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High mobility group A1 (HMGA1) chromatin regulators are upregulated in diverse tumors where they portend adverse outcomes, although how they function in cancer remains unclear. Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors characterized by dense desmoplastic stroma composed predominantly of cancer-associated fibroblasts and fibrotic tissue. Here, we uncover an epigenetic program whereby HMGA1 upregulates FGF19 during tumor progression and stroma formation. HMGA1 deficiency disrupts oncogenic properties in vitro while impairing tumor inception and progression in KPC mice and subcutaneous or orthotopic models of PDAC. RNA sequencing revealed HMGA1 transcriptional networks governing proliferation and tumor-stroma interactions, including the FGF19 gene. HMGA1 directly induces FGF19 expression and increases its protein secretion by recruiting active histone marks (H3K4me3, H3K27Ac). Surprisingly, disrupting FGF19 via gene silencing or the FGFR4 inhibitor BLU9931 recapitulates most phenotypes observed with HMGA1 deficiency, decreasing tumor growth and formation of a desmoplastic stroma in mouse models of PDAC. In human PDAC, overexpression of HMGA1 and FGF19 defines a subset of tumors with extremely poor outcomes. Our results reveal what we believe is a new paradigm whereby HMGA1 and FGF19 drive tumor progression and stroma formation, thus illuminating FGF19 as a rational therapeutic target for a molecularly defined PDAC subtype.

Metastasis is a major clinical challenge for cancer treatment. Emerging evidence suggests that aberrant epigenetic modifications contribute significantly to tumor formation and progression. However, the drivers and roles of such epigenetic changes in tumor metastasis are still poorly understood. Using bioinformatic analysis of human breast cancer gene-expression data sets, we identified histone demethylase RBP2 as a putative mediator of metastatic progression. By using both human breast cancer cells and genetically engineered mice, we demonstrated that RBP2 is critical for breast cancer metastasis to the lung in multiple in vivo models. Mechanistically, RBP2 promotes metastasis as a pleiotropic positive regulator of many metastasis genes, including TNC. In addition, RBP2 loss suppresses tumor formation in MMTV-neu transgenic mice. These results suggest that therapeutic targeting of RBP2 is a potential strategy for inhibition of tumor progression and metastasis.

Aim: To identify rates of post-discharge complications (PDC), associated risk factors, and their influence on early hospital outcomes after esophagectomy., Methods: We used the 2005-2013 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database to identify patients ≥ 18 years of age who underwent an esophagectomy. These procedures were categorized into four operative approaches: transhiatal, Ivor-Lewis, 3-holes, and non-gastric conduit. We selected patient data based on clinical relevance to patients undergoing esophagectomy and compared demographic and clinical characteristics. The primary outcome was PDC, and secondary outcomes were hospital readmission and reoperation. The patients were then divided in 3 groups: no complication (Group 1), only pre-discharge complication (Group 2), and PDC patients (Group 3). A modified Poisson regression analysis was used to identify risk factors associated with developing post-discharge complication, and risk ratios were estimated., Results: 4483 total patients were identified, with 8.9% developing PDC within 30-d after esophagectomy. Patients who experienced complications post-discharge had a median initial hospital length of stay (LOS) of 9 d; however, PDC occurred on average 14 d following surgery. Patients with PDC had greater rates of wound infection (41.0% vs 19.3%, P < 0.001), venous thromboembolism (16.3% vs 8.9%, P < 0.001), and organ space surgical site infection (17.1% vs 11.0%, P = 0.001) than patients with pre-discharge complication. The readmission rate in our entire population was 12.8%. PDC patients were overwhelmingly more likely to have a reoperation (39.5% vs 22.4%, P < 0.001) and readmission (66.9% vs 6.6%, P < 0.001). BMI 25-29.9 and BMI ≥ 30 were associated with increased risk of PDC compared to normal BMI (18.5-25)., Conclusion: PDC after esophagectomy account for significant number of reoperations and readmissions. Efforts should be directed towards optimizing patient's health pre-discharge, with possible prevention programs at discharge.