Atherosclerosis, the leading cause of
cardiovascular disease, is a chronic inflammatory disease involving pathological activation of multiple cell types, such as immunocytes (e.g., macrophage, T cells), smooth muscle cells (SMCs), and endothelial cells. Multiple lines of evidence have suggested that SMC "phenotypic switching" plays a central role in
atherosclerosis development and complications. Yet, SMC roles and mechanisms underlying the disease pathogenesis are poorly understood. Here, employing SMC lineage tracing mice, comprehensive molecular, cellular, histological, and computational profiling, coupled to genetic and pharmacological studies, we reveal that
atherosclerosis, in terms of SMC behaviors, share extensive commonalities with
tumors. SMC-derived cells in the disease show multiple characteristics of
tumor cell biology, including
genomic instability, replicative immortality, malignant proliferation, resistance to cell death, invasiveness, and activation of comprehensive
cancer-associated gene regulatory networks. SMC-specific expression of oncogenic KrasG12D accelerates SMC phenotypic switching and exacerbates
atherosclerosis. Moreover, we present a proof of concept showing that
niraparib, an anti-
cancer drug targeting DNA damage repair, attenuates
atherosclerosis progression and induces regression of lesions in advanced disease in mouse models. Our work provides systematic evidence that
atherosclerosis is a
tumor-like disease, deepening the understanding of its pathogenesis and opening prospects for novel precision molecular strategies to prevent and treat atherosclerotic
cardiovascular disease.