Host heterogeneity shapes clonal selection and organotropism in an extranodal lymphoma mouse model

Tumor metastasis is a leading cause of patient mortality, with tumor dissemination and organotropism representing critical yet complex aspects of tumor biology that involve clonal selection and evolutionary dynamics. Current experimental models inadequately recapitulate the spatiotemporal dissemination and phenotypic heterogeneity of human cancers, highlighting a critical need for more physiologically relevant preclinical platforms. In this study, we utilized a kidney-tropic primary extranodal lymphoma model to explore the role of EFNB1 in lymphoma dissemination across two distinct mouse strains, C57BL/6J and C57BL/10J. Intriguingly, EFNB1-overexpressing lymphoma cells displayed markedly different progression rates and colonization patterns in these strains. EFNB1-null and EFNB1-high lymphomas derived from the two strains underwent distinct clonal selection and exhibited significant transcriptomic heterogeneity, including RNA base substitutions, as well as differential expression of nuclear histone genes and mitochondrial respiratory chain genes. Notably, clonal origin alone did not determine lymphoma organotropism. Collectively, this study establishes a readily reproducible extranodal lymphoma model and demonstrates that host heterogeneity can reshape transcriptional heterogeneity, drive tumor clonal selection, and ultimately dictate organotropism. These findings suggest that host heterogeneity may serve as a valuable prognostic indicator for lymphoma.