bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.09.14.676164

Glycolysis-stratified coordination of fatty acid and glutamine metabolism in pancreatic ductal adenocarcinoma

Fareed, S.
View original source ↗Export metadata ↓

Abstract

BackgroundPancreatic ductal adenocarcinoma (PDAC) is highly lethal and characterized by profound metabolic rewiring. Prior work, including evidence that ketogenic diet (KD) exposure can increase tricarboxylic acid (TCA) activity and glutamine (GLN) dependence and sensitize PDAC to GLN-targeting strategies, suggests that fatty acid (FA) availability may modulate GLN utilization. However, it remains unclear how FA-GLN metabolic coordination varies across tumor glycolytic states and FA classes. ObjectiveTo quantify how FA-GLN coordination varies across PDAC glycolysis tertiles and FA classes (lipid families and chain-length enzyme classes). MethodsRNA-seq and clinical data from a multi-institutional PDAC cohort (n=172) were analyzed to quantify FA and GLN pathway activities using single-sample gene set scoring (GSVA-derived pathway activity scores), followed by stratification of tumors into low, medium, and high glycolysis tertiles using ssGSEA-derived glycolysis scores. FA-GLN associations were evaluated at pathway, enzyme-class (medium-, long-, and very-long-chain FA; VLCFA [≥] C20), and family levels using correlation, Fisher-z meta-analysis, and bootstrap resampling. Family-level contrasts were used to compare FA-GLN coupling between glycolysis strata, and complementary metabolite-inference analyses were performed (n=173) to define metabolite-based tumor phenotypes. Protein-level validation was conducted in an independent PDAC proteomic cohort. ResultsFA-GLN coordination was strongly context-dependent: membrane-focused lipid families--glycerophospholipids (GPL) and sphingolipids (SP)--showed the strongest GLN coupling in glycolysis-low tumors, whereas coupling shifted toward VLCFA enzyme classes in glycolysis-medium tumors and weakened in glycolysis-high tumors. Family-level contrasts confirmed significantly weaker GPL-GLN and SP-GLN associations in high versus low glycolysis. Metabolite-inference analyses identified three metabolic phenotypes that preserved this glycolysis-stratified FA-GLN hierarchy, and protein-level analysis in the CPTAC PDAC cohort partially recapitulated preferential SP-GLN coordination in less glycolytic tumors. Survival analyses suggested glycolysis-state- and chain length-specific trends in FA-linked pathways. ConclusionsTogether, these findings delineate a glycolysis-stratified map of FA-GLN coordination in PDAC and nominate conditional metabolic vulnerabilities with potential therapeutic and dietary relevance. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/676164v7_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@18d1d4corg.highwire.dtl.DTLVardef@17ea4dforg.highwire.dtl.DTLVardef@17a2e43org.highwire.dtl.DTLVardef@7369e2_HPS_FORMAT_FIGEXP M_FIG Conceptual overview illustrating how coordinated fatty-acid and glutamine metabolism shifts across glycolysis-low, medium, and high PDAC tumors, highlighting FA family and chain length-specific metabolic dependencies. C_FIG

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Fareed, S.. 2025-09-17. Glycolysis-stratified coordination of fatty acid and glutamine metabolism in pancreatic ductal adenocarcinoma. https://doi.org/10.1101/2025.09.14.676164

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Tissue resident CD4+ memory T-cells mark response to immune checkpoint inhibition in high-grade glioma

