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WNT2–SOX4 positive feedback loop promotes chemoresistance and tumorigenesis by inducing stem-cell like properties in gastric cancer

Oncogene volume 42, pages 3062–3074 (2023)Cite this article

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Abstract

Gastric cancer (GC) is characterized by its vigorous chemoresistance to current therapies, which is attributed to the highly heterogeneous and immature phenotype of cancer stem cells (CSCs) during tumor initiation and progression. The secretory WNT2 ligand regulates multiple cancer pathways and has been demonstrated to be a potential therapeutic target for gastrointestinal tumors; however, its role involved in gastric CSCs (GCSCs) remains unclear. Here, we found that overexpression of WNT2 enhanced stemness properties to promote chemoresistance and tumorigenicity in GCSCs. Mechanistically, WNT2 was positively regulated by its transcription factor SOX4, and in turn, SOX4 was upregulated by the canonical WNT2/FZD8/β-catenin signaling pathway to form an auto-regulatory positive feedback loop, resulting in the maintenance of GCSCs self-renewal and tumorigenicity. Furthermore, simultaneous overexpression of both WNT2 and SOX4 was correlated with poor survival and reduced responsiveness to chemotherapy in clinical GC specimens. Blocking WNT2 using a specific monoclonal antibody significantly disrupted the WNT2–SOX4 positive feedback loop in GCSCs and enhanced the chemotherapeutic efficacy when synergized with the chemo-drugs 5-fluorouracil and oxaliplatin in a GCSC-derived mouse xenograft model. Overall, this study identified a novel WNT2–SOX4 positive feedback loop as a mechanism for GCSCs-induced chemo-drugs resistance and suggested that the WNT2–SOX4 axis may be a potential therapeutic target for gastric cancer treatment.

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Fig. 1: WNT2 promotes the stem cell-like properties in GCSCs.
Fig. 2: Knockdown of WNT2 inhibits chemoresistance, EMT, and tumor growth in GCSCs.
Fig. 3: WNT2 was transcriptionally regulated by SOX4 in GCSCs.
Fig. 4: SOX4 contributes to WNT2-mediated stemness and chemoresistance in GCSCs.
Fig. 5: WNT2 maintains GCSC stemness by activating the WNT2-FZD8-SOX4 positive feedback loop.
Fig. 6: Anti-WNT2 mAb treatment enhances the therapeutic efficacy of 5-FU plus OXA.

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Data availability

The GC scRNA-seq data used for the analysis of potential TFs regulating WNT2 gene expression in CD44+ CD54+ cells are available on the GEO database (accession number: GSE183904). R software is a free software environment for statistical computing and graphics (https://www.r-project.org). The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We acknowledge Prof. Xianming Mo at Sichuan University for providing the GCSC cells. We thank Dr. Yunxiao Yang in Shenzhen University General Hospital for her assistance with the histological examination. This work was supported by grants from the National Natural Science Foundation of China (82173003 and 82073197), the Science and Technology Program of Guangdong Province in China (2019B030301009), the Industry and Information Technology Foundation of Shenzhen (20180309100135860), the Science and Technology Foundation of Shenzhen (JCYJ20200109113810154) and the Shenzhen Key Laboratory Foundation (ZDSYS20200811143757022).

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  1. These authors contributed equally: Xiang-Yu Tan, Yu-Ting Li.

Authors and Affiliations

  1. Guangdong Province Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China

    Xiang-Yu Tan, Yu-Ting Li, Hua-Hui Li, Li-Xiang Ma, Tian-Tian Zhang, Tu-Xiong Huang & Li Fu

  2. Shenzhen University-Friedrich Schiller Universität Jena Joint PhD Program in Biomedical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China

    Yu-Ting Li & Hua-Hui Li

  3. Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China

    Chui-Mian Zeng

  4. Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, 710032, Shaanxi, China

    Xiao-Di Zhao

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Contributions

Conceptualization, XYT and LF; methodology, XYT, YTL, and LF; investigation, XYT, YTL, HHL, LXM, CMZ, and LF; writing – original draft, XYT, and YTL; writing – review & editing, XYT, YTL, and LF; resources, XYT, YTL, HHL, LXM, CMZ, TTZ, TXH and XDZ; formal analysis, XYT, YTL, and HHL; data curation, XYT, YTL, and HHL; visualization, XYT, YTL, HHL, CMZ; supervision, LF; funding acquisition, LF.

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Correspondence to Li Fu.

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Tan, XY., Li, YT., Li, HH. et al. WNT2–SOX4 positive feedback loop promotes chemoresistance and tumorigenesis by inducing stem-cell like properties in gastric cancer. Oncogene 42, 3062–3074 (2023). https://doi.org/10.1038/s41388-023-02816-1

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