Introduction: Venous thromboembolism (VTE) is a life-threatening complication of anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis whose mechanism remains incompletely elucidated. We tested the hypothesis that elevated microparticle tissue factor activity (MPTFa) or anti-plasminogen antibodies (anti-Plg) may identify patients at risk for VTE. Methods: In this prospective study, patients were enrolled during active disease and followed longitudinally. Twelve patients who experienced a VTE (VTE pos) were compared with patients without VTE (VTE neg , n ¼ 29) and healthy controls (HC, n ¼ 70). MPTFa, anti-Plg, interleukin-6, high-sensitivity C-reactive protein (hs-CRP), Ddimer, serum creatinine, and serum albumin were assessed. Fisher's exact tests and Wilcoxon tests compared categorical and continuous variables, respectively. Cox regression for time to VTE or last follow-up was performed. Results: VTE pos patients had higher MPTFa (peak median ¼ 14.0, interquartile range ¼ 4.3-36.6) than HC (0, 0-3.5) and VTE neg patients (0, 0-1.4). In time-to-event analysis, MPTFa was associated with VTE when measured during both active disease (hazard ratio [HR]; 95% confidence interval [CI]: 1.04; 1.01-1.08) and remission (1.4; 1.11-1.77). Anti-Plg during remission was also associated with VTE (1.17; 1.03-1.33). Each g/dl decrease of serum albumin was associated with a 4-fold increase in VTE risk (4.4; 1.5-12.9). Adjusting for estimated glomerular filtration rate (eGFR), anti-Plg during remission remained significantly associated with VTE. Conclusion: Elevated MPTFa and increased anti-Plg in remission are strong indicators of VTE independent of renal function. Association of anti-Plg during remission with VTE implies hypercoagulability even during disease quiescence. Hypoalbuminemia strongly portends VTE risk, which is a novel finding in ANCA vasculitis. A thrombotic signature would allow improved management of patients to minimize VTE risk and complications of anticoagulation.

Pancreatic cancer is characterized by extensive resistance to conventional therapies, making clinical management a challenge. Here we map the epigenetic dependencies of cancer stem cells, cells that preferentially evade therapy and drive progression, and identify SWI/SNF complex member SMARCD3 as a regulator of pancreatic cancer cells. Although SWI/SNF subunits often act as tumor suppressors, we show that SMARCD3 is amplified in cancer, enriched in pancreatic cancer stem cells and upregulated in the human disease. Diverse genetic mouse models of pancreatic cancer and stage-specific Smarcd3 deletion reveal that Smarcd3 loss preferentially impacts established tumors, improving survival especially in context of chemotherapy. Mechanistically, SMARCD3 acts with FOXA1 to control lipid and fatty acid metabolism, programs associated with therapy resistance and poor prognosis in cancer. These data identify SMARCD3 as an epigenetic modulator responsible for establishing the metabolic landscape in aggressive pancreatic cancer cells and a potential target for new therapies.

Pancreatic Cancer (PC) is projected to be one of the leading causes of cancer related death by 2030. Although other cancers have made significant strides towards improved treatment, PC still remains at a 9% fiver year survival rate due to end-stage diagnosis, aggressive metastasis, and a protective stromal wall. Therefore, to identify novel therapeutic targets, our lab focuses on studying cancer stem cells, a highly chemo-resistant sub-population of pancreatic cancer cells. RNA-seq analysis of these cancer stem cells has revealed a number of genes that are enriched compared to non-therapy resistant cells and normal pancreas. We hypothesize that genes turned on through pancreatic cancer progression contribute to therapy resistance. If PC could be targeted at earlier stages, it would be possible for therapeutics to bypass the wealth of issues that occur as it advances. By cross referencing our RNA-seq analysis to sequencing performed at various stages of pancreatic cancer development in mice, a subset of genes is not only up-regulated in therapy resistant cells, but increases in expression as normal pancreas progresses to an end stage tumor. Preliminary studies have shown that inhibition of these select genes reduces growth of mouse pancreatic cancer in vitro and in vivo. Ongoing studies are to (1) test if inhibition of these genes reduces early stage PC growth in vitro and in vivo, and (2) test how gene knockdown affects human pancreatic cancer cell growth in vitro and in vivo. Citation Format: Matthew L. McDermott, Lesley P. Ferguson, Kendall Chambers, Nirakar Rajbhandari, Tannishtha Reya. Interception of pancreatic cancer progression [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-043.

Pancreatic ductal adenocarcinoma (PDAC) is a disease characterized by aggressive metastasis and resistance to therapy, making clinical management a significant challenge. We have focused on understanding how pancreatic cancer may be influenced by developmental and stem cell signals as they are often aberrantly re-activated during cancer progression. Given the central role for epigenetic regulation in development, we hypothesized that epigenetic factors may be required to sustain the self-renewal and aggressive nature of pancreatic cancer cells. To this end, we carried out a functional screen and identified Smarcd3, a component of the SWI/SNF (Baf) nucleosome remodeling complex, as a novel functional dependency in PDAC. SWI/SNF coordinates context-specific gene regulation in development and is frequently dysregulated in cancer. However, Smarcd3 has not been linked to functions in PDAC and represents a new epigenetic mediator of tumorigenesis. We found that Smarcd3 was uniquely up-regulated in PDAC stem cells and was required for the in vivo propagation of mouse and patient-derived tumors. Further using integrated RNA-seq, ChIP-seq, and network analysis we found that Smarcd3 regulates global SWI/SNF binding and histone acetylation, driving the epigenetic regulation of core cell fate and metabolic programs. Specifically, we found that Smarcd3 regulated genes converging on the mevalonate pathway and ultimately cholesterol biosynthesis, which has been directly implicated in stem signaling in PDAC. Collectively, these data identify Smarcd3 as a critical novel dependency and epigenetic regulator of pancreatic cancer metabolism. Citation Format: Lesley Paige Ferguson, Jovylyn Gatchalian, Nikki Lytle, Nirakar Rajbhandari, Matthew McDermott, Kendall Chambers, Sara Brin Rosenthal, Christian Schuerch, Inti Zlobec, Marten Wartenberg, Eva Diamantis, José A. Galván, Sonia Albini, Lorenzo Puri, Benoit Bruneau, Andrew M. Lowy, Diana Hargreaves, Tannishtha Reya. Defining the role of chromatin remodelers in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-036.