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GPR37 promotes colorectal cancer liver metastases by enhancing the glycolysis and histone lactylation via Hippo pathway

Oncogene volume 42, pages 3319–3330 (2023)Cite this article

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Abstract

Liver metastases are commonly detected in a range of malignancies including colorectal cancer (CRC), unfortunately no effectively strategies for CRC liver metastasis (CRLM). In this study, we found GPR37 expression dramatically increased in human CRLM specimens and associated poor prognosis. GPR37 depletion greatly suppressed the liver metastasis in the mouse models of CRLM. Functional experiments showed that GPR37 knockdown inhibited the growth by reducing the glycolysis of CRC cells. Also, GPR37 knockdown in tumor cells produced decreased levels of two chemokines involved in neutrophil accumulation, which abrogated neutrophil recruitment in the tumor microenvironment of CRLM. Finally, the mechanism studies revealed that GPR37 could activate the hippo pathway, thereby promoting LDHA expression and glycolysis. This leads to increased lactylation of H3K18la, resulting in up-regulation of CXCL1 and CXCL5. These results support a role of the GPR37 in modulating the tumor metabolism and microenvironment in CRLM and GPR37 could be a potential therapeutic target.

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Fig. 1: GPR37 expression up-regulated in CRLM and associated with poor prognosis.
Fig. 2: Targeting GPR37 suppresses the liver metastasis in vivo.
Fig. 3: GPR37 promotes CRLM by enhancing glycolysis and neutrophil recruitment.
Fig. 4: GPR37 activate hippo pathway to enhance the glycolysis of CRC.
Fig. 5: GPR37 enhances H3K18 lactylation resulting in CXCL1 and CXCL5 upregulation.
Fig. 6: Targeting GPR37 with Hypocrellin B enhance the response to anti-PD1 therapy.

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Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

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Funding

Support for this study came from the National Natural Science Foundation of China (Grant No. 81902907), the Shanghai Pujiang Program (Grant No. 2019PJD008), Shanghai Anticancer Association-Shanghai Cancer Center, Fudan University Joint Foundation (Grant No. YJMS202011). Shenkang-Three-year Clinical Research Foundation [No. SHDC2020CR3031B] and [No. SHDC2020CR5007].

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Author notes

  1. These authors contributed equally: Jiamin Zhou, Weiqi Xu, Yibin Wu.

Authors and Affiliations

  1. Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, 200032, PR China

    Jiamin Zhou, Weiqi Xu, Yibin Wu, Miao Wang, Ning Zhang, Longrong Wang, Yun Feng, Ti Zhang, Lu Wang & Anrong Mao

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China

    Jiamin Zhou, Weiqi Xu, Yibin Wu, Miao Wang, Ning Zhang, Longrong Wang, Yun Feng, Ti Zhang, Lu Wang & Anrong Mao

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  1. Jiamin Zhou
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Contributions

JMZ, WQX, and YBW conceived and performed most of the experiments; MW, NZ, LRW, and YF accomplished some of the in vitro experiments. JMZ and TZ accomplished the in vivo studies. JMZ, LW and ARM wrote the manuscript. The paper was approved by all authors.

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Correspondence to Lu Wang or Anrong Mao.

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Zhou, J., Xu, W., Wu, Y. et al. GPR37 promotes colorectal cancer liver metastases by enhancing the glycolysis and histone lactylation via Hippo pathway. Oncogene 42, 3319–3330 (2023). https://doi.org/10.1038/s41388-023-02841-0

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