Tumor heterogeneity is a hallmark of cancer. It occurs due to genetic instability fostering random mutations eventually developing into genetically and phenotypically different clones of a tumor. The inherent potential to kill patients is restricted to a small cancer population that maintains a balance of a well-selected set of mutations and defense mechanisms to withstand therapeutic pressure. We call these cell populations driver cell populations in order to distinguish them from the bulk tumor mass. We postulate that the driver cancer cell population in prostate cancer consists of androgen independent stem cell like cells. At the time of surgery for localized disease these cells are either dormant and need to acquire the ability to proliferate, or already hold the ability to proliferate without androgen stimulus ? or both. Here, we propose to analyze these potential driver populations in a xenograft model of human prostate cancer. Tumors will be processed by DNA content based sorting of cancer cells, and the sorted populations will be subjected to genomic analysis before xenografting, before and after castration, and after in vivo passaging. Consequently, this will allow us to characterize the heterogeneity of a single tumor in a so far unmatched resolution and to identify a castration resistant cell population within the tumor at the time of surgery. Assuming that the castration resistant cell population represents a potential driver population in prostate cancer, the identification of the specific mutations within this population may contribute to the basic understanding of meaningful genetic changes associated with prostate cancer. This should have critical impact on the future design of new therapies.
