Transcriptomic origins of cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

We found that acinar cells in healthy pancreatic tissue harbor an edge sub-population whose transcriptomes show activation of known oncogenic gene sets. The activation of these gene sets parallels the progression of healthy lung tissue to a pre-malignant condition. In addition, edge acinar cells transcriptomically resemble of progenitors of ductal cells in fetal tissue, establishing a link between embryonic reversion andpre-malignant progression. Edge acinar cells are found in multiple published single-cell surveys of humanpancreatic tissue, and accumulate with age. Further, this accumulation is not mutationally driven. Genes upregulated in edge acinar cells continue to be upregulated in pancreatic ductal adenocarcinoma tissue, and are hypo-methylated at their promoters, suggesting instead an epigenetic basis underlying the edge acinar cell state in the human pancreas. This work is now published in Cancer Res. We are now further probing the variability of oncogenic gene sets, its functional underpinnings, and its relation with injury and stress response. With regards to T cell development collaboration, the chromatin and transcriptome data from developing T cells were used to infer a gene regulatory network specific to each intermediate T cell state in the data. This network was then pruned to derive a high-confidence network for each cell state, where each TF is associated with a regulon that consisting of its downstream target genes. We found a set of 106 TFs that were expressed in at least one of these intermediate T cell states, after which we used AUCell to score the activity of each TF's regulon in all cells. We recovered the activity of a regulon (Zbtb7b/Thpok) known to bias CD4+CD8+ T-cells towards a CD8 fate. Remarkably, our analysis is able to distinguish between regulons of TFs that share similar binding site profiles, and whose regulons would have been hard to distinguish in the absence of joint ATAC/RNA-seq profiles of these cells. This collaborative work was published in Immunology. Going forward we will work on characterizing TCR clonotypes in tumors and their transcriptomic and functional differences. With regards to pre-metastatic niche collaboration, we have derived a 50-gene set of genes up-regulated in the lung pre-metastatic niche. Remarkably, these genes are up-regulated in both lung and liver PMNs in mice, independent of the experimental protocol used to initiate the primary tumor. We found that the expression of this gene set is reversed upon treatment with genetically engineered myeloid cells. This treatment appeared to reverse the tumor-mediated immune suppression in lung tissues. Further, the myeloid cell product appears to resemble tumor-infiltrating macrophages and monocytes documented in published data. This collaborative work was published in Cell. Going forward we are working on characterizing the tumor microenvironment of Adrenal Cortical Carcinoma (ACC) using single cell data from several metastatic tumor and adjacent normal tissues (liver and lung).