p62/SQSTM1 as a regulator of metabolic axis in metastatic pancreatic cancer

• Applicant: Dr. Kivanc Görgülü, Ph.D.
• Subject Area: Gastroenterology ; Endocrinology, Diabetology, Metabolism ; Hematology, Oncology ; Cell Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 492436553

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancer types with its highly desmoplastic microenvironment causing metabolic alterations during cancer development and metastasis. Under low nutrient and oxygen, PDAC cells deploy survival mechanisms including autophagy induction. Therefore, in the last decade autophagic machinery of cancer cells has been thought as a therapeutic vulnerability. But these therapeutic strategies have not been successful so far. Thus, enabling therapeutic efficiency via targeting autophagy might be possible by considering the role of specific autophagy regulators during PDAC development and metastasis. Analysis of patient samples has shown that decreased levels of p62/SQSTM1 were correlated with disease progression. We generated mice that express mutant Kras in primary pancreatic cancer cells and have homozygous deletion of p62 and compared with mice harboring only mutant Kras as controls. Interestingly, increased tumor and metastasis incidence have been observed in the absence of p62. However isolated murine pancreatic cancer cells lacking p62 had decreased proliferation and colony forming capacity. These slowly proliferating p62 deficient cancer cells displayed increased metastatic dissemination in vivo. Reverse-phase protein assay demonstrated that p62 deficiency implies altered mitochondrial morphology. Following, these differences, transmission electron microscopy has shown that loss of p62 caused prominent swelling of mitochondria with increased glycolysis. Building on these findings we strive to elaborate on how p62 regulates metastatic dissemination of pancreatic cancer by focusing on metabolic traits. With the convincing in vivo findings, we aim to analyze how p62 regulates metabolic pathways of PDAC leading to increased metastatic dissemination. Understanding the role of p62 and its implication in metabolic liabilities in PDAC will therefore guide us to identify therapeutic vulnerabilities for the metastatic disease.

• DFG Programme: Research Grants