Advisory Committee Chair
Bim Ren
Advisory Committee Members
Adam Beck
Herbert Chen
Anita Hjelmeland
Palaniappan Sethu
Mary Kathryn Sewell-Loftin
Document Type
Dissertation
Date of Award
2022
Degree Name by School
Doctor of Philosophy (PhD) School of Engineering
Abstract
Cancer stem cells (CSCs) are a subpopulation cancer cells that play critical roles in tumor progression, recurrence, metastasis, and drug resistance. CSCs are characterized by self-renewal and plasticity. Protein kinase D-1 (PKD-1) signaling regulates CSC/stemness features in both breast cancers and pancreatic neuroendocrine tumors. In PNETs, PKD-1 signaling regulates not only stemness properties of cancer, but also epithelial-mesenchymal transition (EMT). PNETs are typically well vascularized and heterogeneous. Everolimus (an mTOR inhibitor and the 2nd generation derivative of rapamycin) has been approved as a targeted chemotherapy for PNET patients. Unfortunately, nearly all patients will progress on treatment due to drug resistance to everolimus. We recently observed that rapamycin resistant PNET cells acquire CSC features with high expression of PKD-1 and CD36. CD36 as a fatty acid receptor and scavenger receptor drives stemness feature and promote metastatic potential of CSCs in several types of cancers. CD36-mediated lipid metabolism promotes drug resistance properties in CSCs. By importing free fatty acid (FFA) as a fuel for lipid metabolism in the cells via CD36, tumor cells may demonstrate CSC features and drug resistance. We found out that PKD-1 signaling promoted CSC self- iv renewal via CD36-mediated fatty acid metabolism and likely stimulated arteriolar niche development that nurtures CSCs, thereby conferring PNET resistance to mTOR inhibitors. To further study vascular niches functioning in promoting CSC/stemness properties, we developed a microfluidic device (diamond device) and co-culture approaches to study the mechanism underlying the direct interaction between cancer and endothelial cells (an important component in the vascular niches) within the tumor microenvironment (TME). We observed that PKD-1 in ECs regulated CSC/stemness properties in PNET cells. Furthermore, the stemness properties of PNET induced the EC differentiation.
Recommended Citation
Guo, Yichen Hailey, "PKD-1 Signaling inthe Regulation of Cancer Stem Cell-Like Features and Cancer Cell Interactions with Endothelial Cells in Breast Cancer and Pancreatic Neuroendocrine Tumor" (2022). All ETDs from UAB. 493.
https://digitalcommons.library.uab.edu/etd-collection/493