Abstract. Aging is a critical yet understudied determinant in pancreatic ductal adenocarcinoma (PDAC) risk and outcomes. Despite a strong epidemiological association with age, conventional PDAC precli...

Cancer cells undergo metabolic reprogramming to sustain their energy demands, and favor glycolysis despite the presence of functional mitochondria. This metabolic shift leads to the rapid production of lactate and protons. If not managed, this accumulation of acidic byproducts would lower the intracellular pH (pHi). To counteract this, cancer cells employ diverse mechanisms to extrude excess protons through membrane transporters, and also sequester them within acidic organelles. Consequently, an alkaline pHi provides cancer cells with a survival advantage by promoting their proliferation, migration, and resistance to cell death. Given the role of organellar acidification in sustaining this altered pH balance, targeting this process represents a potential therapeutic vulnerability in cancer. We explore the mechanisms by which cancer cells maintain pH homeostasis, with a particular focus on organellar pH and its impact on tumor progression. In addition, we assess inhibitors of the key transporters involved in organellar acidification and discuss their therapeutic potential in cancer.

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Abstract. Epigenomic dysregulation is widespread in cancer. However, the specific epigenomic regulators and the processes they control to drive cancer phenotypes are poorly understood. We employed a n...

PI5P4Kα is a critical metabolic gatekeeper in PDAC, promoting glucose and iron acquisition to support tumor survival. Arora et al. demonstrate that PI5P4Kα suppression disrupts the metabolic flexibili...

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Zhang et al. demonstrate that macropinocytosis inhibition induces myCAF-to-iCAF conversion through a metabolically stressed, MEK-ERK-dependent intermediate state. This CAF plasticity remodels the pancreatic tumor microenvironment and improves responses to immunotherapy and chemotherapy, supporting macropinocytosis inhibition as a promising approach for combination treatment strategies in pancreatic cancer.

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Pancreatic ductal adenocarcinoma (PDAC) tumors are glutamine deficient, and both tumor cells and cancer-associated fibroblasts (CAFs) rely on this ami…

In this Perspective, Lazure and Gomes argue that metabolic changes that occur as a result of ageing may shape tumour initiation and progression and the development of metastatic disease.

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer for which there is a critical need to identify novel therapeutic targets. Herein we define PSGL-1 as a checkpoint inhibitor using a syngeneic...

PCSK9 regulates low density lipoprotein-cholesterol import and determines organ preference of metastatic pancreatic ductal adenocarcinoma, with PCSK9-low cells metastasizing to the liver and PCSK9-hig...

Aging is a critical yet understudied determinant in pancreatic ductal adenocarcinoma (PDAC). Despite a strong epidemiological association with age, conventional PDAC preclinical models fail to capture...

Secretion of ligands of the human epidermal growth factor (EGFR) family of receptors or erythroblastic leukemia viral oncogene family (ERBB1-4) is a feature common to many cancer cells. However, our u...