Nature | 脂肪肝“教唆”下的生长模式切换——结直肠癌肝转移异质性的新视角

TL;DR - A Nature paper from Sarah-Maria Fendt's team (VIB, Belgium) reports that liver steatosis drives colorectal cancer liver metastases toward the poor-prognosis "replacement" growth pattern via a fatty-acid → MYC → proline → collagen axis, offering a metabolic explanation for metastasis heterogeneity and a patient-stratification biomarker. (Note: this item is biomedical research, not AI methodology.)

• In two treatment-naive CRC cohorts (155 Erasmus MC + 51 Göttingen), hepatic steatosis was the only patient variable independently associated with increased replacement-type metastases (5-yr OS 44.2% vs 73.4% for encapsulated).
• Mechanism: locally enriched liver-derived fatty acids (not systemic lipid levels) raise acetyl-CoA, increasing MYC K323 acetylation, which stabilizes MYC protein (post-transcriptional, no mRNA change) and transcriptionally activates P5CS/PYCR1/PYCR2 and COL1A1.
• Genetic proof: P5cs silencing abolished steatosis-induced replacement metastases; P5cs overexpression alone tripled them on control diet. Exogenous collagen or COL1A1 overexpression alone could not bypass the proline requirement. Consistent across CMT93, MC38, and CT26 models.
• Translation: MYC inhibitor MYCi975 selectively suppressed replacement-type metastases in vivo and in replacement-derived PDOs/PDX; retrospective analysis of the OMO-103 phase I trial showed response correlated with liver fat content rather than dose, suggesting steatosis as a stratification marker.