Steatosis shapes prognosis-defining liver metastasis heterogeneity in CRC.

Authors

Yiming Peng-Winkler, Xiao-Zheng Liu, Sanne M L Verheul, Charlotte Girondel, Sebastian Igelmann, Sara Marie Rotter, Michail Doukas, Ming Liu, Anke Vandekeere, Mélanie Planque, Juan Fernández-García, Sébastien Tabariès, Marta Buetas-Arcas, Sandra Martínez-Martín, Florian Döbbe, Margherita Demicco, Ines Vermeire, Janine Theile, Johannes Ceuppens, Jonas Haesevoets, Emma Tobarra-López, Dorien Broekaert, Johannes Georg Bode, Tom Luedde, Peter Vermeulen, Daniele V F Tauriello, Raquel Perez-Lopez, Steve Stegen, Laura Soucek, Tiago De Oliveira, Lena-Christin Conradi, Peter M Siegel, Cornelis Verhoef, Sarah-Maria Fendt

Published in

Nature. Jul 01, 2026. Epub Jul 01, 2026.

Abstract

Patients with colorectal cancer (CRC) frequently develop liver metastases^1-3. The prognosis of these patients is skewed by the histopathological heterogeneity of their liver metastases^4,5. Patients with 'replacement' metastases have a 5-year overall survival of less than 44.2%, compared with 73.4% in patients with 'encapsulated' (previously known as desmoplastic) metastases⁵; yet there are currently no approved therapies targeting replacement liver metastases. Here we show that treatment-naive patients with CRC with liver steatosis have an increased occurrence of replacement metastases compared with patients without steatosis. Mechanistically, we find that steatosis-promoted fatty acid oxidation increases formation of replacement metastases by increasing MYC stability through acetylation. In turn, MYC activates proline synthesis, fuelling collagen production, enabling growth of replacement metastases. Targeting MYC, P5CS or COL1A1 suppresses the occurrence and growth of replacement metastases in patient-derived organoids, mouse or patient-derived xenograft models. Spatial metabolite and protein analyses of liver metastases from patients with CRC further support this mechanism. In conclusion, we provide a mechanistic understanding of the emergence of liver metastases with poor prognosis in treatment-naive patients with CRC, identifying potential targets for therapeutic intervention.

PMID:
42386979
Bibliographic data and abstract were imported from PubMed on 02 Jul 2026.

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