The impact of sepsis-induced inflammation on pancreatic cancer liver metastasis - 1 PROJECT SUMMARY 2 Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy and the third-leading cause of 3 cancer-related death in adults. A majority of patients who undergo surgery for primary PDAC resection will later 4 develop lethal metastases, despite intra-operative examination confirming the absence of macrometastatic 5 lesions. Liver metastases constitute nearly half of recurrences detected within six months after PDAC resection, 6 which is significantly earlier in the postoperative period compared to other metastatic sites. Several clinical and 7 experimental studies have shown that perioperative inflammation, including infectious complications like sepsis, 8 can promote liver metastasis. This is intriguing because bacterial-derived endotoxin is elevated in PDAC patient 9 plasma during tumor resection. Furthermore, PDAC patients are at increased risk of developing sepsis, which 10 suggests that tumor-systemic communication in part rewires systemic immunity and, consequently, sepsis 11 susceptibility. Despite these observations, we currently lack mechanistic studies investigating the relationship 12 between perioperative inflammation and PDAC liver metastasis. The overarching objective of this project is to 13 determine how pro-metastatic immune responses can be suppressed to protect against liver metastasis during 14 PDAC resection and sepsis-induced inflammation. To define how sepsis-induced inflammation impacts the liver 15 immune microenvironment, I first modeled the perioperative inflammation that PDAC patients may experience 16 during surgery by using the lipopolysaccharide (LPS) model of sterile endotoxemia, and the more clinically 17 relevant cecal and ligation puncture (CLP) model of polymicrobial sepsis. My preliminary data demonstrates that 18 performing CLP prior to seeding PDAC cells in the liver had a pro-metastatic effect. However, LPS challenge 19 had an anti-metastatic effect marked by increased CXCL9 and CXCL10 release and natural killer cell infiltration 20 in the liver during early sepsis response. Therefore, this approach presents an exciting opportunity to define how 21 LPS-induced sepsis elicits an anti-metastatic cascade to reduce liver metastasis. The central hypothesis of this 22 project is that determining how sepsis-induced immune responses influence liver metastasis will reveal critical 23 mechanisms that can be targeted to create a protective ‘anti-metastatic niche’. To test this hypothesis, Aim 1 will 24 elucidate the anti-metastatic signaling mechanisms underpinning LPS-induced sepsis, and uncover potential 25 therapeutic targets that can be exploited to reduce PDAC liver metastasis. Aim 2 will examine the therapeutic 26 potential of targeting pro-metastatic inflammation during sepsis by evaluating how the quality of sepsis-induced 27 immune responses are impacted by systemic immunosuppression, which is a well-established hallmark of 28 PDAC. The findings of these experiments will uncover critical regulators of perioperative inflammation and 29 systemic immunosuppression in PDAC, and set the stage for the development of preventative therapies to 30 reduce the incidence of liver metastasis among resected PDAC patients.
