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

Table 4 Major controversies and priority future directions in the ras homolog enriched in brain-colony stimulating factor 1 receptor-autophagy field

Key question	Current evidence	Major limitation	Why it matters	Priority next step
Is tumor-cell CSF1R broadly reproducible in PDAC	Recent work suggests that tumor-cell CSF1R may participate in metastatic signaling	CSF1R is classically macrophage-enriched, and tissue-level reproducibility remains uncertain	Determines whether this reflects a tumor-cell mechanism, a microenvironmental signal, or both	Spatially resolved validation using multiplex IF, RNAscope, or scRNA-seq[65]
Is autophagy suppressive or permissive for PDAC metastasis	Available evidence supports a context-dependent dual role of autophagy in PDAC progression[34,35]	Stage, treatment context, and model system can alter interpretation	Directly affects therapeutic strategy	Phenotype-linked, context-aware autophagy studies
Are class I and class III PI3K being conceptually conflated	Class I PI3K–AKT–mTOR signaling is generally linked to autophagy suppression, whereas class III PI3K/VPS34 is required for autophagosome initiation	Many studies refer broadly to PI3K without class-specific clarification	Prevents mechanistic overstatement and improves pathway precision	Class-specific wording and validation
Can RHEB-based signatures improve risk stratification	RHEB is associated with poor prognosis in PDAC datasets and functional models[12]	Existing cohorts remain limited and require independent confirmation	Essential for biomarker development and clinical risk stratification	External validation with C-index, calibration, and time-dependent ROC analysis
What is the most rational translational strategy	CSF1R/TAM, PI3K/mTOR, and autophagy are all targetable in principle	Single-pathway strategies may be insufficient in a highly adaptive tumor	Guides clinical trial design	Evaluate mechanism-driven combinations, including CSF1R-directed therapy with chemotherapy, immunotherapy, or pathway-targeted agents[25,63]

RHEB: Ras homolog enriched in brain; CSF1R: Colony stimulating factor 1 receptor; PDAC: Pancreatic ductal adenocarcinoma; AKT: Protein kinase B; PI3K: Phosphatidylinositol 3-kinase; mTOR: Mammalian target of rapamycin; TAM: Tumor-associated macrophage; IF: Immunofluorescence; VPS34: Vacuolar protein sorting 34; scRNA-seq: Single cell RNA sequencing; ROC: Receiver operating characteristic.