Inflammation is not considered as a classic contributor to breast cancer relative to other cancer types such as hepatocellular carcinoma and colorectal cancer etc. We are exploring the role of inflammation in breast cancer under different contexts such as treatment, obesity, and during pulmonary metastasis. 1) One of our major programs is to study causal mechanism by which obesity drives breast cancer progression. Through a strong collaboration with Dr. Fayyaz Sutterwala, we identified a real culprit, i.e. the obesity-associated inflammation as the most critical contributor. In particular, we identified complex cellular and molecular networks within the obese tumor microenvironment. Our currently working model is that adipocytes within the tumor microenvironment become hypertrophic and apoptotic, sending signals to recruit and activate macrophages. Macrophages in turn activate a big protein complex called inflammasome and the consequent cytokine IL-1 production. IL-1 works on adipocytes to induce angiogenic signal that supports further tumor growth and progression. The finished part is currently in press in the Nature Communications. In addition, Dr. Sutterwala and our laboratories found a different working mechanism for the same inflammasome NLRC4 protein in melanoma, a different type of cancer via an infammasome independent function. This work is also in press in the Journal of Clinical Investigation.
Along this line, there are more questions to be addressed than those already being answered. For example, what is the signal that drives inflammasome activation from adipocytes or other tumor microenvironmental factors; how IL-1 induces angiogenic factors in adipocytes and which one is more important in terms of obesity-driven breast cancer progression; can we target these molecules and pathways for breast cancer therapy specific to obese patients etc?
For this project, we will focus on the identification of novel inflammasome activator within the obese tumor microenvironment and on the role of downstream effector Angptl4 in obesity associated angiogenesis, with the ultimate goal to develop specific treatment to obese breast cancer patients who are known to have bad prognosis.
- Ryan Kolb, Liem Phan, Nicholas Borcherding, Yinghong Liu, Fang Yuan, Ann M Janowski, Qing Xie, Kathleen R Markan, Wei Li, Matthew J Potthoff, Enrique Fuentes-Mattei, Lesley G Ellies, Michael Knudsen, Mong-Hong Lee, Sai-Ching Jim Yeung, Cassel L Suzanne, Fayyaz S Sutterwala, Weizhou Zhang*. Obesity-associated NLRC4 inflammasome promotes angiogenesis in breast cancer. Nature Communications. 2016. Oct 6;7:13007. doi: 10.1038/ncomms13007. PMID: 27708283. (*Corresponding author).
- Ann M. Janowski, Oscar R. Colegio, Emma E. Hornick, Jennifer M. McNiff, Matthew D. Martin, Vladimir P. Badovinac, Lyse A. Norian, Weizhou Zhang, Suzanne L. Cassel, and Fayyaz S. Sutterwala. NLRC4 suppresses melanoma tumor progression independently of inflammasome activation. J Clin Invest. 2016 Oct 3;126(10):3917-3928. PMID: 27617861. PMCID: PMC5096827.