Synapse - Progressive plasticity during colorectal cancer metastasis

Progressive plasticity during colorectal cancer metastasis Journal Article

Authors:	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.
Article Title:	Progressive plasticity during colorectal cancer metastasis
Abstract:	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.
Keywords:	model; drainage; surface; greenland ice-sheet; meltwater storage; mass-balance; subglacial; sea-level; water-resources; firn; displacements
Journal Title:	Nature
Volume:	637
Issue:	8047
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	2025-01-23
Start Page:	947
End Page:	954
Language:	English
ACCESSION:	WOS:001346057600009
DOI:	10.1038/s41586-024-08150-0
PROVIDER:	wos
PMCID:	PMC11754107
PUBMED:	39478232
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK authors are Dana Pe’er and Karuna Ganesh -- Erratum issued, see DOI: 10.1038/s41586-024-08560-0 -- Source: Wos