Computational Pathology Research for Cancer Modeling, Diagnostics and Biomarkers

Division Of Basic Sciences - Nci

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Abstract

Diagnostic difficulties can be encountered when discriminating between microenvironmental, precancerous, and cancer cells, which presents further challenges in attempting to define microenvironmental conditions that may promote cancer development. Cancer microenvironmental contributions to soft tissue sarcoma progression are relatively undefined, particularly during sarcoma onset. Malignant peripheral nerve sheath tumor (MPNST), a type of soft tissue sarcoma that exhibits rapid, aggressive growth was analyzed in samples obtained from tumor and tumor microenvironment during precancer and cancer development in a human cancer model. We showed broad activation of inflammation/immune-associated signaling networks and revealed gene expression patterns that uniquely characterize the transition from precancerous to cancer microenvironment. Macrophages were identified as potential contributors to microenvironmental phenotypes. Comparative genomics analysis of MPNST versus benign lesions in both humans and zebrafish led to identification and functional validation of extracellular matrix protein, periostin (POSTN), in human MPNST providing insight into how the microenvironment may regulate MPNST initiation and progression. Research was also conducted into cancer drug resistance as eventual tumor evasion of targeted therapy continues to limit cancer patient treatment success. Examination of resistance-promoting crosstalk between two key cancer cell signal transduction cascades involving Ras/MAPK and PI3K/AKT/mTOR signaling, which are frequently dysregulated in various human cancers, were evaluated under trametinib inhibition of MEK. Emphasis was placed on the anti-cancer drug trametinib suppressive effect on cell cycle entry and its potential role in drug resistance in a model of human mucosal melanoma. D-type cyclins were investigated following trametinib treatment of five mucosal melanoma cell lines exhibiting differential drug sensitivities. Signaling pathway activation, proliferation, survival, cell death, and cell cycle were analyzed in the context of D-type cyclin expression. Cyclin D2 expression was manipulated using siRNA knock down or inducible recombinant overexpression. Trametinib diminished cyclin D1 in all cell lines. While relatively trametinib-resistant mucosal melanoma cells exhibited capacity to upregulate cyclin D2, which promoted proliferation, sensitive mucosal melanoma cells lacked similar cyclin D2 compensation when cyclin D1 was suppressed by inhibiting MEK. Inhibition of the compensatory cyclin D2 response in resistant cells conferred sensitivity to trametinib. Induced cyclin D2 overexpression in otherwise trametinib-sensitive mucosal melanoma cells promoted survival. Upregulated PI3K/AKT/mTOR signaling under trametinib treatment was suppressed by mTORC1/2 inhibition, which similarly diminished cyclin D2 response. The compensatory switch from preferential reliance on cyclin D1 to D2 in this model plays a role in mucosal melanoma resistance to MEK inhibition. The research provided insight into targeted therapy resistance and molecular mechanisms of drug resistance in the context of small molecule combination therapy.