<div>
<p>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. </p>
<p>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. </p>
<p>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<sup>+ </sup>T cells which in turn were found
to eliminate PAR1 knockout tumors. When PAR1<sup>KO</sup> 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 <i>Csf2</i> and <i>Ptgs2</i>, and PDAC
tumor immune evasion. Together these findings provide novel insights into the
mechanisms and drivers of PDAC initiation and immune evasion.</p>
</div>
<br>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/12235754 |
| Date | 04 May 2020 |
| Creators | Patrick G Schweickert (8793230) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/Investigating_the_respective_roles_of_SOX9_and_PAR1_in_pancreatic_ductal_adenocarcinoma_initiation_and_immune_evasion/12235754 |
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