MAN1A1 promotes colorectal cancer liver metastasis by maintaining TGFBR2 protein stability

Abstract

Emerging biochemical and genetic evidence has firmly established aberrant protein glycosylation as a critical regulator of oncogenic transformation, with glycocalyx remodeling profoundly influencing tumor microenvironment dynamics and metastatic progression. Despite the well-documented association between metastatic dissemination and poor clinical outcomes in patients with colorectal cancer, the underlying molecular mechanisms remain incompletely characterized. Through integrative analysis of single-cell RNA sequencing data from a public database, we identify the Golgi-resident α-1,2-mannosidase MAN1A1 as a consistently upregulated enzyme in malignant epithelial cells derived from colorectal cancer liver metastases. Clinically, elevated MAN1A1 expression is correlated with reduced overall survival, suggesting that MAN1A1 is both a prognostic biomarker and therapeutic target for colorectal cancer liver metastases. Genetic manipulation of MAN1A1 in colorectal cancer cells demonstrates that although the proliferation capacity of colorectal cancer cells remains unchanged, MAN1A1 overexpression significantly enhances migratory and invasive capacities in transwell assays, suggesting its specific involvement in metastatic progression. Mechanistic investigations reveal that MAN1A1 exerts its pro-metastatic effects by significantly prolonging the TGFBR2 protein half-life. Together, our work identifies MAN1A1 as both a prognostic biomarker and a promising therapeutic target, highlighting the critical role of glycan remodeling in the metastatic progression of colorectal cancer.

1. Introduction

Colorectal cancer (CRC), which ranks as the second deadliest and third most commonly diagnosed malignancy worldwide, constitutes a substantial global health burden [1,2]. In recent years, substantial progress has been made in CRC management, marked by both the development of novel therapeutic modalities and the widespread adoption of organized screening programs, which have collectively contributed to earlier disease detection and improved survival outcomes [3–5]. As the primary destination for hematogenous spread in CRC, the liver renders CRC-associated hepatic metastases a critical obstacle in clinical treatment [6–9]. The clinical management of distant metastases remains a significant therapeutic challenge, with only 15%–20% of patients with colorectal liver metastases (CRLMs) meeting eligibility criteria for curative-intent surgical resection. The remaining majority of patients face dismal 5-year survival rates of less than 10%, with hepatic involvement representing the principal determinant of CRC-specific mortality [10].

The progression and metastatic dissemination of CRC are orchestrated by the dynamic interplay between multifaceted regulatory networks. Notably, aberrant glycosylation has been established as a molecular hallmark of malignant transformation, where cancer-associated metabolic reprogramming, dysregulated glycan precursor biosynthesis, and epigenetic alterations in glycosyltransferase expression collectively generate a metastasis-competent glycophenotype [11,12]. Inhibiting the biosynthesis of glycans on tumor cell surfaces exerts dual anti-tumor effects through distinct yet complementary mechanisms: disrupted glycoprotein processing triggers endoplasmic reticulum (ER) stress-mediated apoptosis, whereas the unmasking of tumor-associated antigens (TAAs) enhances immune recognition and clearance, collectively reversing immune suppression [13–15]. Clinical proteomics has revealed cancer-type-specific glycosignatures: fucosylated glycoconjugates are associated with triple-negative breast cancer, whereas high-mannose clusters characterize glioma recurrence and metastases in cholangiocarcinoma [16].