Tumor Microenvironment

The macro and microenvironments within which malignant neoplasms arise can exert profound influences on tumor behaviors that range from a complete reversion of the malignant phenotype to the promotion of tumor cell invasion and metastatic growth. In addition to tumor cells, the architecture of most solid tumors includes an assortment of non-malignant cell types derived from distinct developmental lineages that carry out structural or functional roles including fibroblasts, muscle cells, nerves, and vasculature. We have determined that components of tumor microenvironments (TME) also contribute to de novo and acquired treatment resistance. In current practice, the majority of cancer-directed therapeutics do not exclusively target malignant cells, but also injure benign cells in the local, and potentially the distant host microenvironments. Such collateral damage is quite evident for non-specific therapies that involve DNA-damaging modalities such as genotoxic drugs and ionizing radiation. Ongoing work centers on characterizing a DNA Damage Secretory Program in the TME that is comprised of a remarkable spectrum of proteases, growth factors and cytokines. The composite effects of this program promote tumor cell proliferation, invasion, metastasis, and also enhance resistance to therapeutics.

Questions and Projects

  • Does aging influence microenvironment features to promote tumor progression and potentially resistance to treatment?
  • What are the key components of the DNA damage secretory program (DDSP)? How do they promote drug resistance? Can they be effectively targeted?
  • How does the DDSP differ in different cells/tissues?
  • How does the DDSP influence the immune cell repertoire in the local and metastatic TME?
chemotherapy-induced damage to the tumor microenvironment
Chemotherapy-induced damage to the tumor microenvironment results in upregulation of paracrine-acting WNT16.


  • Sun Y et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med.2012 Sep; 18(9):1359-68. PMID: 22863786.
  • Gomez-Sarosi L.DNA Damage Induces a Secretory Program in the Quiescent TME that Fosters Adverse Cancer Phenotypes. Mol Cancer Res. 2017 Mar 29. doi: 10.1158/1541-7786. PMID: 28356331.
  • Nava Rodrigues D et al. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. J Clin Invest. 2018 Sep 4. PMID: 30179225'
  • Bianchi-Frias D. The Aged Microenvironment Influences the Tumorigenic Potential of Malignant Prostate Epithelial Cells. Mol Cancer Res. 2018 Sep 17. PMID: 30224545