XDec Simplex Map of Breast Cancer Cell States Enables Precise Modeling and Targeting of Breast Cancer

Abstract

The characterization of cancer cell states within the tumor microenvironment is a key to understanding tumor biology and an important step toward the development of precision therapies. To reconstruct this information from bulk RNA-seq profiles, we developed the XDec Simplex Mapping (XDec-SM) approach, a reference-optional deconvolution method that leverages single-cell information, when such information is available, to map tumors and the states of constituent cells onto a biologically interpretable, low-dimensional space. When applied to breast tumors in The Cancer Genome Atlas (TCGA), XDec-SM infers the identity of constituent cell types and their proportions. XDec-SM also infers cancer cells states within individual tumors that associate with DNA methylation patterns, driver somatic mutations, pathway activation and metabolic coupling between stromal and breast cancer cells. By projecting tumors, cancer cell lines, and PDX models onto the same map, we identify both in vitro and in vivo models with matching cancer cell states. Map position is also predictive of therapy response, thus opening the prospects for precision therapy informed by experiments in model systems matched to tumors in vivo by cancer cell state.

Proteogenomic analysis of chemo-refractory high-grade serous ovarian cancer

“…To characterize the tumor microenvironment, we analyzed global proteomic and RNA-seq profiles (FFPE discovery cohort) using two deconvolution methods, XDec 57 and BayesDebulk 58 ( STAR Methods ). The estimated proportions of major cell types showed large variation across the 5 tumor clusters ( Figures 6A and S6C ; Table S6 ).…”

“… (A) Heatmap illustrating cell-type compositions of the FFPE discovery cohort (n = 158). The first four sections display cell-type proportions estimated by XDec 57 and BayesDebulk. 58 The fifth section includes the normalized global abundance of key immune cell markers.…”

Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function

“…XDec is a reference-free cell type deconvolution algorithm that predicts the proportion and expression profile of constituent cell types in complex samples using RNA-seq data. 47…”

“…XDec is a reference-free cell type deconvolution algorithm that predicts the proportion and expression profile of constituent cell types in complex samples using RNA-seq data. 47 Single-cell RNA-seq data of cardiomyocytes, fibroblasts, endothelial cells, and immune cells from mouse hearts with TAC treatment (series GSE120064) were obtained to identify informative features. One hundred pseudobulk profiles of each cell type were created by summation for feature selection in XDec stage 0.…”

“…75 Because heart tissue consists of both cardiomyocytes and noncardiomyocytes (eg, fibroblasts, endothelial cells, immune cells), and to examine the effects of ERR agonism on each cell type, we further applied deconvolution of the bulk RNA-seq profile using XDec (Figure 4H; Figure S7). 47,76 Deconvolution of heart bulk RNA-seq profiles of vehicle or 332-treated sham or TAC mouse heart samples identified 4 cardiomyocyte cell states with unique expression profiles (profiles 1 through 4 in Figure S9A). Meanwhile, only one profile was identified for immune cell-like (profile 7), endothelial-like (profile 8), and cardiofibroblast-like (profile 9) populations, which may indicate that ERR agonism primarily targets the cardiomyocytes.…”