Impact of the aging niche on cancer phenotypes probed using mouse cancer models produced by somatic engineering.

SUMMARY Aging is the greatest risk factor for cancer development, yet the physiological and molecular mechanisms underlying this relationship remain poorly understood. Undoubtedly, one contributing factor is time – i.e. the years or decades needed for a single cell to acquire sufficient mutations to trigger overt disease. However, other factors certainly play a role, including age-related changes in cell metabolism, DNA damage responses, immune cell function, and the abundance of senescent cells. While understanding how these factors influence tumorigenesis will reveal strategies to improve cancer intervention and treatment, facile models to study cancer in aged animals are lacking. Addressing this critical challenge, we incorporate somatic tissue engineering methods to introduce oncogenic mutations directly into the organs of aged mice, thereby obviating the time and costs of intercrossing and aging cohorts of multi-allelic genetically engineered mouse models (GEMMs). We have developed a range of such “non-germline GEMMs” (nGEMMs) of different target organs and cancer genotypes and shown that the resulting cancers recapitulate molecular and histological features of the corresponding human disease. We have also produced nGEMMs using aged mice and shown that the developing tumors have distinct immune infiltrates with different tumor surveillance capabilities. This proposal combines the unique capabilities of nGEMMs with state-of-the-art tissue analyses to assess the contribution of the aged environment to cancer manifestation in different organ contexts and compares results to settings in which dietary or genetic factors uncouple biological age from chronological age. Implementation of advanced single cell methods will produce a detailed picture of cell type and cell state differences in tumors developing in aged animals and perturbation studies will explore tumor cell intrinsic and extrinsic factors underlying age- related phenotypes. The proposed experiments will benefit from combining our expertise in cancer biology with that of Dr. Laura Niedernhofer, who has extensive experience in studying organismal aging. Our studies will establish broadly portable models for studying cancer in aged mice at a breadth and pace that was previously impossible and produce novel insights into how the epigenetic and physiological processes linked to age contribute to an increase in cancer incidence and/or progression.