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A low amino acid environment promotes cell macropinocytosis through the YY1-FGD6 axis in Ras-mutant pancreatic ductal adenocarcinoma

Oncogene volume 41, pages 1203–1215 (2022)Cite this article

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Abstract

Pancreatic ductal adenocarcinoma (PDAC), cancer with a high mortality rate and the highest rate of KRAS mutation, reportedly internalizes proteins via macropinocytosis to adapt to low amino acid levels in the tumor microenvironment. Here, we aimed to identify a key regulator of macropinocytosis for the survival of tumor cells in a low amino acid environment in PDAC. FYVE, RhoGEF, and PH domain-containing protein 6 (FGD6) were identified as key regulators of macropinocytosis. FGD6 promoted PDAC cell proliferation, macropinocytosis, and tumor growth both in vitro and in vivo. The macropinocytosis level was decreased with FGD6 knockdown in PDAC cell lines. Moreover, FGD6 promoted macropinocytosis by participating in the trans-Golgi network and enhancing the membrane localization of growth factor receptors, especially the TGF-beta receptor. TGF-beta enhanced macropinocytosis in PDAC cells. Additionally, YAP nuclear translocation induced by a low amino acid tumor environment initiated FGD6 expression by coactivation with YY1. Clinical data analysis based on TCGA and GEO datasets showed that FGD6 expression was upregulated in PDAC tissue, and high FGD6 expression was correlated with poor prognosis in patients with PDAC. In tumor tissue from KrasG12D/+/Trp53R172H/−/Pdx1-Cre (KPC) mice, FGD6 expression escalated during PDAC development. Our results uncover a previously unappreciated mechanism of macropinocytosis in PDAC. Strategies to target FGD6 and growth factors membrane localization might be developed for the treatment of PDAC.

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Fig. 1: FGD6 is a candidate for regulators of macropinocytosis and its expression is associated with a poor prognosis for pancreatic cancer patients.
Fig. 2: FGD6 promotes cell viability by modulating the macropinocytosis of PDAC cells.
Fig. 3: FGD6 promotes TGFBRII and EGFR membrane localization.
Fig. 4: FGD6 participates in the trans-Golgi network and promotes receptor location on the plasma membrane.
Fig. 5: A low amino acid environment inhibits the Hippo pathway and attenuates the increase in FGD6 expression and pancreatic cancer cell macropinocytosis.
Fig. 6: YY1 transcription coactivator with YAP initiates FGD6 expression.
Fig. 7: A schematic presentation illustrating the potential mechanism by which FGD6 participates in Ras-mutant PDAC cell macropinocytosis.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (81672837, to H.-Z. Nie; 81872242, to Y.-L. Zhang; 82002485, to Q.Li), the Natural Science Foundation of Shanghai (21ZR1461400, to H.-Z. Nie; 19ZR1452500 to X.-M. Yang), Shanghai Municipal Health Commission (202040104, to Y.-L. Zhang).

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  1. These authors contributed equally: Yi-Fan Zhang, Qing Li, Pei-Qi Huang, Tong Su.

Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China

    Yi-Fan Zhang, Qing Li, Pei-Qi Huang, Shu-Heng Jiang, Li-Peng Hu, Xue-Li Zhang, Yue Sun, Hong Pan, Xiao-Mei Yang, Jun Li, Yan-Zhi Gai, Lei Zhu, Lin-Li Yao, Dong-Xue Li, Zhi-Gang Zhang, Yan-Li Zhang & Hui-Zhen Nie

  2. Department of Gynecology and Obstetrics, Shanghai Key Laboratory of Gynecology and Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Tong Su

  3. Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Yong-Wei Sun & De-Jun Liu

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Contributions

Conception and design: H.Z.N., Y.L.Z., D.J.L., and Y.F.Z. Development of methodology: Y.S., L.L.Y., and D.X.L. Acquisition of data: Y.F.Z., Q.L., P.Q.H., T.S., S.H.J., L.P.H., X.M.Y., and X.L.Z. Analysis and interpretation of data: Y.F.Z., L.Z., and Q.Y. Writing review and/or revision of paper: Y.F.Z., H.Z.N., Y.L.Z., D.J.L., Z.G.Z., and S.H.J. Study supervision: H.Z.N. and Z.G.Z.

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Correspondence to De-Jun Liu, Yan-Li Zhang or Hui-Zhen Nie.

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Zhang, YF., Li, Q., Huang, PQ. et al. A low amino acid environment promotes cell macropinocytosis through the YY1-FGD6 axis in Ras-mutant pancreatic ductal adenocarcinoma. Oncogene 41, 1203–1215 (2022). https://doi.org/10.1038/s41388-021-02159-9

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