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Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality. Nevertheless, anti-stromal therapies for pancreatic cancer patients have had mixed results, suggesting there are multifaceted, anti and pro-tumorigenic roles of fibrosis in tumor pathogenesis. We found that human PDACs lacking epithelial TGFβ activity have elevated epithelial Stat3 activity and develop a stiffer, matricellular-enriched fibrosis that associates with high epithelial tension and shorter patient survival. Using several Kras-driven mouse models, we found that both the loss of TGFβ signaling and elevated β1 integrin mechanosignaling engage a positive feedback loop whereby Stat3 signaling modulates pancreatic cancer malignancy by increasing matricellular fibrosis and tissue tension. By contrast, epithelial Stat3 ablation attenuated pancreatic malignancy by reducing the stromal stiffening and epithelial contractility induced by loss of TGFβ signaling. In PDAC patient biopsies, higher matricellular protein and activated Stat3 associated with SMAD4 mutation and shorter survival. The findings implicate epithelial actomyosin tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors, and highlight Stat3 as a key driver of the phenotype. These data illustrate how tumor genotype can directly tune tissue mechanics and support the development of genotype-driven, anti-stromal therapies targeting PDAC. Citation Format: Hanane Laklai, Yekaterina Miroshnikova, Michael Pickup, Eric Collisson, Kim Grace, Alex Barrett, Ryan Hill, Johnathon Lakins, David Schlaepfer, Janna Mouw, Valerie LeBleu, Sergey Novitskiy, Julie Johansen, Valeria Poli, Rahgu Kalluri, Laura Wood, Matthias Hebrok, Kirk Hansen, Harold Moses, Valerie Weaver.{Authors}. Genotype tunes PDAC tension to induce matricellular-fibrosis and tumor aggression. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A50.

BackgroundNo single biomarker has yet been able to predict disease course in patients with rheumatoid arthritis (RA). However combinations of biomarkers and changes therein early during treatment may be predictive of later treatment response.ObjectivesInvestigate correlations between early changes (Δ) in the validated multi-biomarker disease activity (MBDA) score and Δ in disease activity measurements – Disease Activity Score (DAS28-CRP), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and C-reactive protein (CRP) – in early RA patients (the OPERA cohort).MethodsIn the randomized double-blinded OPERA trial, 180 treatment-naive patients were randomized to an adalimumab (ADA) group (oral methotrexate (MTX) in combination with ADA) or a placebo group (oral MTX and placebo-ADA). Intra-articular glucocorticoids were also injected into swollen joints (1). DAS28-CRP, CDAI, SDAI, and CRP were measured at baseline (BL) and at 3, 6 and 12 months. MBDA score, calculated based on serum concentrations of CRP, interleukin-6, chitinase-3-like protein 1, vascular endothelial growth factor A, matrix metalloproteinase 1 and 3, vascular cell adhesion molecule 1, epidermal growth factor, tumor necrosis factor receptor type I, serum amyloid A, leptin and resistin, with a range of 1–100, was determined retrospectively at the same time points on banked serum samples (2).Correlations between ΔMBDA scores and Δ disease activity measurements were analyzed by Spearman's correlation coefficient.ResultsPatients had a median age of 55.2 (range: 18.7–86) years, disease duration of 84 (range: 42–214) days; 66% were female; 72% and 65% were RF and anti-CCP positive, respectively. At BL, median DAS28-CRP was 5.6 (3.3–8.6) and median MBDA score was 59 (12–90). MBDA scores were low (<30) in 8 (4%) patients, moderate (30–44) in 25 (14%) and high (>44) in 147 (82%) patients. There were no statistically significant correlations between BL MBDA score and other disease activity measurements at 3 or 6 months in the placebo or ADA groups.Median ΔMBDA scores from BL to 3 months (ΔMBDA score0–3m) and to 6 months (ΔMBDA score0–6m) were -16.5 and -20, respectively. Median ΔDAS28-CRP from BL to 6 months (ΔDAS28-CRP0–6m) and to 12 months (ΔDAS28-CRP0–12m) were -2.9 and -3.2, respectively. ΔMBDA score0–3m and ΔDAS28-CRP0–6m were significantly correlated in the placebo and ADA groups, as were ΔMBDA score0–6m and ΔDAS28-CRP0–12m. ΔMBDA score0–3m also significantly correlated with ΔDAS28-CRP, ΔCDAI, ΔSDAI and ΔCRP from BL to 6 months and from BL to 12 months (Table 1).ConclusionsIn patients with early RA from the OPERA cohort, ΔMBDA score from BL to 3 or 6 months were correlated with longer-term ΔDAS28-CRP, ΔCDAI, ΔSDAI and ΔCRP. Correlations were generally similar between treatment groups.ReferencesHørslev-Petersen K, et al., Ann Rheum Dis 2014; 73:654–661Hirata et al. Current Biomarker Findings 2015, 5:69–78Disclosure of InterestC. H. Brahe: None declared, M. Østergaard Grant/research support from: Abbvie, BMS, Boehringer-Ingelheim...

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