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<p>Colorectal cancer (CRC) develops through a series of progressive genetic mutations, with alterations in <i>APC</i> and <i>TP53</i> being the most frequently observed in the early stages. Although the loss of <i>APC</i> is recognized as a significant initiating event, the epigenetic processes through which the simultaneous inactivation of <i>APC</i> and <i>TP53</i> facilitates the onset of colorectal tumorigenesis remain poorly characterized. To address this gap, we developed a human colon organoid model using CRISPR-Cas9 to achieve a double knockout of <i>APC</i> and <i>TP53</i>. Through extensive multi-omics profiling, we characterized the epigenetic landscape distinctive of early-stage CRC. We identified <i>KIT</i>, a receptor tyrosine kinase, as a critical oncogenic driver that is significantly upregulated in ΔDKO (<i>APC</i> and <i>TP53</i> double knockout) organoids, thereby activating the MAPK and Wnt signaling pathways to augment proliferation and tumorigenesis. Furthermore, AP-1 transcription factors (FOS/JUN) regulate <i>KIT</i> expression via chromatin remodeling. Functional analyses indicated that KIT is integral to sustaining the elevated proliferation rates observed in ΔDKO organoids. These findings reveal a novel AP-1/KIT signaling axis that is central to the early progression of CRC, thereby presenting a promising avenue for therapeutic intervention.</p><p></p>

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Activation of KIT signaling promotes early tumorigenesis through the AP-1 pathway in APC/TP53 double-knockout human colon organoids

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月4日

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  • Younghee Choi,
  • Eunju Kim,
  • Soo-Yeon Cho,
  • Jihyun Park,
  • Youngwon Cho,
  • Sungho Kim,
  • Sang-Hyun Song,
  • Tae-You Kim

摘要

Colorectal cancer (CRC) develops through a series of progressive genetic mutations, with alterations in APC and TP53 being the most frequently observed in the early stages. Although the loss of APC is recognized as a significant initiating event, the epigenetic processes through which the simultaneous inactivation of APC and TP53 facilitates the onset of colorectal tumorigenesis remain poorly characterized. To address this gap, we developed a human colon organoid model using CRISPR-Cas9 to achieve a double knockout of APC and TP53. Through extensive multi-omics profiling, we characterized the epigenetic landscape distinctive of early-stage CRC. We identified KIT, a receptor tyrosine kinase, as a critical oncogenic driver that is significantly upregulated in ΔDKO (APC and TP53 double knockout) organoids, thereby activating the MAPK and Wnt signaling pathways to augment proliferation and tumorigenesis. Furthermore, AP-1 transcription factors (FOS/JUN) regulate KIT expression via chromatin remodeling. Functional analyses indicated that KIT is integral to sustaining the elevated proliferation rates observed in ΔDKO organoids. These findings reveal a novel AP-1/KIT signaling axis that is central to the early progression of CRC, thereby presenting a promising avenue for therapeutic intervention.