期刊
NATURE CANCER
卷 1, 期 1, 页码 28-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s43018-019-0006-x
关键词
-
类别
资金
- NIH [P01-CA129243, P01-CA094060, P30-CA008748, K08-CA230213, T32-CA009207, T32-GM007739, F30-CA203238]
- Department of Defense Innovator Award [W81XWH-12-0074]
- Damon Runyon Clinical Investigator Award
- American Cancer Society Postdoctoral Fellowship
- AACR Basic Cancer Research Fellowship
- Conquer Cancer Foundation of ASCO Young Investigator Award
- Shulamit Katzman Endowed Postdoctoral Research Fellowships
- Damon Runyon Postdoctoral Fellowship
- Burroughs Wellcome Career Award at the Scientific Interface
- Alan and Sandra Gerry Metastasis and Tumour Ecosystems Center
- Stand Up To Cancer Colorectal Cancer Dream Team [SU2C AACR-DR22-17]
The authors identify a population of L1CAM-positive cells that, following loss of epithelial integrity, promote intestinal tissue regeneration and mediate metastasis initiation and chemoresistance in colorectal cancer. Metastasis-initiating cells with stem-like properties drive cancer lethality, yet their origins and relationship to primary-tumor-initiating stem cells are not known. We show that L1CAM(+) cells in human colorectal cancer (CRC) have metastasis-initiating capacity, and we define their relationship to tissue regeneration. L1CAM is not expressed in the homeostatic intestinal epithelium, but is induced and required for epithelial regeneration following colitis and in CRC organoid growth. By using human tissues and mouse models, we show that L1CAM is dispensable for adenoma initiation but required for orthotopic carcinoma propagation, liver metastatic colonization and chemoresistance. L1CAM(high) cells partially overlap with LGR5(high) stem-like cells in human CRC organoids. Disruption of intercellular epithelial contacts causes E-cadherin-REST transcriptional derepression of L1CAM, switching chemoresistant CRC progenitors from an L1CAM(low) to an L1CAM(high) state. Thus, L1CAM dependency emerges in regenerative intestinal cells when epithelial integrity is lost, a phenotype of wound healing deployed in metastasis-initiating cells.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据