Fig. 6

Identified ENPP1⁺ gene signature is sustained in human breast cancer tumors. a Uniform Manifold Approximation and Projection (UMAP) of scRNA-seq data of 31 human breast cancer tumors showing the different cell compartments (Left panel) and the ENPP1 expression levels (Right panel). b UMAP of the tumor cell compartment showing the upregulated expression of the indicated genes that overlap with expression of ENPP1 in tumor cells. c Dot plot for the gene features (CD3E, CD8A and ENPP1) in each sample patient from EGAD00001006608 scRNA-seq dataset.²² Point size reflects the percentage of gene expression (pct.exp) for the corresponding feature in each sample. The color scale indicates the average scaled gene expression (avg.exp.scaled) of each feature. d Schematic representation of the acquisition of ENPP1⁺ phenotype leading to radioresistance. Top left: During primary tumor growth, tumor cells precondition local and distant sites. After resection, remaining preconditioned cells along with wound repair events, create a host niche for the engraftment of residual cells and/or CTC that acquire a gene transcriptomic signature characterized by enhanced genome integrity and stem-like features. In this preconditioned environment, engrafted cells with the acquired ENPP1⁺-transcriptomic signature exhibit a resistant phenotype mediated by changes in dePARylation and phopho-ATM kinetics, thereby favoring HR-mediated DNA damage repair. This mechanism endows cells ´ability to overcome IR-mediated genotoxic stress. Concurrent inhibition of ENPP1 and ATM post-IR impairs DNA repair and boosts immunocompetency by eliciting STING activation in both tumor and non-tumor cells demonstrating a therapeutic susceptibility (Figure generated by BioRender)