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

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. ### Competing Interest Statement M.T.L is a founder of and limited partner in StemMed Ltd., and a Manager in StemMed Holdings L.L.C., its general partner, and is a founder of and equity stake holder in, Tvardi Therapeutics Inc. L.E.D. is a compensated employee of StemMed, Ltd. The remaining authors declare no competing interests.