Molecular mechanisms of prostate cancer metastasis

Although locally invasive prostate cancer is nearly always curable, metastatic prostate cancer is usually fatal. Our research is focused on elucidating mechanisms that promote metastatic progression and underlie phenotypic heterogeneity of metastases. Toward this end, we have developed a series of genetically engineered mouse models (GEMMs) that recapitulate the phenotypic heterogeneity of metastatic prostate cancer. The centerpiece of this collection of GEMMs is the NPKEYFP mouse model, which develops highly penetrant bone metastasis. This model is complemented by additional GEMMs, namely the NPMEYFP and NPp53EYFP mice, that display distinctive metastatic phenotypes. We have performed transcriptomic analyses at the bulk tissue and single-cell level of prostate tumors and metastases from these GEMMs to identify candidate drivers (master regulators (MRs)) of metastatic progression and phenotypic heterogeneity. Furthermore, we have isolated circulating tumor cells (CTCs) from these metastatic GEMMs to study their heterogeneity at the cellular level. In particular, we have established a pipeline to isolate and molecularly characterize individual CTCs as organoids and to study the CTCs at the single-cell level. Our investigations have uncovered several themes that shape the direction of our research. In particular, our findings support the concept that specific mutational events (such as loss of function of p53 and activation of MYC and RAS signaling) as well as cellular plasticity are key drivers of metastatic progression and phenotypic heterogeneity. Thus, we will investigate our hypothesis that heterogeneity of metastasis represents the culmination of molecular, cellular, and organismal differences, as follows: In Aim 1, we will study mechanisms of metastatic progression by: (a) investigating the role of the histone methyltransferase NSD2 by analyses of a new GEMM with gain of function of NSD2 in prostate tumors; and (b) studying cell-intrinsic mechanisms of metastatic progression at the single-cell level in primary tumors and lung and bone metastases. In Aim 2, we will investigate molecular mechanisms of phenotypic heterogeneity of metastasis by analyses of our GEMMs that display a range of metastatic phenotypes. In Aim 3, we will examine cellular heterogeneity of circulating tumor cells (CTCs) at the single-cell level using organoid models and single-cell sequencing approaches. Taken together, our studies are highly innovative in their combination of sophisticated inducible mouse models, single-cell analyses, organoid culture methods, and computational systems approaches to investigate a central problem in cancer biology. Our studies of precision modeling of prostate cancer metastasis may ultimately help guide individualized patient care.