Defining oncogenic determinants in prostate cancer initiation and progression

Abstract

Prostate tumors harbor substantial biological heterogeneity with highly various treatment response. In recent years, the next-generation sequencing technology has enabled comprehensive genomic analysis of primary and metastatic prostate cancer and uncovered previously uncharacterized genetic alterations in cancer genome. Functionally association the genetic abnormalities with the prostate cancer initiation and progression is necessary for a better understanding of the prostate cancer biology. In this work, we describe a combinatorial genetic strategy applied to an organoid transformation assay to rapidly generate diverse, clinically relevant prostate cancer models. Importantly, coupling with single-cell or spatially resolved next-generation sequencing we are able to resolve the clonal architecture of the resultant tumors to uncover polygenic drivers of cancer phenotypes. We successfully recapitulated prostate tumor initiation with a focal giant cell histology and identified potential genetic alteration KMT2C associated with this phenotype. Lineage plasticity is recognized as a common mechanism for treatment resistance in cancer. The shift from an androgen receptor (AR)-positive lineage to an AR-negative lineage has increased over the past decade due to the use of 2nd generation AR inhibitors. However, the genetic determinants driving the progression of prostate cancer to an AR-null state and the acquisition of neuroendocrine differentiation remain largely unknown. We have delineated critical roles of the pioneer factors ASCL1 and NEUROD1 in neuroendocrine transdifferentitation and uncovered their abilities to silence AR expression and signaling by remodeling chromatin at the somatically acquired AR enhancer and global AR binding sites with enhancer activity. We have demonstrated a tuft cell lineage driven transcription factor POU2F3 is associated with downregulation of AR signaling pathways under low androgen conditions. In summary, our work has contributed to a deeper understanding of the genetic determinants involved in the initiation and progression of prostate cancer. By employing innovative genetic strategies and leveraging next-generation sequencing technologies, we have made significant strides in unraveling the complexities of prostate cancer biology.