Progressive plasticity during colorectal cancer metastasis

• 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
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-024-08150-0

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.