Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas-Streptomyces-Saccharopolyspora-Bacillus clausii) highly predictive of long-term survivorship in both discovery and validation cohorts. Through human-into-mice fecal microbiota transplantation (FMT) experiments from STS, LTS, or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease.

In studies of mouse and human pancreatic tumors and precursors, we found that immune cell-derived IL17 regulated development of tuft cells and stem cell features of pancreatic cancer cells via increased expression of DCLK1, POU2F3, ALDH1A1, and IL17RC. Strategies to disrupt this pathway might be developed to prevent pancreatic tumor growth and progression.

Introduction: We aimed to determine the prevalence and landscape of germline mutations among patients with young onset pancreatic ductal adenocarcinoma (PDAC) as well as their influence in prognosis. Methods: Patients from two cohorts were studied, the High Risk Cohort (HRC) which included 584 PDAC patients who received genetic counseling at MD Anderson Cancer Center and a General Cohort (GC) with 233 metastatic PDAC patients. We defined germline DNA sequencing on 13 known pancreatic cancer susceptibility genes. The prevalence and landscape of mutations was determined and clinical characteristics including survival were analyzed. Results: A total of 409 patients underwent genetic testing (277 from HRC and 132 from GC). As expected, the HRC had higher prevalence of germline mutations compared to the GC: 17.3% vs 6.81%. The most common mutations in both cohorts were in BRCA1/2 and mismatch repair (MMR) genes. Patients younger than 60 years old had significantly higher prevalence of germline mutations in both the HRC (OR: 1.93 +/−1.03–3.70, P: 0.039) and GC (4.78 +/−1.10–32.95, P: 0.036). Furthermore, PDAC patients with germline mutations in the GC had better overall survival than patients without mutations (HR= 0.44, 95% CI of HR: 0.25–0.76, p: 0.030). Discussion Germline mutations are highly prevalent in patients with PDAC of early-onset and can be predictive of better outcomes. Considering emerging screening strategies for relatives carrying susceptibility genes as well as impact on therapy choices, genetic counseling and testing should be encouraged in PDAC patients, particularly those of young onset.

Pancreatic ductal adenocarcinoma (PDAC) arises from premalignant lesions known as pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). 1 Even early-stage pancreatic cancer still maintains a poor prognosis; therefore, early detection strategies should be aimed at detecting premalignant lesions rather than cancer itself. 2 Several institutions have developed programs for high-risk populations, including the University of Texas MD Anderson Cancer Center (MDACC), in which patients with germline mutations at increased susceptibility for PDAC or with a strong family history of PDAC undergo regular surveillance. 3 Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder with a mutation in the Serine-Threonine Kinase 11/Liver Kinase B1 (STK11/LKB1) tumor suppressor gene located on chromosome 19p13.3. 4-6 Peutz-Jeghers syndrome is associated with a 132-fold increase risk for PDAC as compared to the general population and is clinically characterized by mucocutaneous pigmentation, gastrointestinal hamartomatous polyps, and predisposition to lung, breast, gastrointestinal and gynecological malignancies.

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