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Tumor cell-secreted PLD increases tumor stemness by senescence-mediated communication with microenvironment

Abstract

Cancer cells are in continuous communication with the surrounding microenvironment and this communication can affect tumor evolution. In this work, we show that phospholipase D2 (PLD2) was overexpressed in colon tumors and is secreted by cancer cells, inducing senescence in neighboring fibroblasts. This occurs through its lipase domain. Senescence induced by its product, phosphatidic acid, leads to a senescence-associated secretory phenotype (SASP) able to increase the stem properties of cancer cells. This increase in stemness occurs by Wnt pathway activacion. This closes a feedback loop in which senescence acts as a crosspoint for the generation of CSCs mediated by phospholipid metabolism. We also demonstrate the connexion of both phenomena in mouse models in vivo showing that a high PLD2 expression increased stemness and tumorigenesis. Thus, the patients with colon cancer show high levels of PLD2 and SASP factor genes expression correlating with Wnt pathway activation. Therefore, we demonstrate that tumor cell-secreted PLD2 contributes to tumor development by modifying the microenvironment, making it a possible therapeutic target for cancer treatment. This mechanism may also explain the high levels of Wnt pathway activation in colon cancer.

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Acknowledgements

We thank the donors, the HUVR-IBiS Biobank (Andalusian Public Health System Biobank and ISCIII-Red de Biobancos PT13/0010/0056) for the human specimens used in this study, Carolina Castilla for the assistance with IHC assays and Carmen Saez for histological analyses. SM-G was supported by a Sara Borrell grant from ISCIII (CD16/00230). AC lab was supported by grants from the Spanish Ministry of Economy and Competitivity, Plan Estatal de I + D + I 2013–2016, ISCIII (Fis: PI15/00045), and CIBER de Cáncer (CD16/12/00275), co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-1848), and Consejeria de Salud of the Junta de Andalucia (PI-0397–2017). This work was also supported by Fundacion BBVA. Especial thanks to the AECC Foundation for supporting this work. JG-C is supported by Grant HL056653–14 from the NIH.

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Correspondence to Amancio Carnero.

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Muñoz-Galván, S., Lucena-Cacace, A., Perez, M. et al. Tumor cell-secreted PLD increases tumor stemness by senescence-mediated communication with microenvironment. Oncogene 38, 1309–1323 (2019). https://doi.org/10.1038/s41388-018-0527-2

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