Through comparisons with a large number of epigenomes of normal fetal and adult human tissue, Dr Pomerantz and his colleagues found that the epigenetic program activated in metastatic tissue was most similar to that activated in a cell line from the human urogenital sinus, the fetal structure that creates the prostate, and fetal tissue developmentally most related to the prostate. The findings suggest that localized prostate cancer metastasizes not by inventing a new mechanism, but by tapping into a developmental program used by its embryonic ancestors that allow it to migrate through the body and invade foreign tissue.

“It makes sense that the cancer cell will reach for that low-hanging fruit. Because just like an embryo, a cancer needs to have cells that . . . are able to travel and take up residence somewhere else,” Dr Pomerantz said.

Comparisons with breast cancer tissue suggested that this specific mechanism might be unique to prostate cancer, but Dr Pomerantz said he suspects that other cancers could also be exploiting latent developmental programs. In addition, he and his colleagues also found that the sequences encoding the prostate-specific regulatory elements harbored genetic variants associated with prostate cancer risk.

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Further analyses suggested that the epigenetic machinery used in fetal development doesn’t entirely disappear, but that “traces” of this program remain long into adulthood, as evidenced by other transcription factors, FOXA1 and HOXB13, that linger around embryonic regulatory regions — as if they’re “poised” to reactivate latent developmental programs, Dr Pomerantz said.

“I think it’s an excellent approach to understanding . . . where do these [epigenetic] changes come from,” said Dr Quigley of the study. “It’s really consistent with the long-known relevance of developmental pathways in cancer.”

In a second study published on July 13, 2020, Dr Quigley and his colleagues focused on a specific kind of epigenetic alteration to DNA — methylation, which regulates gene expression by modifying the accessibility of DNA to transcription factors.2 They reported distinct differences in methylation between metastatic prostate cancer tissue, primary prostate cancer tissue, and benign human tissue.

Interestingly, they observed a distinct epigenomic-based subtype in 22% of 100 examined mCRPC samples. This was associated with hypermethylation as well as somatic mutations in genes such as TET1, DNMT3B, BRAF, and IDH1, which are key components of the methylation machinery. “[These genes] are associated with these global increases in methylation in the tumors in which they are mutated,” Dr Quigley said.

Dr Quigley said he expects such observations to spur the next cycle of functional studies that model such epigenetic changes in laboratory models and experimentally decipher what these epigenetic changes mean and how they alter prostate cancer cell function. Further down the road, that could pave the way for developing biomarkers based on epigenetic changes, or even novel therapies that tinker with the epigenetic machinery.

“As we explore the critical regulatory regions driving prostate cancer progression, we can begin to figure out which factors make these regulatory elements work, and which factors can be targeted and taken away to short-circuit these new regulatory programs,” Dr Pomerantz said. The ultimate question is, “can we rewire the epigenome and re-differentiate these cells to turn them back into the normal, benign tissue?”


  1. Pomerantz MM, Qiu X, Zhu Y et al. Prostate cancer reactivates developmental epigenomic programs during metastatic progression. Nat Genet. 2020;52(8):790-799. doi:10.1038/s41588-020-0664-8
  2. Zhao SG, Chen WS, Li H et al. The DNA methylation landscape of advanced prostate cancer. Nat Genet. 2020;52(8):778-789. doi:10.1038/s41588-020-0648-8