Transcriptomic origins of cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Since the publication of or Edge cell work we have extended the project in three directions. 1. The project has led us to thinking about reversible cell states and how oncogenic or tumor-promoting cell states in the tumor microenvironment can be altered by drugs (small molecules or cytokines). We are currently developing a computational pipeline to do so. We learn each drugs effect on the global transcriptome in a specific cell types (from public datasets like CCLE and CytoSig) and by comparing that with the transcriptional difference between two cell states (say, exhausted T cells versus active T cell states) we attempt to prioritize individual drugs by their potential to reverse cell state. This approach recovers, for instance, IL12 as a potential therapy to alter pre-metastatic niche in lung cancer (previously identified by our collaborator Dr Rosie Kaplan). The work is under progress. 2. In our edge cell work we had made an intriguing observation that the transcriptional effect of KRASG12D mutations in pancreatic cells (in independent experiments) is highly concordant with the transcriptional difference between our detected edges cells and non-edge cells in the non-malignant (also unmutated) pancreatic acinar cells. This suggests existence of transcriptional "phenocopy" of KRASG12D mutation. This has led to design of a new subproject (not yet started) where we will define such phenocopies for various key oncogenic mutations in different cancer types and assess its efficacy in clinical prognosis. This will substantially expand the scope of the current mutation-based approaches in practice in the clinic. 3. We have made substantial progress in analyzing and characterizing the tumor and adjacent normal micro-environment of lung and liver metastasized Adrenal Cortical Carcinoma (ACC) tumors in the NCI cohort. This work is done in collaboration with Dr. Rosie Kaplan. Bulk (80%) of the work is completed and we have found several cell type-specific states in the metastasis and adjacent normal microenvironment (for example, Tip and Stalk endothelial cells, Exhausted T cell, etc) uniquely found in met and adjacent environments that are prognostic of patient survival in TCGA. We have also observed substantive functional differences between the Cortisol-producing and non-cortisol-producing malignant cells that could explain their differential aggressiveness.