Contribution of fatty acid metabolism to the advanced and metastatic phenotype of pancreatic cancer
Worldwide Cancer Research
Instituto de InvestigaciÃ³n Sanitaria AragÃ³n
Pancreatic Ductal Adenocarcinoma (PDAC) is an extremely lethal disease due to the current lack of effective therapies and extreme malignancy of the tumours once diagnosed. We have recently shown that PDAC is hierarchically organised with Cancer Stem Cells (CSCs) constituting a major source for disease progression, including metastasis and relapse following chemotherapy. Interestingly, increased lipid scavenging and aberrant fatty acid metabolism have been linked to pancreatic tumour progression and poor prognosis in PDAC patients. We have recently reported that, in contrast to differentiated tumour cells, pancreatic CSCs are highly dependent on mitochondrial oxidative phosphorylation (OXPHOS, Sancho et al, Cell Metabolism 2015). This metabolism confers the ability of using a wider range of substrates able to feed the TCA cycle, including fatty acids. Now, our preliminary results indicate that: 1) CSCs store and metabolise fatty acids for full tumorigenic capacity; 2) Energy deprivation promotes a highly dedifferentiated and aggressive phenotype through PPARdelta. We hypothesise that CSCs are able to modulate lipid storage/utilisation conferring them with high resilience and plasticity to adapt to the changing and challenging conditions during tumour progression and metastasis. Thus, in the present project we aim to analyse the specific role of fatty acid metabolism in the advanced and metastatic phenotype of PDAC by addressing the following three aims: 1. To study the role of lipid uptake and storage in CSCs to cope with situations of metabolic stress. 2. To investigate the role of PPARd in the acquisition of an advanced/metastatic phenotype in pancreatic cancer 3. To validate new therapeutic strategies targeting lipid metabolism Our ultimate aim is to identify and validate most effective CSC-targeting strategies with great translational potential, to improve the still miserable prognosis of PDAC patients.
2.1 Biological and endogenous factors