ArticleGut2023
Lysosomal lipid switch sensitises to nutrient deprivation and mTOR targeting in pancreatic cancer.
Article in Gut, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed, 31 citations in OpenAlex.
- PI3K/AKT signaling pathway: molecular crossroads in tumorigenesis and therapeutic innovation.Signal transduction and targeted therapy · 2026Review
- Multilayered control of mRNA delivery to cell protrusions drives localized mini-cytoplasm establishment for stress-induced cell activation.Nature communications · 2026Article
- The RNA methylation modification as an immunometabolic regulatory hub in pancreatic cancer: from mechanistic insights to clinical translation perspectives.Molecular cancer · 2026Review
- Targeting the ferritinophagy-lysosome axis as a therapeutic vulnerability in gastroenteropancreatic neuroendocrine tumors.Cell reports. Medicine · 2026Article
- Metabolic plasticity in pancreatic ductal adenocarcinoma progression and response to treatment.Molecular cancer · 2026Review
- GOT1 Inhibition Induces Extracellular Matrix Remodeling in Pancreatic Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Induced mitochondrial deficit by NDUFS3 transient silencing reduces RAB7 expression and causes lysosomal dysfunction in pancreatic cancer cells.Cell communication and signaling : CCS · 2025Article
- Adaptation mechanisms in cancer: Lipid metabolism under hypoxia and nutrient deprivation as a target for novel therapeutic strategies (Review).Molecular medicine reports · 2025Review
- G3BP2 promotes tumor progression and gemcitabine resistance in PDAC via regulating PDIA3-DKC1-hENT in a stress granules-dependent manner.Acta pharmacologica Sinica · 2025Article
- Demystifying metabolic‒immune crosstalk: how amino acid metabolic reprogramming shapes the malignant phenotype and macrophage polarization of biliary and pancreatic tumors.International journal of biological sciences · 2025Review
- Polyphenols in Pancreatic Cancer Management: Exploring the Roles and Mechanisms of Resveratrol and Epigallocatechin.Oncology research · 2025Review
- A lipid metabolism and lysosome-based risk signature for prognosis and immune response prediction in uterine corpus endometrial carcinoma.Frontiers in genetics · 2025Article
- Characterization of Chemoresistance in Pancreatic Cancer: A Look at MDR-1 Polymorphisms and Expression in Cancer Cells and Patients.International journal of molecular sciences · 2024Article
- Emerging mechanisms and promising approaches in pancreatic cancer metabolism.Cell death & disease · 2024Review
- The lncRNA LINC01605 promotes the progression of pancreatic ductal adenocarcinoma by activating the mTOR signaling pathway.Cancer cell international · 2024Article
- Dysregulation of a Subset of Circulating and Vesicle-Associated miRNA in Pancreatic Cancer.Non-coding RNA · 2024Article
- Mutant KRAS Mediates circARFGEF2 Biogenesis to Promote Lymphatic Metastasis of Pancreatic Ductal Adenocarcinoma.Cancer research · 2023Article
- The Glutaminase-1 Inhibitor [Pharmaceuticals (Basel, Switzerland) · 2023Article
- Targeting Class I-II-III PI3Ks in Cancer Therapy: Recent Advances in Tumor Biology and Preclinical Research.Cancers · 2023Review
- Review
Corrections and comments
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Authors and funding
24 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectivePancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited therapeutic options. However, metabolic adaptation to the harsh PDAC environment can expose liabilities useful for therapy. Targeting the key metabolic regulator mechanistic target of rapamycin complex 1 (mTORC1) and its downstream pathway shows efficacy only in subsets of patients but gene modifiers maximising response remain to be identified.
designThree independent cohorts of PDAC patients were studied to correlate PI3K-C2γ protein abundance with disease outcome. Mechanisms were then studied in mouse (KPC mice) and cellular models of PDAC, in presence or absence of PI3K-C2γ (WT or KO). PI3K-C2γ-dependent metabolic rewiring and its impact on mTORC1 regulation were assessed in conditions of limiting glutamine availability. Finally, effects of a combination therapy targeting mTORC1 and glutamine metabolism were studied in WT and KO PDAC cells and preclinical models.
resultsPI3K-C2γ expression was reduced in about 30% of PDAC cases and was associated with an aggressive phenotype. Similarly, loss of PI3K-C2γ in KPC mice enhanced tumour development and progression. The increased aggressiveness of tumours lacking PI3K-C2γ correlated with hyperactivation of mTORC1 pathway and glutamine metabolism rewiring to support lipid synthesis. PI3K-C2γ-KO tumours failed to adapt to metabolic stress induced by glutamine depletion, resulting in cell death.
conclusionLoss of PI3K-C2γ prevents mTOR inactivation and triggers tumour vulnerability to RAD001 (mTOR inhibitor) and BPTES/CB-839 (glutaminase inhibitors). Therefore, these results might open the way to personalised treatments in PDAC with PI3K-C2γ loss.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.