Muntasell, A. | bioRxiv Science

bioRxiv2017

A pan-cancer landscape of interactions between solid tumors and infiltrating immune cell populations

Throughout their development, tumors are challenged by the immune system and acquire features to evade its surveillance. A systematic view of these traits is still lacking. Here, we identify genomic and transcriptomic traits associated to the immune-phenotype of 9,403 tumors of 29 solid cancers. In highly cytotoxic immune-phenotypes we found tumors with low clonal heterogeneity enriched by alterations of genes involved in epigenetic regulation, ubiquitin mediated proteolysis, antigen-presentation and cell-cell communication, which may drive resistance. Tumors with immune-phenotypes with mid cytotoxicity present an over-activation of processes involved in invasion and remodeling of neighboring tissues that may foster the recruitment of immune-suppressive cells. Tumors with poor cytotoxic immune-phenotype tend to be of more advanced stages and present frequent alterations in cell cycle, hedgehog, beta-catenin and TGF-beta pathways, which may drive the immune depletion. These results may be exploited to develop novel combinatorial targeting strategies involving immunotherapies.

bioinformatics↗

bioRxiv2016

Impact of Zygosity in Bimodal Phenotype Distributions

Allele number, or zygosity, is a clear determinant of gene expression in diploid cells. But the relationship between the number of copies of a gene and its expression can be hard to anticipate, especially when the gene in question is embedded in a regulatory circuit that contains feedbacks. Here we study this question making use of the natural genetic variability of human populations, which allows us to compare the expression profiles of a receptor protein in natural killer cells between donors infected with human cytomegalovirus (HCMV) with one or two copies of the allele. Crucially, the distribution of gene expression in many of the donors is bimodal, indicative of the presence of a positive feedback somewhere in the regulatory environment of the gene. Three separate gene-circuit models differing in the location of the positive feedback with respect to the gene can all reproduce well the homozygous data. However, when the resulting fitted models are applied to the hemizygous donors, only one model (the one with the positive feedback located at the level of gene transcription) reproduces the experimentally observed gene-expression profile. In that way, our work shows that zygosity can help us relate structure and function of gene regulatory networks.\n\nAuthor SummaryNearly all mammalian cells, including human cells, have two copies of each chromosome, and thus possess two potentially different copies of each gene (which might be in some cases non-functional or even absent). Naiively one might expect that two identical copies of the gene would lead to the protein being expressed at twice the rate, but many factors can alter this simple calculation. One of these factors is the existence of feedback mechanisms affecting in one way or another the regulatory circuit in which our gene of interest is embedded. Here we study the relationship between the number of gene copies and the expression of a receptor protein that plays a crucial role in the recognition of pathogens by natural killer cells, which are important elements of the innate immune system. Experimental data of virus-infected donors reveals a bimodal expression profile of this receptor, typical of a positive feedback, and a clear difference between donors with one or two copies of the gene. Mathematical modeling allows us to find the likely location of the feedback loop within the genes regulatory circuit, by requiring the correct model to reproduce the expression profiles of both types of donors.

systems biology↗