Uncovering the heterogenous role of senescence in prostate immune suppression and tumorigenesis
Description: Title: Uncovering the heterogenous role of senescence in prostate immune suppression and tumorigenesis
One in eight men will develop prostate cancer in his lifetime. Though most prostate cancers remain indolent or, if progressed, respond well to standard-of-care hormone therapy, many patients will relapse following treatment and develop castration-resistant prostate cancer (CRPC), which is deadly and lacking in effective treatments. It is still unclear why some prostate cancers remain indolent for decades, yet others progress rapidly and fail to respond to therapy. There is thus a dire unmet need for new markers indicative of disease progression and novel therapeutic interventions for treatment-resistant prostate cancer.
We have developed mouse models of prostate tumorigenesis that recapitulate the steps of human prostate cancer to study the mechanisms driving cancer progression and therapy resistance. In both mouse and human prostate cancer samples, we have identified markers of a pathway known as cellular senescence in early as well as advanced lesions. Cellular senescence is a program that stops damaged cells from growing and can lead to their removal by the immune system before they can become cancerous. However, if cellular senescence is left uncontrolled as it is during aging, it can also promote inflammation that can stimulate tumor growth or resistance to cancer therapy. Thus, it is possible that senescence could contribute to tumor progression and immune suppression in prostate cancer. Indeed, we have found that removal of senescent cells can delay tumor onset and activate immune responses in our prostate cancer models. We believe that by dissecting how different senescent cell types interact with the immune system and impact inflammation, we can understand how benign prostate tissues become malignant and how to target senescence for immunotherapy in advanced prostate cancer.
Here we will track and characterize different types of pro- and anti-tumorigenic senescent cells during different stages of cancer progression in our mouse models and in human prostate cancer patient samples. We will then test the impact of senolytic therapies that kill senescent cells on prostate tumor growth and immune activity. Finally, we will combine senolytic therapies with immunotherapies that are currently ineffective on their own in prostate cancer in our models to see if targeting senescence can be used to immunologically control prostate cancer. By understanding how senescence contributes to cancer progression and immune suppression, we hope to identify (a) new prognostic markers of cancer progression and (b) new therapeutic targets and strategies for advanced prostate cancer patients.
Funder: American Cancer Society
Amount: $792,000
Funding type: award
Start date: 2024-01-01
End date: 2027-12-31
Investigator: Marcus Ruscetti
Institution: University of Massachusetts Chan Medical School
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 0
Funder award ID: RSG-23-1151969-01-IBCD
OpenAlex ID: G2048626398