期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 12, 页码 E2357-E2364出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1701219114
关键词
colorectal cancer; adenoma-carcinoma sequence; organoids; metastasis; niche independence
资金
- NWO-ZonMw Veni [91614138]
- Dutch Cancer Society Fellowship [BUIT-2013-5847]
- European Research Council Grant COLONCAN
- European Research Council Grant CANCER-RECURRENCE [648804]
- CancerGenomics.nl (Netherlands Organisation for Scientific Research)
- Cancer Research UK
- Versus Arthritis [21139] Funding Source: researchfish
In the adenoma-carcinoma sequence, it is proposed that intestinal polyps evolve through a set of defined mutations toward metastatic colorectal cancer (CRC). Here, we dissect this adenoma-carcinoma sequence in vivo by using an orthotopic organoid transplantation model of human colon organoids engineered to harbor different CRC mutation combinations. We demonstrate that sequential accumulation of oncogenic mutations in Wnt, EGFR, P53, and TGF-beta signaling pathways facilitates efficient tumor growth, migration, and metastatic colonization. We show that reconstitution of specific niche signals can restore metastatic growth potential of tumor cells lacking one of the oncogenic mutations. Our findings imply that the ability to metastasize-i.e., to colonize distant sites-is the direct consequence of the loss of dependency on specific niche signals.
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