Integrative analysis identifies LHFPL6 as a CAF-specific prognostic biomarker in colorectal cancer

TL;DR

This study identifies LHFPL6 as a key biomarker in cancer-associated fibroblasts that predicts poor outcomes in colorectal cancer patients.

Contribution

LHFPL6 is newly identified as a CAF-specific prognostic biomarker with therapeutic potential in colorectal cancer.

Findings

LHFPL6 expression is strongly associated with worse survival outcomes in colorectal cancer patients.

LHFPL6 knockdown reduces tumor cell proliferation, migration, and invasion in co-culture models.

LHFPL6 is predominantly expressed in fibroblasts and correlates with CAF scores and ECM/EMT pathways.

Abstract

Recent studies have emphasized the contributions of cancer-associated fibroblasts (CAFs) to cancer initiation, immune suppression, and treatment resistance. Advancing our molecular understanding of CAFs is therefore crucial to improve outcomes for colorectal cancer (CRC) patients. In this study, integrative analysis of single-cell RNA-sequencing data from GSE166555 and GSE144735 identified ten cellular subpopulations. Consensus clustering exhibited four distinct CAF subtypes, with the C4 subtype showing elevated expression of most CAF-specific genes, and predominant enrichment of stromal activation signatures. Functional enrichment analysis of C4-specific transcripts showed dominant enrichment in extracellular matrix (ECM) remodeling pathways. Univariate Cox regression analysis identified eight survival-critical genes, among which LHFPL6 demonstrated the highest specificity and sensitivity for discriminating C4 (AUC = 0.98). Multiple cohorts further confirmed that higher LHFPL6 expression was associated with worse survival outcomes across diverse clinical endpoints (all p < 0.05). Multivariate Cox regression analysis established LHFPL6 as an independent prognostic factor (HR = 5.889, p = 0.017). Additionally, LHFPL6 was predominantly expressed in fibroblasts and positively correlated with CAF scores. Co-expressed genes of LHFPL6 showed significant enrichment in ECM signatures and epithelial–mesenchymal transition (EMT) pathways. Functional experiments using CAF-tumor co-culture models demonstrated that LHFPL6 knockdown suppressed SW480 malignant behaviors, as evidenced by reduced proliferation, migration, and invasion. This study demonstrates that LHFPL6 serves as a promising prognostic biomarker and potential therapeutic target for CRC.

The online version contains supplementary material available at 10.1007/s10238-025-01954-y.

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