Senescent CAFs in Breast Cancer Progression

Cancer predominantly affects the elderly, with a significant incidence of breast cancer in women aged 50-70. While cell mutations contribute to tumorigenesis, age-related changes in the tumor microenvironment, particularly in cancer-associated fibroblasts (CAFs), which themselves are diverse subsets with distinct roles, including inflammatory, vascular, and myofibroblast CAFs (iCAF, vCAF, and myCAF, respectively)1, may play a crucial role. Importantly, CAF subsets display substantial variability between different tissues and even within the same tissue2. Our study identifies senescent CAFs (senCAFs) as key players in breast cancer progression. In exciting new data we find that 1) senCAFs are frequently found in DCIS where they predict recurrence and in triple negative breast cancer (TNBC), estrogen receptor positive (ER+) BC, and Her2/Neu+ BC. 2) senCAFs are restricted to the myCAF population, raising the possibility that they are a developmental endpoint and do not simply appear stochastically in response to tissue level stress. 3) Depletion of senCAFs significantly reduces primary tumor progression and metastasis. 4) senCAFs modify the biophysical features of the extracellular matrix (ECM), which can impact host immune responses and tumor progression2. 5) senCAFs modify NK cell killing activity, which supports tumor growth. 6) senCAFs increase BC lung metastasis. Together, these data lead to our hypothesis that senCAFs alter the biophysical properties of the ECM and immune responses to increase tumor growth and metastasis. To address this exciting hypothesis, we will use state of the art immunological and biophysical techniques in novel genetically engineered mouse models (GEMM) that we have built and human BC specimens in the following Aims. 1) Determine the organ specific effects of senCAFs on metastatic BC progression; 2) Determine how senCAFs impact ECM dynamics and tumor cell migration; and 3) Determine the impact of senCAFs on NK cell function in BC tumor progression. Our study on senCAFs, a novel component of the breast cancer microenvironment, may uncover critical mechanisms in breast cancer progression, guiding the development of immunotherapeutic and senolytic strategies.