Shedding light on stromal – epithelial interactions in prostate cancer carcinogenesis and mortality

Shedding light on stromal – epithelial interactions in prostate cancer carcinogenesis and mortality

The prostate consists of two distinct anatomical compartments: the glandular epithelium and surrounding stroma. Experimental studies point to interactions between these compartments in the development of prostate cancer as well as its progression to metastatic disease. Considerable knowledge of stromal-epithelial interactions has been gained through experimental models. We now have the opportunity to test these hypotheses in human prostate cancer cohorts. To date, this has been challenging because of the complexity in characterizing molecular changes in epithelium separately from stroma in archival tissue, as well as the lack of statistical methodologies to quantify cross-talk across the compartments. Our proposal represents a paradigm shift by developing and applying novel biostatistical methodologies to genome wide molecular data of epithelium and stroma in well annotated prostate tissue cohorts.

In cancer research it is common to investigate samples representing a mixture of different cell types, unless a time consuming micro-dissection is performed prior to analysis. On the one hand this makes it difficult to understand the relation between features of these samples and disease subtypes or clinical outcomes, but on the other it also offers a completely untapped opportunity to better investigate the role of the cells immediately surrounding the tumor. This proposal is to develop from the ground up the analytic tools to address these issues, and to demonstrate the utilization of the tools by investigating mechanisms by which obesity may affect the tumor-stroma interaction in prostate cancer patients.

We hypothesize that the morphologic progression of normal prostate to PIN to invasive cancer is driven in part by molecular alterations in stromal tissue. In addition, the cross-talk between epithelium and stroma contributes to tumor development and dedifferentiation. We posit that the stroma harbors molecular changes associated with lethal prostate cancer, and that these markers interact with tumor alterations to drive lethal disease. By developing robust bioinformatic approaches, we can disentangle the relative stromal and tumor signals within admixed samples and apply these to prostate cancer expression profiling data sets.

The proposed study will test and validate critical pathways in the stromal-epithelial environment associated with prostate carcinogenesis, illuminate alterations in pathways in the microenvironment that drive lethal disease, and develop novel bioinformatic tools to characterize stromal-epithelial cross-talk. We propose to integrate genome wide mRNA and miRNA expression data in cohorts from the US, Sweden and Ireland, and to translate results to detect novel chemopreventive and therapeutic strategies. Our proposal directly addresses two of the overarching PCF-Mazzone Challenge Program areas: 1) Co-targeting tumor microenvironment and 2) Biomarkers to distinguish indolent from metastatic prostate cancer. It builds upon a longstanding international collaboration of prostate cancer researchers, unique pathoepidemiology cohorts, and expertise in the fields of pathology, epidemiology, molecular biology, oncology and bioinformatics.

The principal investigators for this study are Massimo Loda and Lorelei Mucci. The research team, though, is made up of almost the entire ToPCaP team. Funding is provided by the Prostate Cancer Foundation.