The interaction between pancreatic stellate cells and tumour during pancreatic cancer

UoM administered thesis: Phd

  • Authors:
  • Ahlam Sultan

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of cancer. It is well known that cancer cell prefers glycolysis as its main metabolic pathway (Warburg effect). In our previous studies, we found that this switch is critical for cancer cells to maintain their intracellular calcium homeostasis because glycolytic ATP is important for fueling PMCA. However, one of the main characteristics of PDAC cells is that it has an abundant stroma. There is an accumulation of evidence suggesting a metabolic cross-talk between cancer cells and their stoma (revere Warburg effect). In this project, we have investigated the effects of cancer-stromal interaction with a focus on pancreatic cancer cell metabolism and metabolic regulation of [Ca2+]i homeostasis by co-culturing PDAC cells (MiaPaCa-2) with pancreatic stellate cells (hPSCs). This has been achieved by testing the relative effect of metabolic inhibitors on cellular ATP and fura-2 Ca2+ overload for both cells in co-culture. Moreover, their metabolic phenotype in co-culture has been determined by using Seahorse flux analyzer. Our results are showing that there was no change in the calcium homeostasis regulation in PDAC cells in co-culture. However, we have found significant changes in their metabolism (increase mitochondrial respiration; decrease glycolysis). We next have identified that citrate is the main metabolite that is secreted by hPSCs to fuel PDAC cells mitochondria and decrease glycolysis by performing a footprint metabolomic analysis of the condition media collected from hPSCs. We have further confirmed that citrate can be taken up and consumed by PDAC cell. More importantly, we have tested the effect of citrate in PDAC cells metabolism and found that it mimics the PDAC cells response in co-culture. These findings elucidate a novel metabolic interaction between PDAC cells and hPSCs where citrate plays a major role in such interaction.

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Original languageEnglish
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Award date3 Jan 2020