Doctor of Philosophy (PhD)
Biochemistry & Molecular Biology
Moorthy P. Ponnusamy
Pancreatic cancer is one of the most lethal of all types of cancer with an overall 5-year survival rate of less than 8%. Cancer cells in pancreatic tumor are heterogeneous, and it is poorly understood which population is most responsible for the cancer initiation, progression and metastasis. Recent studies provide evidence for the existence of a highly tumorigenic and metastatic cells within a heterogeneous tumor known as the cancer stem cells (CSCs). Studies also provided ample evidence for the existence of distinct types of CSC populations in a heterogeneous tumor with type specific genotypic, phenotypic and functional characteristics. But, it is not clear how CSCs are induced, and how these cells are involved in the metastasis process. Several external factors such as cigarette smoking and alcohol consumption have been shown to induce CSCs in lung and breast cancers. Cigarette smoking is also associated with 30% of pancreatic cancer cases. The association of smoking with CSC induction is also well appreciated in lung cancer and other cancers. Based on these studies, we aimed to investigate whether and how cigarette smoke induce CSCs in pancreatic cancer in the first part of my dissertation. My second goal primarily explores the metastatic function of CSCs in pancreatic cancer. Previous studies have shown the existence of distinct CSC populations in a heterogeneous tumor. For instance, breast tumors consist of two distinct CSC populations such as ALDH+ and CD44+CD24-. The study also demonstrated that ALDH+ cells rely on oxidative phosphorylation for their energy needs, whereas CD44+CD24- population rely on glycolysis. Recent studies also proposed the propensity of a specific cancer cell with specific metabolic profile metastasizes to specific organ. For instance, liver has a high glycolytic environment, and a metastatic cell required to be highly glycolytic in nature to overcome the glycolytic barrier in the liver. Based on these studies, we have hypothesized that distinct types of CSC populations with type specific stemness and metabolic profiles metastasize to specific organ. Overall, my dissertation is broadly divided into two major chapters. We experimentally demonstrated that cigarette smoke induces pancreatic CSC populations by activating CHRNA7 mediated FOSL1 signaling. We also demonstrated for the first time that pancreatic tumors consist of distinct sub-types of CSC populations with sub-type specific stem cell and metabolic features. I also experimentally proved that distinct sub-types of CSC populations with type-specific metabolic profiles are involved in organ-specific metastasis. Taken together, our findings demonstrate a clear mechanism of CSC induction. In addition, our investigation suggests the existence of distinct sub-types of CSC populations with specific metabolic, stemness and metastatic profiles. In conclusion, our work provides a solid foundation for the understanding of CSCs in pancreatic cancer thereby opening new avenues for further research in developing CSC-targeted therapy for pancreatic cancer and its metastasis.
Nimmakayala, Rama Krishna, "Induction and metastasis of cancer stem cells in pancreatic cancer" (2019). Theses & Dissertations. 375.