Stromal senescence in lethal prostate cancer: a novel target for prognosis and therapy

Our overarching hypothesis is that senescent stromal fibroblasts, especially if they elicit an inflammatory response, promote progression to lethal disease in men with prostate cancer. Senescent stromal fibroblasts may result from telomere attrition, but also other aging and non-aging mechanisms, and can elicit inflammation that acts in cancer initiation and promotion to a lethal state. Our preliminary findings implicate prostate stromal cell telomere shortening and intraprostatic inflammation, both are intimately linked to the biology of cellular senescence, in prostate cancer. Thus, we expect that specifically senescent fibroblasts, which have been shown to secrete cytokines and other growth promoting factors, will be present in prostate-cancer associated stroma and be related to lethal disease in men with prostate cancer. To address our hypothesis, we developed and documented a multi-marker tissue-based strategy to uniquely identify fibroblasts, one of two major cell types in the prostate stroma, the subset of fibroblasts that are senescent, and the associated immune infiltrate. We propose these aims: 1. Evaluate the association between senescent stromal fibroblasts, especially in the presence of stromal inflammation, in prostatectomy tissue and risk of progression to metastatic prostate cancer in men with intermediate and high-risk disease (Cohort 1). 2. Evaluate the association between senescent stromal fibroblasts, especially in the presence of stromal inflammation, and risk of progression to metastasis or rapidly rising PSA in a second, independent cohort of men with intermediate and high-risk disease (Cohort 2). 3. Determine whether senescent fibroblasts are present in prostate metastases, and if so, their heterogeneity across metastatic sites in bone and in soft tissues, in men who died of castrate-resistant prostate cancer. We will identify senescent stromal fibroblasts in fixed prostate tissues using multiplex in situ immunofluorescence staining with quantification via image analysis. In Aims 1 and 2, we will calculate the density of specific senescent stomal fibroblasts per stromal area, the proportion with associated inflammation, and estimate adjusted relative risks of lethal disease progression. Given that Black men have substantially higher prostate cancer mortality rates, we will estimate associations separately in Black men. If our hypothesis is confirmed, we will determine prognostic performance of senescent stromal fibroblasts, and assess whether their addition enhances performance of existing cancer cell-based genomic prognostic tests already measured in Cohorts 1 and 2. Goal 1 is to inform the pressing clinical need for identifying which men’s, including Black men’s prostate cancers are very likely to kill and, equally important, which ones are very unlikely to kill. If our hypothesis is confirmed, data from our work could be incorporated into a prognostic tool. Goal 2 is to inform novel therapeutics (senolytics) that eliminate senescent stromal fibroblasts in men at risk for progression or harboring metastases. A prognostic tool incorporating senescent stromal fibroblasts could also serve as a companion diagnostic, in that it would identify men with these senescent cells for targeting.