Biology subjects

Ialchina, R.

Publications and source records attributed to Ialchina, R..

3 recordsLinked to original sources

bioRxiv2026

Glucose derived redox equivalents preserve PKA activity and glucagon secretion during hypoglycaemia

The release of glucagon from pancreatic alpha cells is a core component of hypoglycaemic counter regulation. Several mechanisms regulate glucagon release including paracrine control by neighbouring cell types, and changes in extracellular glucose. While the inhibitory effect of glucose on glucagon secretion is well established, the exact way in which glucose metabolism contributes to alpha cell function remains unclear. Here, we use live-cell imaging of the redox potential in alpha cells within intact islets to investigate whether non-mitochondrial glucose metabolism contributes to the potentiation of glucagon secretion at low glucose. Our findings show that increased glucose metabolism through the pentose phosphate pathway elevates the cytosolic redox potential in alpha cells. Using a combination of antioxidant treatment and pre-incubation in 5 mM glucose, we find that the cytosolic redox potential affects PKA activity in alpha cells and that changes in whole body redox state affects the counterregulatory response in mice. These findings indicate that prior glucose-driven redox potential charging is essential for maintaining glucagon secretion at low glucose.

physiology↗

bioRxiv2024

Tumor microenvironment acidosis favors pancreatic cancer stem cell properties and in vivo metastasis

The acidic tumor microenvironment favors cancer aggressiveness via incompletely understood pathways. Here, we asked whether acidic environments select for cancer stem cell (CSC) properties. Bulk RNA-seq of Panc-1 human pancreatic cancer cells adapted to extracellular pH 6.5 revealed upregulation of CSC markers including CD44, EpCam, Nestin and aldehyde dehydrogenases, and CSC pathway enrichment. We therefore assessed CSC characteristics of acid-adapted (AA) and non-adapted (Ctrl) PaTu8988s and MiaPaca-2 pancreatic cancer cells. Compared to Ctrl, AA cells exhibited increased ALDH- and {beta}-catenin activity and pancreatosphere-forming efficiency, classical CSC characteristics. Panc-1, PaTu8988s and MiaPaCa-2 AA cells differed in CSC marker expression, and AA cells did not exhibit typical flow cytometric CSC populations. However, single-nucleus sequencing identified the acid adaptation-induced emergence of a population with clear CSC characteristics. Finally, in an orthotopic mouse model, AA Panc-1 cells drove strongly increased aggressiveness and liver metastasis compared to Ctrl cells. We conclude that acid-adaptation of pancreatic cancer cells leads to enrichment of a CSC phenotype with unusual traits, providing new insight into how acidic tumor microenvironments favor cancer aggressiveness.

cancer biology↗

bioRxiv2023

Adaptation to an acid microenvironment promotes pancreatic cancer organoid growth and drug resistance in a p53-dependent manner

The harsh environments in poorly perfused tumor regions have been proposed to select for traits that may drive cancer aggressiveness. Here, we tested the hypothesis that tumor acidosis interacts with driver mutations to exacerbate cancer hallmarks, including drug resistance, in pancreatic cancer. We gradually adapted mouse organoids from normal pancreatic duct (mN) and early PDAC (mP, with KRAS G12V mutation and +/- p53 knockout), from pH 7.4 (physiological level) to 6.7, representing acidic tumor niches. Acid adaptation rewired organoid transcriptional activity, increased viability and, strikingly, increased Gemcitabine- and Erlotinib resistance. Importantly, this response only occurred in organoids expressing wild-type p53 and was most pronounced when acid-adapted cells were returned to physiological pH (mimicking increased perfusion or invasion). While the acid adaptation transcriptional change was overall not highly similar to that induced by drug adaptation of the organoids, acid adaptation induced expression of cytidine deaminase (Cda) and ribonucleotide reductase regulatory subunit M2 (Rrm2), both associated with Gemcitabine resistance, and inhibition of these proteins partially restored Gemcitabine sensitivity. Thus, adaptation to the acidic tumor microenvironment increases drug resistance even after cells leave this niche, and this is in part dependent on acid-adaptation-induced transcriptional upregulation of Cda and Rrm2.

cancer biology↗