Multi-omics analysis of patient-derived organoids reveals that E3 ligase COP1 promotes liver metastasis and oxaliplatin resistance in colorectal cancer through LUZP1 degradation and MYL9 phosphorylation.

Abstract

Colorectal cancer liver metastasis (CRLM) and chemotherapy resistance remain major clinical challenges, with the underlying molecular mechanisms yet to be fully elucidated. In this study, based on analyses of five initial clinical cohorts from FUSCC, the E3 ubiquitin ligase COP1 was identified as a critical driver of CRLM and resistance to oxaliplatin-based chemotherapy. Using an organoid biobank derived from paired primary colorectal tumors and liver metastases, integrated multi-omics analyses (WES, bulk RNA-seq, scRNA-seq) of patient-derived organoids (PDOs) from CRLM revealed significantly elevated COP1 expression in liver metastases compared to primary tumors. High COP1 levels were associated with poor prognosis, increased liver metastatic burden, and resistance to oxaliplatin-based chemotherapy. In vitro and in vivo functional experiments demonstrated that COP1 facilitates CRLM progression by ubiquitinating and degrading LUZP1, thereby releasing DAPK3 from LUZP1-mediated suppression. This process leads to enhanced MYL9 phosphorylation and activation of epithelial-mesenchymal transition (EMT) as well as the JAK2-STAT3-CCND2 signaling axis-pathways crucial for liver metastasis and resistance to oxaliplatin-based chemotherapy. These findings establish the COP1-LUZP1-MYL9 axis as a therapeutic target for CRLM and oxaliplatin-based chemoresistance. Clinically, COP1 expression profiling in PDOs from postoperative specimens enables a precision strategy for managing oxaliplatin-based chemoresistance, especially in the context of FOLFOX.