Loss of ALK4 promotes cancer progression through regulating TGF-β receptor N-glycosylation

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• The transforming growth factor-β (TGF-β) pathway plays a dual role in cancer, inhibiting initial tumor formation but promoting metastasis later.
• Activin receptor-like kinase 4 (ALK4), a TGF-β family receptor, is often lost or mutated in cancers, correlating with poor patient outcomes.
• The precise role and molecular mechanisms of ALK4 in cancer progression are not fully understood.

Purpose of the Study:

• To investigate the function and mechanism of ALK4 in cancer progression.
• To elucidate how ALK4 loss influences TGF-β signaling pathways.
• To identify potential therapeutic targets based on ALK4's role in cancer.

Main Methods:

• In vitro assays assessing anchorage-independent growth, migration, invasion, and epithelial-mesenchymal transition.
• In vivo studies using breast and pancreatic cancer models.
• Analysis of TGF-β receptor N-linked glycosylation and cell surface stabilization.
• Investigation of the roles of β1,6 N-acetylglucosaminyltransferase V (MGAT5) and galectin-3.

Main Results:

• ALK4 loss significantly enhanced cancer cell growth, migration, invasion, and epithelial-mesenchymal transition in vitro.
• ALK4 deficiency promoted tumor progression in vivo in breast and pancreatic cancer models.
• ALK4 loss led to increased N-linked glycosylation and cell surface stabilization of TGF-β receptors.
• Upregulation of MGAT5 and galectin-3 by ALK4 loss was identified as a key mechanism promoting receptor stabilization and TGF-β signaling.

Conclusions:

• Loss of ALK4 expression drives cancer progression and metastasis by enhancing canonical TGF-β signaling.
• The mechanism involves increased MGAT5-mediated glycosylation and galectin-3 binding, stabilizing TGF-β receptors at the cell surface.
• Targeting MGAT5 or N-glycosylation represents a potential therapeutic strategy to counteract ALK4-loss-induced cancer progression.