Transcriptomic insights into age-associated extracellular matrix promotion of breast cancer

Abstract

Aging is a key risk factor for breast cancer; however, the independent effects of the aged extracellular matrix (ECM) remain understudied. To address this, we developed a novel hybrid in vivo model that enables the independent investigation of age-related ECM influences on breast cancer development and progression. To examine the effects of genes known to be enriched in a cancerous and aged microenvironment, we first seeded normal or stable knockdown cells onto decellularized ECM (dECM) from aged murine mammary glands and implanted them into young Rag1 −/− mice. We identified LOX as a principal driver of tumor progression, with knockdown reducing invasion, in vitro and in vivo, and stress-related pathways. To further isolate the independent influence of ECM aging on tumor growth, normal MCF10A cells were seeded atop young or aged matrices and implanted. Aged tumors exhibited significantly greater volume and a larger tumorigenic region when compared to young tumors, with single-cell RNA sequencing revealing enrichment of inflammatory and invasive genes. Together, these findings identify LOX as a driver of tumor progression and a potential therapeutic target and demonstrate that the aged ECM alone is sufficient to promote breast cancer progression.