Project 1: Tumor Microenvironment Initiators of the Metastatic Cascade in High-Risk Prostate Cancer

There is an increasing incidence of men with newly diagnosed prostate cancer (PC) presenting with locally advanced or metastatic disease, a population that comprises >60% of the men who die from the disease. The failure of early detection has led to the initiation of multiple clinical trials testing neoadjuvant therapies in an attempt to cure these patients. Analysis of pre-treatment samples from neoadjuvant trials have identified genomic alterations that associate with a treatment resistance. More recent studies indicate the tumor microenvironment (TME) can initiate the metastatic cascade. However, it remains unclear how and when genomic alterations co-opt different cell types in a complex 3-dimensional TME to initiate the metastatic cascade. We have recently found that activated fibroblasts and macrophage sub-populations induce lymphovascular sprouting and permeability. Based on these data sets, we hypothesize that somatic alterations in tumor DNA co-opt stromal and immune cells in the TME to promote invasion and intravasation of lympho-vascular channels. To test this hypothesis, we have three cohorts of patients with high-risk prostate cancer (surgery alone, neoadjuvant Abiraterone, and neoadjuvant chemohormonal therapy) that undergo PSMA PET/MRI scans prior to surgery. This scan is used to develop 3D mold of the prostate to perform whole mount sectioning and dissection of multi-focal PC for multi-plex molecular analysis. Samples from these specimens are used to create patient-specific “TMEs on a Chip” using a humanized Micro-Physiologic System (MPS) of the prostate with surrounding lympho-vasculature. This novel model system allows culture of patient tumor cells and stromal cells to identify the factors that induce lymphatic permeability and culminate in tumor invasion and intravasation.

Project 1 Aims:

Aim 1 – To evaluate molecular features across multi-focal lesions associated with recurrence and metastatic disease in high-risk prostate cancer.

Aim 2 – To identify the underlying molecular mechanisms in the prostate TME that initiate invasion and metastatic disease.

Aim 3 – To examine functional alterations induced by cellular components and interactions in the prostate TME that initiate the metastatic cascade.