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Crosstalk between GLTSCR1-deficient endothelial cells and tumour cells promotes colorectal cancer development by activating the Notch pathway

Cell Death & Differentiation volume 32, pages 1231–1243 (2025)Cite this article

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Abstract

Cancer stem cells (CSCs) typically reside in perivascular niches, but whether endothelial cells of blood vessels influence the stemness of cancer cells remains poorly understood. This study revealed that endothelial cell-specific GLTSCR1 deletion promotes colorectal cancer (CRC) tumorigenesis and metastasis by increasing cancer cell stemness. Mechanistically, knocking down GLTSCR1 induces the transformation of endothelial cells into tip cells by regulating the expression of Neuropilin-1 (NRP1), thereby increasing the direct contact and interaction between endothelial cells and tumour cells. In addition, GLTSCR1 inhibits JAG1 transcription by competing with acetylated p65(Lys-310) to bind to the BRD4 interaction site. Therefore, GLTSCR1 deficiency increases JAG1 expression in endothelial cells. Subsequently, increased JAG1 levels on tip cell membranes bind to Notch on CRC cell membranes, activating the Notch signalling pathway in tumour cells and increasing CRC cell stemness. Taken together, our findings highlight the roles of endothelial cells in CRC development.

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Fig. 1: GLTSCR1-deficient endothelial cells promote CRC tumorigenesis and metastasis.
Fig. 2: GLTSCR1-deficient endothelial cells regulate CRC stemness through direct contact with tumour cells.
Fig. 3: GLTSCR1-deficient endothelial cells regulate CRC stemness through direct contact with tumour cells.
Fig. 4: GLTSCR1 deficiency promotes tip cell transformation by regulating Neuropilin-1.
Fig. 5: GLTSCR1 deficiency promotes cancer cell stemness by the Notch signalling pathway.
Fig. 6: GLTSCR1 suppresses JAG1 expression by competitively inhibiting the interaction between BRD4 and acetylated p65 (AC-Lys310).
Fig. 7: The mechanism diagram of this article.

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Data availability

The raw RNA-sequencing data have been submitted to the National Center for Biotechnology Information (accession number: PRJNA1107142). All data are available from the corresponding authors upon request.

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Acknowledgements

We thank Qiong Huang from the core facility platform of Zhejiang University School of Medicine for technical support. We thank the Laboratory Animal Center of Zhejiang University for technical assistance with mice management.

Author contrionutions

Conceptualization: HZ. Experimental methodology: LL and MD. Writing – original draft: LL. Help with editing and critical reading of the final manuscript: HZ and FH. Data analysis: LL and QH. Supervision and funding: HZ, FH and ML. All Authors read and approved the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (81871937, 82472952, 82001586, 82173223, and 82072629), and CAMS Innovation Fund for Medical Sciences (CIFMS, 2019-I2M-5-044).

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  1. These authors contributed equally: Lu Liu, Fengyan Han.

Authors and Affiliations

  1. Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital (Yiwu), Zhejiang University School of Medicine, Hangzhou, 310058, China

    Lu Liu, Mengli Deng, Qizheng Han & Honghe Zhang

  2. Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, 310058, China

    Lu Liu, Mengli Deng, Qizheng Han, Maode Lai & Honghe Zhang

  3. School of Basic Medical Sciences, The Fourth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China

    Fengyan Han

  4. Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China

    Maode Lai

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Correspondence to Fengyan Han, Maode Lai or Honghe Zhang.

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The study was conducted in accordance with the principles of the Declaration of Helsinki principles and its subsequent revisions. Animal experiments performed in accordance with a protocol approved by the Institutional Animal Care and Use Committee at the Zhejiang University (Project Approval Code: ZJU20240166).

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Liu, L., Han, F., Deng, M. et al. Crosstalk between GLTSCR1-deficient endothelial cells and tumour cells promotes colorectal cancer development by activating the Notch pathway. Cell Death Differ 32, 1231–1243 (2025). https://doi.org/10.1038/s41418-025-01450-6

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