Our laboratory has identified the T-box transcription factor brachyury as a driver of EMT in human carcinomas. We have shown that high levels of expression of this molecule result in the acquisition of tumor cell motility and invasiveness in vitro and facilitate metastatic dissemination in vivo in animal models of cancer. We have now demonstrated that the level of brachyury expression in human carcinoma cells directly correlates with resistance to cytotoxic treatments, including chemotherapy and radiation, and that treatment in vitro or in vivo with cycles of chemotherapy selects for a population of highly mesenchymal, invasive and brachyury positive tumor cells. By conducting detailed mechanistic studies we have shown that brachyury is able to mediate resistance to cell death via modulation of cell cycle progression and mitigation of p53-mediated DNA damage responses. Due to its relevant role in cancer metastasis and resistance, and its potential as a cancer target, we have studied in detail the pattern of expression of brachyury across a range of human tissues. Our results demonstrated that brachyury is preferentially expressed in human carcinomas, including lung, breast and colon, while being absent in the majority of normal tissues evaluated, with the exception of some levels detected in normal testis and some thyroid tissues. We recently conducted a comprehensive study of brachyury expression in breast carcinomas and have demonstrated that this EMT driver is overexpressed in primary as well as metastatic breast cancer tissues, and that high levels of brachyury mRNA in primary breast tumors correlate with poor clinical outcome in patients treated with tamoxifen therapy post-surgery. We have recently developed a yeast-recombinant vector expressing the full-length brachyury protein and demonstrated its ability to elicit CD4+ and CD8+ brachyury-specific T-cell immune responses in vivo in animal models as well as in vitro with human T cells. The brachyury-specific T cells, in turn, were shown to lyse target tumor cells that express the brachyury protein. These results formed the rationale for a currently ongoing Phase I clinical trial of yeast-brachyury vaccine in patients with advanced carcinomas. We have made the paradoxical observation that reducing, rather than increasing, the level of the target brachyury in some carcinoma cells enhances their cytotoxic response to brachyury-specific T cells. This observation was expanded to demonstrate that tumor cells with very high levels of brachyury may be less sensitive to various immune effector cells, including antigen-specific T cells, NK, LAK cells or the immune mediators FasL and TRAIL, than tumor cells with intermediate or low levels of brachyury. Studies are ongoing to identify strategies aimed at reducing brachyury and mesenchymal features to render tumor cells more susceptible to immune attack.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Scientific Cores Intramural Research (ZIC)
Project #
1ZICBC010937-07
Application #
8938441
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Hamilton, Duane H; McCampbell, Kristen K; Palena, Claudia (2018) Loss of the Cyclin-Dependent Kinase Inhibitor 1 in the Context of Brachyury-Mediated Phenotypic Plasticity Drives Tumor Resistance to Immune Attack. Front Oncol 8:143
Hamilton, Duane H; David, Justin M; Dominguez, Charli et al. (2017) Development of Cancer Vaccines Targeting Brachyury, a Transcription Factor Associated with Tumor Epithelial-Mesenchymal Transition. Cells Tissues Organs 203:128-138
David, Justin M; Dominguez, Charli; McCampbell, Kristen K et al. (2017) A novel bifunctional anti-PD-L1/TGF-? Trap fusion protein (M7824) efficiently reverts mesenchymalization of human lung cancer cells. Oncoimmunology 6:e1349589
Dominguez, Charli; McCampbell, Kristen K; David, Justin M et al. (2017) Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer. JCI Insight 2:
Dominguez, Charli; David, Justin M; Palena, Claudia (2017) Epithelial-mesenchymal transition and inflammation at the site of the primary tumor. Semin Cancer Biol 47:177-184
Shah, Sagar R; David, Justin M; Tippens, Nathaniel D et al. (2017) Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer. Cell Rep 21:495-507
Heery, Christopher R; Palena, Claudia; McMahon, Sheri et al. (2017) Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury. Clin Cancer Res 23:6833-6845
David, Justin M; Dominguez, Charli; Palena, Claudia (2017) Pharmacological and immunological targeting of tumor mesenchymalization. Pharmacol Ther 170:212-225
Tsang, Kwong Y; Fantini, Massimo; Fernando, Romaine I et al. (2017) Identification and characterization of enhancer agonist human cytotoxic T-cell epitopes of the human papillomavirus type 16 (HPV16) E6/E7. Vaccine 35:2605-2611
Fernando, Romaine I; Hamilton, Duane H; Dominguez, Charli et al. (2016) IL-8 signaling is involved in resistance of lung carcinoma cells to erlotinib. Oncotarget :

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