Angelo Michael DeMarzo , MD , PhD

Research Summary

• Identification and Characterization of Proliferative Inflammatory Atrophy (PIA): In 1999, Dr. De Marzo and colleagues (William G. Nelson) described proliferative inflammatory atrophy (PIA) as a potential precursor lesion for prostate cancer.

  • His team identified molecular characteristics of PIA, including the induction of stress response and inflammatory genes in atrophic “intermediate luminal” cells, indicating inflammatory cell-induced injury.

  • They characterized transitions between atrophic lesions and high-grade prostatic intraepithelial neoplasia (PIN), the main presumptive neoplastic precursor to prostate cancer, and also verified that PIA cells can merge with small cancer lesions.

  • Further work led by Karen Sfanos, linked bacterial infection to PIA and its direct transition to PIN and early prostate cancer, showing that intermediate luminal cells in PIA can develop TMPRSS2-ERG gene fusions.

• Role of MYC Oncogene in Prostate Cancer Development and Progression: Dr. De Marzo’s lab demonstrated that nucleolar enlargement, a key diagnostic feature of almost all cases of PIN and prostate cancer, is driven by MYC overexpression. MYC protein was also found in a subset of basal and intermediate luminal cells in PIA.

  • He and colleagues discovered molecular mechanisms by which MYC transforms prostate epithelial luminal cells and drives cancer progression, showing that MYC:

    • Drives rRNA synthesis and nucleolar gene expression.

    • Overexpression drives EZH2, a key oncogene in prostate cancer.

    • Causes widespread chromatin remodeling in PIN cells by decreasing global H3K27me3.

    • Increases hTR (TERC), the RNA component of telomerase, regulating prostate cancer cell proliferation.

    • Increases mitochondrial DNA copy number and mtRNA expression in PIN and adenocarcinoma.

  • Recent collaborative studies led by Srinivasan Yegnasubramanian and Mindy Graham confirmed elevated expression of MYC target genes in basal, atrophic/intermediate, and cancer clusters compared to benign luminal epithelial cells, aligning with prior findings that MYC protein overexpression is a frequent and early event in prostate cancer. This suggests MYC activation occurs early in a subset of PIA luminal intermediate cells, driving a gene expression program similar to prostatic adenocarcinoma cells.

• Chronic Inflammation as a Driver of Carcinogenesis: In rat studies, he and Dr. Nelson reported that the charred meat carcinogen (PhIP) acts as both a prostatic tumor initiator and promoter, with neoplastic precursor lesions accompanied by chronic inflammatory cell infiltrates.

  • In mouse studies led by collaborator Charles J. Biebeich they showed that by inducing prostatic inflammation by cytokine overexpression can lead to PIA development.

  • Ongoing work suggests these mice develop PIN lesions that overexpress MYC with age, supporting the hypothesis that chronic inflammation can drive PIA and PIN development by inducing MYC expression.

  • He also led an international effort to standardize terminology among genitourinary pathologists regarding the morphological patterns of prostate atrophy.

  • Collaborative efforts with Elizabeth A. Platz found an association between inflammation in benign prostatic tissue and prostate cancer elsewhere in biopsy specimens.

• Genomic Alterations and Precursor Lesions: A recent collaborative study with Srinivasan Yegnasubramanian and William G. Nelson provided strong evidence that some PIA and many PIN lesions have intermediate somatic genomic alterations, specifically examining DNA methylation of the GSTP1 promoter. These findings offer key molecular evidence that some PIN lesions are transitional precursors to invasive prostatic adenocarcinoma.

  • His lab, along with Alan K. Meeker was among the first to show telomere shortening specific to luminal cells in high-grade PIN.

• Diagnostic and Prognostic Marker Development: Dr. De Marzo and colleagues (Dr. Bieberich) introduced the use of NKX3.1 into diagnostic histopathology practice as an important marker of prostate cancer in difficult diagnostic settings. This marker is now widely adopted in clinical practice to distinguish high-grade bladder from prostate cancer and determine the origin of metastatic tumors.

  • Working with Tamara Lotan, they also implemented the use of PTEN IHC as a prognostic marker in prostate cancer.

  • Collaborative efforts with Dr. Bieberich’s group showed that MYC overexpression and Pten loss synergize to drive genetic instability and metastasis in a mouse model.

In summary, this work has improved the understanding of prostate cancer by establishing a new model where chronic inflammation and MYC oncogene overexpression drive the progression from precursor lesions (PIA and PIN) to invasive cancer. This work suggests that targeting the causes of chronic prostatic inflammation or inhibiting MYC could lead to novel prevention and treatment strategies.