Su1066 – Novel Metabolomic Predictors of Incident Colorectal Cancer in Men and Women

cohort (N=292) of EAC and non/pre-malignant biopsy samples.Functional assessments of selected pathways, using small interfering RNAs (siRNA) and small molecule inhibitors (SMI), were performed in human non-dysplastic, dysplastic, EAC cell lines and tumor xenograft models.Results: RNA-Seq and integrative pathway-modeling identified significant hyperactivation of JNK/Jun and/or TGF-β/Smad signaling sub-networks in the majority (84%) of EACs, a finding that was independently confirmed in the validation cohort.Inhibition of JNK/Jun or TGF-β/Smad signaling components with siRNAs and/or SMIs against JNK or TGFβRI led to the several notable findings.First, SMIs of JNK or TGFβRI arrested the growth and migratory potential of EAC cells and markedly suppressed the growth of EAC tumors in vivo.Second, oncogenic TGF-β signaling is mediated in a Smad4-independent manner, strikingly distinct from colon cancers where this pathway functions as a tumor suppressor.Finally, the pro-tumorigenic TGF-β signaling turns on as early as the dysplastic phase of EAC progression.Conclusions: Using an integrated systems biology and pharmacogenetic approach we identified the majority of EACs as being dependent on the JNK/Jun and TGF-β/Smad signaling pathways.These pathways can be further explored as biomarkers of cancer risk, novel chemopreventive and therapeutic targets to improve treatment paradigms for this currently refractory and lethal malignancy. Su1063