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<p>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<sup>(Lys-310)</sup> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年1月27日

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  • Lu Liu,
  • Fengyan Han,
  • Mengli Deng,
  • Qizheng Han,
  • Maode Lai,
  • Honghe Zhang

摘要

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.