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Consistent bioinformatics analysis approaches of chemically perturbed biological systems are needed in order to achieve meaningful integration of results from multiple experiments in support of cancer systems biology research. Our initial efforts have focused on identifying and contrasting molecular mechanisms that reveal biochemical events affecting non-small cell lung cancers in the context of combination drug therapies as a model for defining these approaches. While the link between growth factor receptor mutations, target inhibitor drugs and non-small cell lung cancer is well established, the basis of variable response in different patient cohorts is still poorly understood and is the subject of ongoing investigations. Data for our efforts were provided by the NCI's Center for Advanced Preclinical Research. Mice genetically engineered to develop erlotinib-sensitive lung adenocarcinomas were subjected to drug compounds that are currently in clinical trials, as well as erlotinib, individually and in combination, to study early response and development of late resistance. Metabolite data, gene expression data, and histological data were collected and used in defining the initial analysis approach. While evaluation of analysis approaches continues, preliminary results already indicate these data can be effective in assessing drug efficacy on reducing tumor burden. Further efforts are underway to develop analysis techniques to explore the underlying dynamic processes. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) presents the poorest prognosis among the breast cancer subtypes and no current standard therapy. Here, we performed an in-depth molecular analysis of a mouse model that establishes spontaneous lung metastasis from JygMC(A) cells. These primary tumors resembled the triple-negative breast cancer (TNBC) both phenotypically and molecularly. Morphologically, primary tumors presented both epithelial and spindle-like cells but displayed only adenocarcinoma-like features in lung parenchyma. The use of laser-capture microdissection combined with Nanostring mRNA and microRNA analysis revealed overexpression of either epithelial and miRNA-200 family or mesenchymal markers in adenocarcinoma and mesenchymal regions, respectively. Cripto-1, an embryonic stem cell marker, was present in spindle-like areas and its promoter showed activity in primary tumors. Cripto-1 knockout by the CRISPR-Cas9 system inhibited tumor growth and pulmonary metastasis. Our findings show characterization of a novel mouse model that mimics the TNBC and reveal Cripto-1 as a TNBC target hence may offer alternative treatment strategies for TNBC.