RHEB-CSF1R signaling, autophagy, and metastatic plasticity in pancreatic cancer: Current advances, controversies, and translational opportunities

Abstract

A recent study comprehensively described an autophagy-related mechanism in pancreatic cancer in which ras homolog enriched in brain (RHEB) interacts with and upregulates colony stimulating factor 1 receptor (CSF1R), thereby increasing phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin phosphorylation, attenuating autophagy-associated readouts, and promoting epithelial-mesenchymal transition and metastatic behavior. By integrating patient cohorts, public datasets, cell-based assays, co-immunoprecipitation, and an in vivo liver metastasis model, the study advances a potentially actionable biomarker framework and therapeutic hypothesis. In this article, we place these findings within the broader biological context of pancreatic ductal adenocarcinoma and discuss how RHEB-centered signaling may intersect with CSF1R-associated biology, autophagy regulation, and metastatic plasticity. We further highlight key unresolved issues, including validation of tumor-cell CSF1R expression and subcellular localization, rigorous assessment of autophagy flux beyond static markers, and external validation of prognostic performance. Addressing these questions may clarify the biological scope and translational potential of the proposed RHEB-CSF1R-phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin-autophagy axis in pancreatic cancer metastasis.

Keywords: Pancreatic cancer; Ras homolog enriched in brain; Colony stimulating factor 1 receptor; Autophagy; Phosphatidylinositol 3-kinase/protein kinase B/mammalian pathway; Epithelial-mesenchymal transition; Metastasis; Tumor microenvironment

Core Tip: A recent study comprehensively summarized that a tumor-cell ras homolog enriched in brain-colony stimulating factor 1 receptor complex promotes pancreatic cancer metastasis by increasing phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin phosphorylation, suppressing autophagy, and inducing epithelial-mesenchymal transition. Building on this work, the present article discusses how ras homolog enriched in brain-centered signaling may connect tumor-cell metabolic adaptation, macrophage-associated biology, autophagy regulation, and metastatic plasticity in pancreatic ductal adenocarcinoma. We emphasize current advances, major controversies, and translational opportunities, with particular focus on tumor-cell colony stimulating factor 1 receptor, autophagic flux, and biomarker-guided therapeutic development.