvarez, C., Ferreira, A.,Milan, M., 2017. JAK/STAT controls organ size and fate specification by regulating morphogen production and signalling. Nat. Commun. 8, 13815.
    Romero-Pozuelo, J., Demetriades, C., Schroeder, P.,Teleman, A.A., 2017. CycD/Cdk4 and discontinuities in Dpp signaling activate TORC1 in the Drosophila wing disc. Dev. Cell 42, 376-387 e375.
    Rose-John, S., 2018. Interleukin-6 family cytokines. Cold Spring Harb. Perspect. Biol. 10, 2.
    Sanchez-Vega, F., Mina, M., Armenia, J., Chatila, W.K., Luna, A., La, K.C., Dimitriadoy, S., Liu, D.L., Kantheti, H.S., Saghafinia, S., et al., 2018. Oncogenic signaling pathways in the cancer genome atlas. Cell 173, 321-337.
    Teleman, A.A., Chen, Y.W.,Cohen, S.M., 2005. 4E-BP functions as a metabolic brake used under stress conditions but not during normal growth. Genes Dev. 19, 1844-1848.
    Wang, X., Bao, H., Huang, Y.C., Barua, A., Lai, C.M., Sun, J., Zhou, Y., Cong, F., Gong, S., Chang, C.H., et al., 2024. Sex-dimorphic tumor growth is regulated by tumor microenvironmental and systemic signals. Sci. Adv. 10, 49, eads4229.
    West, C.,Silverman, N., 2018. p38b and JAK-STAT signaling protect against Invertebrate iridescent virus 6 infection in Drosophila. PLoS Pathog. 14, e1007020.
    Wright, V.M., Vogt, K.L., Smythe, E.,Zeidler, M.P., 2011. Differential activities of the Drosophila JAK/STAT pathway ligands Upd, Upd2 and Upd3. Cell. Signal. 23, 920-927.
    Wu, M., Pastor-Pareja, J.C.,Xu, T., 2010. Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. Nature 463, 545-548.
    Yamamoto, M., Ohsawa, S., Kunimasa, K.,Igaki, T., 2017. The ligand Sas and its receptor PTP10D drive tumour-suppressive cell competition. Nature 542, 246-250.
    Zhai, Z., Boquete, J.P.,Lemaitre, B., 2018. Cell-specific Imd-NF-kappaB responses enable simultaneous antibacterial immunity and intestinal epithelial cell shedding upon bacterial infection. Immunity 48, 897-910.
    Zhai, Z., Kondo, S., Ha, N., Boquete, J.P., Brunner, M., Ueda, R.,Lemaitre, B., 2015. Accumulation of differentiating intestinal stem cell progenies drives tumorigenesis. Nat. Commun. 6, 10219.
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出版历程
  • 收稿日期:  2025-02-05
  • 录用日期:  2025-04-25
  • 修回日期:  2025-04-24
  • 刊出日期:  2026-01-31

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