“Molecular divergence shapes lung- and liver-preferential metastasis in HER2-positive breast cancer”

Abstract

Abstract Metastatic colonization of distant organs remains the primary cause of breast-cancer-specific mortality, yet the underlying mechanisms governing organ-preferential colonization remain poorly understood. To better delineate the underlying mechanisms to establish successful metastatic niches, animal models recapitulating the pathogenesis of human breast cancer are necessary. Through iterative in vivo selection, we established a liver-enriched HER2 + murine breast cancer model, NT2.5LV, which achieved 95% hepatic penetrance within 10 weeks. Comparative whole-genome and bulk RNA sequencing of NT2.5LV, the lung-enriched counterpart NT2.5LM, and the parental primary breast tumor cell line NT2.5 revealed conserved genomic alterations, including Erbb2 amplification, and Cdkn2a/b deletion, despite their distinct organ-preferential phenotypes. NT2.5LM displayed transcriptional homologous-recombination-repair suppression and a type-I interferon-stimulated gene response coupled with immune-checkpoint remodeling, and lung-enriched integrin-mediated adhesions. Conversely, NT2.5LV activated proliferative and metabolic programs with MMP-mediated ECM remodeling suitable to the hepatic microenvironment. These organ-preferential strategies were validated in two independent clinical cohorts MET500 and AURORA. Integrated multi-omic and immunohistochemical analyses demonstrated that NT2.5LV recapitulates key features of human HER2 + breast tumors, including HER2 overexpression. NT2.5LM additionally exhibited a transcriptionally anti-apoptotic, BH3-primed state. The HER2-targeted tyrosine kinase inhibitor neratinib reduced primary tumor growth and the frequency of gross visceral metastases in vivo, establishing NT2.5LV as a clinically relevant preclinical model to assess HER2-targeted therapies.