Citations

Abstract Background Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer (CRC). Genome-wide interaction analysis (GxE) has identified a few variants that may modify the effects of NSAIDs on CRC risk. However, limited statistical power remains a concern. Restricting analyses by using functional genomic information to aggregate variants into biologically relevant sets can reduce the number of tests, thereby increasing statistical power. We tested the interactions between variant models of gene expression and NSAIDs use on CRC risk. Methods Functional weights of each variant were estimated using PrediXcan based on jointly measured transcriptomes and genomes data of transverse colon tissues from the Genotype-Tissue Expression (GTEx) Project for all genes with sufficient heritability (≥1%). A mixed-effects model was used to assess the GxE effects in a gene among 9,917 incident CRC cases and 10,533 controls from 17 (nested) case-control studies from the Colon Cancer Family Registry (CCFR) and Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). GxE analysis was done by modeling the interaction between predicted gene expression and NSAID use (fixed effects), and residual variant-specific GxE effects that are not accounted for (random effects). Regular user of aspirin and/or non-aspirin NSAIDs was compared to non-regular users. False discovery rate (FDR) was used to account for multiple comparison and FDR≤0.2 was considered genome-wide significant. Secondary analysis was performed on significant genes and duration of use among users. Results Regular use of aspirin was higher among controls (30.3%) compared to cases (24.3%). Among the 4,842 genes tested, SORD significantly modified the effect of regular use of aspirin on CRC risk (p-interaction = 1.45×10-5; FDR=0.07). The SORD gene encodes sorbitol dehydrogenase (SORD), which oxidizes sorbitol to fructose in the polyol pathway. Decreased SORD concentrations were previously observed to dramatically increase in colorectal adenoma cells when compared to normal mucosa cells, suggesting the involvement of dysregulated polyol metabolisms in colorectal tumorigenesis. However, the duration of aspirin use was not statistically significantly associated with SORD gene expression on CRC risk (p=0.149) among 5,560 aspirin users. No significant interactions were observed between genetically determined colon gene expression levels and any NSAID use or non-aspirin NSAID use at FDR<0.2. Conclusions Incorporating functional information, we discovered a novel gene that may interact with aspirin use to confer CRC risk. These findings provide preliminary support for new biological insights that could help understand the chemopreventive mechanisms of aspirin on CRC. We aim to replicate these findings in additional studies. Citation Format: Xiaoliang Wang, Yu-Ru Su, Andrew T. Chan, Stephanie Bien, Sonja I. Bernt, Hermann Brenner, Graham Casey, Jenny Chang-Claude, Steven J. Gallinger, Robert W. Haile, Tabitha A. Harrison, Michael Hoffmeister, Mark A. Jenkins, Amit Joshi, Yi Lin, Noralane M. Lindor, Loic Le Marchand, Hongmei Nan, Polly A. Newcomb, John D. Potter, Martha L. Slattery, Steve N. Thibodeau, Emily White, Li Hsu, Ulrike Peters. Functionally informed genome-wide interaction analysis of nonsteroidal anti-inflammatory drugs on colorectal cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2965.

Abstract Introduction: We and others have shown that pancreatic stellate cells (PSCs) in the tumor-associated stroma of PDAC promote tumor progression and resistance to therapy but the precise mechanisms are unclear. We investigated the role of PSC-derived DKK3, a member of the Dickkopf family of glycoproteins, in PDAC progression, metastasis and response to chemotherapy. Methods: We evaluated expression of DKK3 in human PDAC tissue and cell lines, human PSCs and in a genetically engineered mouse model (GEMM) of PDAC. The paracrine and autocrine effects of DKK3 on PDAC and PSCs were examined by treatment with exogenous DKK3 and gain- and loss of function assays for proliferation, migration, invasion, and gemcitabine-induced apoptosis. The effects of DKK3 on PDAC progression and metastasis were determined by shRNA neutralization and genetic ablation in orthotopic xenograft models and the KPC autochthonous model of PDAC. We developed novel monoclonal antibodies (mAbs) against DKK3 and tested their ability to neutralize DKK3 and prolong survival in mouse models of PDAC. Results: DKK3 was expressed at 4.5 times higher levels in human PDAC by Affymetrix profiling compared to normal pancreas and was present in 99% (118/119) of samples on a tissue microarray with moderate to high expression in 59%. In a GEMM of PDAC, DKK3 appeared early with preneoplastic PanIN lesions with increased expression in invasive carcinoma. DKK3 was strongly expressed by PSCs with minimal to no expression in PDAC cells and knockdown by shRNA reduced PSC proliferation and migration by 60% and 84% compared to controls (p<0.001). Treatment of Panc1 and BxPC3 cells with DKK3 stimulated migration and invasion by 100-300% (p<0.001) and proliferation of DKK3-silenced Panc1 cells was decreased by 80% (p<0.001). Overexpression of DKK3 in L3.6pl cells increased colony formation in gemcitabine by >90% (p<0.001) with 65% reduction in apoptosis (p<0.01), indicating that DKK3 contributes to PDAC resistance to chemotherapy. When we ablated DKK3 in KPC mice by breeding with DKK3-knockout mice, tumor growth was inhibited and survival increased by 45% (p=0.0002). In addition, fewer PanIN lesions developed in DKK3-null mice suggesting that DKK3 may contribute to the early developmental stages of PDAC. DKK3 neutralizing mAbs abrogated DKK3-mediated induction of PDAC cell migration, invasion and resistance to gemcitabine in vitro. Furthermore, treatment with DKK3 mAb significantly inhibited primary tumor growth, reduced peritoneal metastases and prolonged survival in an orthotopic model of PDAC by 43% compared to control mAb (p=0.005; HR 0.24, 95% CI 0.01-0.30). Conclusions: These data are the first report, to our knowledge, of a tumor-promoting function of DKK3 and our results suggest that neutralization of DKK3 may be an effective approach as a primary treatment for PDAC and to enhance responsiveness to chemotherapy. Citation Format: Liran Zhou, Hongmei Husted, Todd Moore, Mason Lu, Defeng Deng, Yan Liu, Vijaya Ramachandran, Thiruvengadam Arumugam, Baoan Ji, Huamin Wang, Jeffrey E. Lee, Craig D. Logsdon, Rosa F. Hwang. Targeting stromal-derived Dickkopf-3 (DKK3) for the treatment of pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2961. doi:10.1158/1538-7445.AM2017-2961

Abstract Kelvin–Voigt fractional derivative (KVFD) model parameters have been used to describe viscoelastic properties of soft tissues. However, translating model parameters into a concise set of intrinsic mechanical properties related to tissue composition and structure remains challenging. This paper begins by exploring these relationships using a biphasic emulsion materials with known composition. Mechanical properties are measured by analyzing data from two indentation techniques—ramp-stress relaxation and load-unload hysteresis tests. Material composition is predictably correlated with viscoelastic model parameters. Model parameters estimated from the tests reveal that elastic modulus E 0 closely approximates the shear modulus for pure gelatin. Fractional-order parameter α and time constant τ vary monotonically with the volume fraction of the material’s fluid component. α characterizes medium fluidity and the rate of energy dissipation, and τ is a viscous time constant. Numerical simulations suggest that the viscous coefficient η is proportional to the energy lost during quasi-static force-displacement cycles, E A . The slope of E A versus η is determined by α and the applied indentation ramp time T r . Experimental measurements from phantom and ex vivo liver data show close agreement with theoretical predictions of the η − E A relation. The relative error is less than 20% for emulsions 22% for liver. We find that KVFD model parameters form a concise features space for biphasic medium characterization that described time-varying mechanical properties.