Hybrid In Vivo Breast Cancer Model Reveals Transcriptomic Insights into Cancer Progression with Age

Aging is a key risk factor for breast cancer, yet the independent role of the extracellular matrix (ECM) in tumor progression remains understudied. Recent studies have investigated healthy mammary tissue and aging to understand their relationship; however, the independent effects of the aged ECM remain understudied. Herein, we describe a hybrid in vivo model where MCF10A ductal carcinoma (DCIS.com) cells, with or without knockdown of select targets, were seeded onto decellularized ECM from aged murine mammary glands and implanted into the mammary fat pads of young Rag1-/- mice. Knockdown of selected targets, IL1B and LOX, reduced tumor growth on aged matrices in vivo and P4HA1 knockdown enhanced tumor growth. Additionally, analysis of LOX on aged ECM highlighted LOX as a driver of tumor progression where knockdown reduced transcriptomic programs related to invasion and cellular stress. To isolate the individual ECM influence on tumor growth, MCF10A cells were seeded atop young or aged matrices where it was found that tumors grown on the aged ECM after implantation exhibited significantly greater volume and a larger tumorigenic region when compared to those from the young ECM. Furthermore, single cell RNA-sequencing revealed transcriptional enrichment of inflammatory and invasive genes within the aged matrix. Together, these results identify LOX as a driver of tumor progression and potential therapeutic target, and demonstrate that the aged ECM alone can promote breast cancer progression.