 Progressive plasticity during colorectal cancer metastasisAndrew Moorman,
Elizabeth K. Benitez,
Francesco Cambulli,
Qingwen Jiang,
Ahmed Mahmoud,
Melissa Lumish,
Saskia Hartner,
Sasha Balkaran,
Jonathan Bermeo,
Simran Asawa,
Canan Firat,
Asha Saxena,
Fan Wu,
Anisha Luthra,
Cassandra Burdziak,
Yubin Xie,
Valeria Sgambati,
Kathleen Luckett,
Yanyun Li,
Zhifan Yi,
Ignas Masilionis,
Kevin Soares,
Emmanouil Pappou,
Rona Yaeger,
T. Peter Kingham,
William Jarnagin,
Philip B. Paty,
Martin R. Weiser,
Linas Mazutis,
Michael D’Angelica,
Jinru Shia,
Julio Garcia-Aguilar,
Tal Nawy,
Travis J. Hollmann,
Ronan Chaligné,
Francisco Sanchez-Vega,
Roshan Sharma,
Dana Pe’er () and
Karuna Ganesh ()
Nature, 2025, vol. 637, issue 8047, 947-954 Abstract: 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. Date: 2025 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:637:y:2025:i:8047:d:10.1038_s41586-024-08150-0 Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-024-08150-0 Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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