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    Aging extracellular matrix (ECM) significantly promotes breast cancer progression. Targeting LOX within the aged ECM offers a potential therapeutic strategy for reducing tumor invasion and stress.

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    Area of Science:

    • Oncology
    • Biomaterials Science
    • Aging Research

    Background:

    • Aging is a significant risk factor for breast cancer.
    • The extracellular matrix (ECM) plays a crucial role in tumor progression, but the impact of an aged ECM is understudied.
    • Understanding the aged ECM's independent contribution to breast cancer is vital.

    Purpose of the Study:

    • To investigate the independent role of the aged extracellular matrix (ECM) in promoting breast cancer progression.
    • To identify molecular targets within the aged ECM that influence tumor growth.
    • To evaluate the therapeutic potential of targeting specific genes in the context of an aged ECM.

    Main Methods:

    • Development of a hybrid in vivo model using MCF10A ductal carcinoma cells on decellularized aged murine mammary gland ECM.
    • Implantation of engineered matrices into young Rag1-/- mice.
    • Genetic manipulation (knockdown) of specific targets (IL1B, LOX, P4HA1) within the tumor cells.
    • Analysis of tumor growth, volume, and tumorigenic regions.
    • Single-cell RNA-sequencing to analyze transcriptional changes.

    Main Results:

    • Knockdown of IL1B and LOX reduced tumor growth on aged matrices; P4HA1 knockdown enhanced growth.
    • LOX was identified as a driver of tumor progression, with its knockdown reducing invasion and cellular stress transcriptomic programs.
    • Tumors grown on aged ECM exhibited significantly greater volume and larger tumorigenic regions compared to those on young ECM.
    • Single-cell RNA-sequencing revealed enrichment of inflammatory and invasive genes in tumors within the aged matrix.

    Conclusions:

    • The aged extracellular matrix (ECM) alone can promote breast cancer progression.
    • LOX is a key driver of tumor progression within the aged ECM and represents a potential therapeutic target.
    • Targeting LOX may mitigate invasion and cellular stress associated with aged ECM-driven breast cancer.