Colorectal cancer (CRC) remains one of the most heterogeneous malignancies, with substantial variability in molecular characteristics, therapeutic response, and clinical outcomes.

Among the four consensus molecular subtypes (CMS1–CMS4), each defined by distinct biological and clinical features, CMS4 - the mesenchymal subtype - is characterized by the most aggressive disease progression, extensive stromal infiltration, and a markedly poor prognosis.

Despite advances in transcriptomic profiling, the clinical implementation of CMS classification remains limited due to the lack of robust and clinically accessible biomarkers capable of accurately distinguishing these subtypes.

In a recent Genes & Diseases study, researchers from Chinese Academy of Medical Sciences and Peking Union Medical College identified plexin C1 (PLXNC1) as a novel biomarker strongly associated with CMS4 CRC and demonstrated its critical role in promoting tumour progression, metastasis, and immune evasion.

A combination of bioinformatic analysis and experimental validation revealed that PLXNC1 mRNA and protein levels are significantly upregulated in CRC tissues relative to adjacent normal tissues.

Data from the Oncomine database and CPTAC, alongside validation via tissue microarrays, confirmed that elevated PLXNC1 expression serves as an independent risk factor for poor overall survival.

Transcriptomic analyses further revealed that PLXNC1 expression was highly enriched in CMS4 tumours, allowing efficient discrimination of this subtype from other CRC molecular subgroups; while ROC analysis across multiple independent datasets demonstrated that PLXNC1 possesses high sensitivity and specificity in identifying CMS4 tumours, often outperforming traditional staging methods.

To characterize the biological landscape associated with PLXNC1 expression, the authors employed bulk and single-cell RNA sequencing datasets together with tumour microenvironment deconvolution algorithms.

CRC tumours with high PLXNC1 expression exhibited a pronounced mesenchymal phenotype, accompanied by elevated stromal infiltration, ECM remodeling, angiogenesis, complement activation, and an immunosuppressive tumour microenvironment, highlighting PLXNC1’s role in facilitating metastasis and immune escape.

Functional experiments further validated the oncogenic role of PLXNC1 in CRC progression. In vitro proliferation, migration, and invasion assays showed that PLXNC1 significantly enhanced malignant cellular behaviors, whereas PLXNC1 knockdown suppressed tumour cell growth, migration, and invasiveness.

Complementary in vivo studies using subcutaneous xenograft and liver metastasis mouse models confirmed that PLXNC1 promoted tumour growth and metastatic colonization.

RNA-seq analyses showed that PLXNC1 regulates multiple pathways involved in EMT, stromal remodelling, and immune suppression, thereby reinforcing CMS4-associated phenotypes.

Through co-culture experiments and in vivo immune analyses, the researchers showed that PLXNC1 impaired the cytotoxic activity of CD8⁺ T cells, thereby facilitating immune escape and tumour progression.

This suggests that PLXNC1 not only contributes to the intrinsic aggressiveness of CRC cells but also shapes an immunosuppressive microenvironment that protects tumours from immune-mediated elimination.

Overall, the study establishes PLXNC1 as a promising biomarker and therapeutic target for CMS4 colorectal cancer, providing new insights into the molecular mechanisms underlying tumour aggressiveness, metastasis, and immune suppression in high-risk CRC.

Source: Compuscript Ltd