Progressive plasticity during colorectal cancer metastasis

• 成果类型: Article
• 署名作者: Moorman, A. R.; Benitez, E. K.; Cambuli, F.; Jiang, Q.; Mahmoud, A.; Lumish, M.; Hartner, S.; Balkaran, S.; Bermeo, J.; Asawa, S.; Firat, C.; Saxena, A.; Wu, F.; Luthra, A.; Burdziak, C.; Xie, Y.; Sgambati, V.; Luckett, K.; Li, Y.; Yi, Z.; Masilionis, I.; Soares, K.; Pappou, E.; Yaeger, R.; Kingham, P.; Jarnagin, W.; Paty, P.; Weiser, M. R.; Mazutis, L.; D'Angelica, M.; Shia, J.; Garcia-Aguilar, J.; Nawy, T.; Hollmann, T. J.; Chaligne, R.; Sanchez-Vega, F.; Sharma, R.; Pe'er, D.; Ganesh, K.
• 署名单位: Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Cornell University; Weill Cornell Medicine; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Howard Hughes Medical Institute; University System of Ohio; Case Western Reserve University; Bristol-Myers Squibb
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1836
• DOI: 10.1038/s41586-024-08150-0
• 发表日期: 2025-01-23
• 关键词: greenland ice-sheet; meltwater storage; mass-balance; subglacial drainage; sea-level; water-resources; surface; firn; MODEL; displacements

摘要

As cancers progress, they become increasingly aggressive-metastatic tumours are less responsive to first-line therapies than primary tumours, they acquire resistance to successive therapies and eventually cause death1,2. Mutations are largely conserved between primary and metastatic tumours from the same patients, suggesting that non-genetic phenotypic plasticity has a major role in cancer progression and therapy resistance3-5. However, we lack an understanding of metastatic cell states and the mechanisms by which they transition. Here, in a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that, although primary tumours largely adopt LGR5+ intestinal stem-like states, metastases display progressive plasticity. Cancer cells lose intestinal cell identities and reprogram into a highly conserved fetal progenitor state before undergoing non-canonical differentiation into divergent squamous and neuroendocrine-like states, a process that is exacerbated in metastasis and by chemotherapy and is associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues compared with their intestinal lineage-restricted primary tumour counterparts. We identify PROX1 as a repressor of non-intestinal lineage in the fetal progenitor state, and show that downregulation of PROX1 licenses non-canonical reprogramming. Colorectal cancer metastasis involves dramatic plasticity and loss of PROX1-mediated repression of non-intestinal lineages.