Progressive plasticity during colorectal cancer metastasis

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 death . Mutations are largely conserved between primary and metastatic tumours from the s...

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Bibliographic Details
Published in:	Nature (London)
Main 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, Chaligné, R, Sanchez-Vega, F, Sharma, R, Pe'er, D, Ganesh, K
Format:	Journal Article
Language:	English
Published:	England 30-10-2024
Online Access:	Get full text
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Summary:	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 death . 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 resistance . 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-024-08150-0