FBXW7 suppresses gastric cancer development and progression via ubiquitination-mediated degradation of MMP2.

Background: Gastric cancer (GC) remains a major cause of cancer-related mortality, highlighting the need to clarify the stromal and post-translational mechanisms underlying its progression.

Methods: We integrated single-cell RNA sequencing, independent transcriptomic cohorts, clinical tissue analyses, functional assays, co-immunoprecipitation (Co-IP), multiple immunofluorescence labeling, and a xenograft model to investigate the cellular distribution, biological function, and mechanisms of regulation for matrix metalloproteinase 2 (MMP2) in GC.

Results: Single-cell analysis of paired tumor and adjacent normal tissues suggested an increased relative abundance of fibroblast populations and higher extracellular matrix-associated activity in GC tissues. MMP2 was preferentially expressed in cancer-associated fibroblasts, particularly in transcriptionally defined universal fibroblast-like and myofibroblastic CAF states. Trajectory analysis further suggested that the MMP2-high universal fibroblast-like population occupies an early and potentially transitional position along the fibroblast-state continuum. These findings were supported by an independent single-cell dataset, TCGA-STAD analysis, and tissue staining. In CAF-gastric cancer cell co-culture assays, CAFs enhanced tumor-cell migration and invasion, while modulation of the FBXW7-MMP2 axis altered these phenotypes. MMP2 overexpression promoted GC cell proliferation, migration, and invasion, whereas MMP2 silencing had the opposite effects. Mechanistically, FBXW7 interacted with the intracellular pool of MMP2, enhanced its K48-linked polyubiquitination, and reduced MMP2 protein stability through a proteasome-dependent process. FBXW7 overexpression attenuated MMP2-associated malignant phenotypes in vitro and restrained MMP2-driven tumor growth in vivo. Clinical tissue analyses further showed an inverse association between FBXW7 and MMP2 expression, while elevated MMP2 was associated with unfavorable survival.

Conclusion: Our findings identify MMP2-high fibroblast states as an important stromal feature of GC and reveal FBXW7-associated regulation of intracellular MMP2 stability as a potential therapeutic vulnerability.