Dissecting the oncogenic and pro-metastatic roles of PTHLH-mediated calcium signaling in pancreatic cancer

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PROJECT SUMMARY Pancreatic cancer is a major health issue in the US, with only 7% of patients surviving beyond 5 years and nearly all patients presenting with metastases. Identifying factors that increase metastasis may aid early detection methods and discover therapeutically targetable pathways to help with the clinical management of this disease. To this end, we have generated a mouse model to delete the Ctnnd1 gene (which codes for the protein p120catenin or p120ctn), which is necessary for E-CADHERIN stability and whose deletion results in enhanced epithelial-to-mesenchymal transition (EMT) and metastasis in the Pdx-cre; KrasG12D; p53f/f (KPC) pancreatic cancer mouse model. We show that KPC-p120ctnKO mice have dramatically enhanced metastatic burden relative to control littermates. An unbiased screen of tumor cells from these mice resulted in the identification of misregulated calcium signaling through the secreted factor Parathyroid Hormone Like Hormone (PTHLH) as a previously unappreciated contributor of EMT/metastasis. Importantly, Pthlh deletion in orthotopic transplantation experiments showed significantly reduced tumor growth and metastasis, suggesting PTHLH as an oncogenic and pro-metastatic factor. Furthermore, treatment with an anti-PTHLH monoclonal neutralizing antibody reduced cell proliferation and migration, demonstrating a potential clinical benefit. Finally, we have generated a preliminary cohort of KPC-PthlhKO mice that have increased survival relative to KPC controls and are currently embarking on a preclinical trial with anti-PTHLH antibody in KPC mice, to determine if blocking PTHLH will attenuate this disease. Thus, we hypothesize that PTHLH is a driver of pancreatic tumorigenesis and metastasis. This will be achieved through the following interrelated Specific Aims: Aims 1 and 2 are to define the effect of Pthlh deletion or inhibition upon pancreatic epithelial cell identity and ultimately, metastatic colonization. In the same context, we will explore the role that other regulators (Camk2b and Mcu) of calcium signaling (Aim 3) play in these processes and identify novel downstream signaling components involved in calcium-mediated pancreatic cancer metastases. Finally, in Aim 4, we will determine the role of PTHLH in orchestrating the immune microenvironment and co-treat with immunotherapy. The proposed training in this K99-R00 application outlines an integrated plan of mentored research and career development activities, as well as a specific strategy for my pathway to an independent research career in pancreatic cancer. This award will allow me to refine existing and gain additional skills with the guidance of my research mentors, Drs. Stanger and Rustgi, as well as an interdisciplinary advisory committee. Taken together, the scientific proposal and training/career development plans will provide a compelling foundation for me to become eventually a successful independent NIH funded faculty member.