Background: Immune checkpoint inhibitors (ICI) are efficacious in many solid tumors, but response in glioma is restricted to a small subgroup. The determinants of response and resistance to ICI remain poorly understood. Methods: Here we exploit a syngeneic hypermutated high-grade glioma model with dichotomous response to combined PD-1 and CTLA-4 inhibition to unravel determinants of tumor-infiltrating T-cells driving response. Tumor-infiltrating T-cells from ICI-responsive and non-responsive tumors were analyzed by single-cell RNA and T-cell receptor sequencing and tumor-reactive T-cell receptor clonotypes were functionally validated to characterize their transcriptional phenotypes. We verify our findings in IDH1 wildtype glioblastoma patients treated with neoadjuvant pembrolizumab. Results: ICI response was associated with intratumoral clonal expansion of tumor-reactive cytotoxic T-cells and increased infiltration of CXCR6+ CD4+ tissue resident memory T-cells (Trm). CD4 stem-like memory T-cells in responding tumors demonstrated elevated interferon responses, following trajectories toward clonally expanded Trm, versus trajectories toward exhaustion in non-responsive tumors. In responsive tumors, CD4+ Trm interacted with infiltrating CXCR3+ tumor-reactive and clonally expanded, yet transcriptionally versatile cytotoxic T-cells. Probing the post neoadjuvant ICI high-grade glioma patient tissue dataset, we confirmed increased CXCR6 expression in CD4+ T cells and the association of CD4+ Trm with prolonged overall survival. Conclusion: These findings identify CD4 tissue-resident memory T-cells as determinants of ICI response in IDH1 wildtype high-grade glioma and warrant their further investigation to improve immunotherapy outcomes.

cancer biology↗
bioRxiv2026

Circadian gene-network distortion in high-risk neuroblastoma across multiple biological reference contexts

Background: The circadian clock regulates cellular homeostasis, and its disruption has been implicated in aggressive neuroblastoma, particularly in tumours harbouring MYCN- amplification. However, it remains unclear whether alterations are restricted to individual clock genes or extend to circadian gene network coordination. We therefore examined circadian clock network disruption in adverse neuroblastoma across multiple biological contexts. Methods: We estimated circadian gene network dysregulation using Delta-CCD in tumours from two neuroblastoma cohorts (SEQC n=498 and Kocak n=649), comparing clinical features associated with outcome across canonical, adrenal-tissue matched, and developmental references. Robustness was assessed by cross-cohort meta-analysis and leave-one-gene-out analyses. Cox proportional hazards models adjusted for clinical covariates assessed association between individual clock gene expression patient outcome. Results: Delta-CCD was highest in tumours classified as high-risk (study-specific definition) across reference contexts in both cohorts. MYCN-amplified tumours showed a more reference-dependent pattern, strongest in adrenal context, while stage 4 tumours showed a similar but weaker pattern. Additional analyses supported the high-risk signal as a distributed network-level alteration rather than a single-gene phenomenon. Conclusions: High-risk neuroblastoma is characterised by robust disruption of coordinated clock gene network organisation across canonical and tissue-matched references, extending beyond individual clock genes. The extent of circadian dysregulation depends on the reference state used.

cancer biology↗
bioRxiv2026

BAP1 loss and PRAME expression converge to remodel the tumor-immune ecosystem during uveal melanoma progression

Uveal melanoma (UM) is characterized by a small number of recurrent genetic alterations that determine metastatic propensity. BAP1 loss and PRAME expression define the dominant prognostic axes in UM, yet how they promote malignant progression remains unclear. We profiled 190,535 cells from normal uvea, uveal nevus, primary and metastatic UM using single-cell transcriptomics, T cell receptor sequencing, spatial transcriptomics and isogenic perturbation models. Normal melanocytes, nevus cells and UM cells formed a transcriptional continuum marked by loss of differentiation and emergence of neural crest-like, stress-responsive, hypoxic-glycolytic and immune-interacting states. BAP1 loss and PRAME expression imposed distinct but convergent immunoregulatory programs, inducing interferon and TNF-NFkB signaling and MHC-I expression, with HLA-E showing the strongest response. These alterations were accompanied by macrophage and CD8+ T cell remodeling. PRAME-enriched tumor regions formed spatially organized niches enriched for macrophages and plasma cells. These findings define BAP1 loss and PRAME expression as distinct but convergent axes of tumor-immune coevolution and nominate HLA-E as a candidate mediator of immune resistance.

cancer biology↗