184 Molecular profiling of heterogeneous tumor cells

Abstract

Activation of Wnt signaling has emerged as one of the major oncogenic aberrations in human cancers, which has been demonstrated to play critical roles in the maintenance of the undifferentiated cancer stem/progenitor cell phenotype, as well as to directly stimulate the malignant growth of tumors. Mutations in the downstream signaling components, including APC, AXIN, and b-catenin, have been well described in several cancer types, and recent studies have further extended the Wnt activation mechanisms beyond these downstream mutations to upstream signaling molecules in this pathway. By screening primary cancer cells established from the patient derived xenograft models, we identified multiple cancer types that secrete Wnt stimulating ligands. We also successfully established primary cancer cell line harboring recurrent R-spondin fusion mutations. Inhibition of the activated Wnt signaling in these cancer cells results in reduced cancer cell growth, indicating the critical dependence of cancer cells on the autocrine Wnt signaling. Thus, these in vitro and in vivo models provide a valuable resource for the high throughput screening of Wnt antagonists, efficacy assessment of candidate Wnt inhibitors, biomarker analysis, as well as the preclinical development of Wnt targeted therapeutics.