Human heart-tumor interaction in ischemic / failing heart is mediated by cardiac mesenchymal stromal cells

Background & Aim Heart disease may promote tumor growth (reverse cardio-oncology). However, the mechanisms linking heart disease to cancer in humans remain unclear, and therapies are limited. We hypothesized that cardiac mesenchymal stromal cells (MSCs) are involved in heart-tumor interaction. Methods & Results We analyzed single-cell RNA sequencing data from lung cancer tumors, ischemic cardiomyopathy, and controls to examine receptor-ligand interactions from the NicheNET ligand-receptor dataset. This approach allowed us to predict which cardiac cells potentially send ligands to tumor cell receptors. We identified cardiac fibroblasts and pericytes from ischemic hearts as robust potential sources of tumorigenic ligands, including periostin, nerve growth factor, platelet-derived growth factors, and other pro-tumorigenic mediators (Figure 1A). Next, we isolated cMSCs, including fibroblasts and pericytes, from 18 ischemic heart disease (IHD)/heart failure (HF) patients undergoing heart surgery and 12 control donors undergoing valve repair. cMSCs were derived from 3 different locations: left ventricle (LV), right atrium (rAT), or epicardial fat. We used ATAC-seq with footprinting analysis and a functional cancer cell proliferation assay with A549 cells to assess the pro-tumorigenic effects of cardiac MSCs from IHD/HF compared to control and the epigenetic programs and spatial differences in cMSCs driving these effects. We observed increased activity of chromatin remodeling and epigenetic-modifying transcription factors (TFs), including CTCF, CTCFL, and TET1, as well as potentially tumorigenic TFs such as TWIST1, SNAI1, and HIF-2α in MSCs from the left ventricle of IHD/HF patients. This suggests that disease-activated cMSCs undergo chromatin remodeling to promote pro-angiogenic, pro-survival, and pro-cycling programs (Figure 1B). Additionally, conditioned media from IHD/HF LV-MSCs—but not rAT-MSCs—induced a 29% increase in lung cancer cell proliferation (p<0.001, Figure 1C). Conclusions For the first time, we show that human ischemic or failing hearts reprogram cardiac mesenchymal stromal cells to secrete pro-tumorigenic factors and stimulate proliferation of lung cancer cells. Understanding this interaction could foster the development of preventive treatment for heart disease and cancer.