Characterizing the role of senescence in prostate cancer inception and relapse

Cancer is often described as a wound that does not heal. Along with its role in regulating immune responses, senescence also plays a pivotal role in wound healing responses and tissue regeneration. While these senescence responses have been shown to act as a potent barrier to tumorigenesis, there is also strong evidence that prolonged senescence may create an environment that fosters tumor development if such a “wound” is not resolved. We will use prostate cancer, a tumor type whose initiation has been associated with senescence induction, as a disease system to understand the impact of senescence in cancer onset and relapse.

To understand the role of senescence and senescence-mediated inflammation in prostate cancer initiation, we are leveraging genetically engineered mouse models (GEMMs) of prostate cancer development and genetic and pharmacological tools to turn senescence on and off. Using these systems we can then assess the impact of senescence and SASP manipulation on anti-tumor immunity and disease progression in our models.

The standard of care for localized prostate cancer is androgen deprivation therapy (ADT), also known as chemical castration. Whereas the majority of patients will respond initially to these therapies, some will relapse and develop intractable castration-resistant prostate cancer (CRPC), for which new therapy options are desperately needed. Our preliminary data shows that senescence and inflammatory responses are induced following castration of the mouse prostate, suggesting that senescence could play a role in responses to ADT. We are assessing the impact of inducing or inhibiting senescence on the development of CRPC following castration therapy in our prostate cancer mouse models. Of particular interest will be whether senescence induction after castration therapy could promote anti-tumor immune responses to fully block the development of CRPC. With access to prostate cancer patient specimens through the UMCCTS Biorepository and Tissue Bank, we are also probing the link between senescence, inflammation, and response to ADT in the human setting. Together these results will shed new light into the functional role of senescence and its impact on inflammation and wound healing in determining cancer inception, as well as relapse of existing tumors following therapy.