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Investigating the respective roles of SOX9 and PAR1 in pancreatic ductal adenocarcinoma initiation and immune evasion

thesis
posted on 04.05.2020, 18:17 by Patrick G Schweickert

Pancreatic ductal adenocarcinoma (PDAC) is a poorly immune responsive, treatment refractory disease, representing the fourth leading cause of cancer deaths in the United States. A lack of significant improvements in patient prognoses over the last few decades highlights the necessity for a more basic understanding of how PDAC develops and progresses. To this end, the research outlined here investigates the contributions of SOX9 and PAR1 in PDAC initiation and tumor immune evasion, respectively.

SOX9 is a developmental transcription factor important for proper pancreas development that is restricted to only a small subset of cells in the adult organ. However, SOX9 is aberrantly expressed in precancerous lesions of the pancreas and throughout PDAC development. Using genetically engineered mouse models we demonstrated that PDAC precursor lesions cannot form in the absence of SOX9 and conversely formed at an accelerated rate when SOX9 was ectopically expressed. Surprisingly deletion of SOX9 in primary mouse PDAC cell lines had no impact on tumor growth in subcutaneous allograft experiments, indicating that although SOX9 expression is necessary for PDAC initiation, it is dispensable in many cases for tumor maintenance and growth. Research investigating the transcriptional changes induced by SOX9 prior to lesion formation is ongoing to identify additional downstream factors critical for disease initiation.

Previous research has shown that PDAC tumors frequently display low levels of immune infiltration, which is a major limitation for the use of immune-based therapeutics and is generally an unfavorable prognostic factor. We show that in primary mouse tumor cells ablation of the thrombin receptor PAR1 caused a significant increase in the infiltration of tumor targeting CD8a+ T cells which in turn were found to eliminate PAR1 knockout tumors. When PAR1KO and PAR1 expressing PDAC tumor cells were co-injected into wild type mice, cells lacking PAR1 were preferentially targeted and eliminated by the immune system, indicating that PAR1 provides cell autonomous protection during an active anti-tumor adaptive immune response. Furthermore, we identified a previously underappreciated association between PAR1-mediated expression of Csf2 and Ptgs2, and PDAC tumor immune evasion. Together these findings provide novel insights into the mechanisms and drivers of PDAC initiation and immune evasion.


Funding

NIH NCI CA211098

NIH NCI CA124586

History

Degree Type

Doctor of Philosophy

Department

Biological Sciences

Campus location

West Lafayette

Advisor/Supervisor/Committee Chair

Stephen Konieczny

Additional Committee Member 2

Claudio Aguilar

Additional Committee Member 3

James Fleet

Additional Committee Member 4

Andrea Kasinski

Licence

Exports