Our laboratory is interested in understanding signal transduction pathways involved in the pathogenesis of cancer with a specific focus on the following areas:
Elucidating the role of inflammation and NF-κB activation in the pathogenesis
Chronic inflammation predisposes to diverse types of human cancer. We are interested in studying how inflammation promotes cancer. The NF-κB family of transcriptional regulators plays a central role in inflammation and may also drive inflammation induced cancer. Our laboratory has found that the receptor interacting protein (RIP, RIP1), an essential component of the NF-κB signaling pathway, is a key node that mediates cross-talk between inflammatory and oncogenic pathways. For example, RIP1 plays a role in regulation of EGFR expression. RIP1 also plays a role in regulation of cell cycle progression and is overexpressed in glioblastoma (GBM) the most common adult brain tumor. Increased RIP1 expression in GBM confers a worse prognosis. We use cell culture, in vivo mouse models as well as tissue from human cancers to investigate the inflammation cancer interface in glioblastoma and other cancers. We are also exploring the role of RIP1 and NF-κB activation in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis.
Epidermal growth factor signaling in cancer
The epidermal growth factor receptor is frequently amplified and mutated in human cancer. EGFRvIII is a mutant EGFR found commonly in GBM and is tumorigenic than the wild type receptor. We are interested in understanding downstream signaling mechanisms that make the mutant EGFRvIII more oncogenic. We have shown that EGFRvIII specifically induces a narrow set of oncogenic signals that includes the generation of autocrine loops involving the wild type EGFR in glioma cells. We propose that differential induction of downstream signals by EGFRvIII results in increased oncogenic potential.
Increased expression of the EGFR can paradoxically induce growth inhibition and apoptosis. We are also interested in exploring how paradoxical effects of EGFR overexpression can be exploited to treat tumors that express high levels of the EGFR.
Selected Recent Publications
Ramnarain DB, Park S, Lee DY, Hatanpaa KJ, Scoggin SO, Otu H, Libermann TA, Raisanen J, Ashfaq R, Wong ET, Wu J, Elliott R, and *Habib AA. Differential gene expression analysis reveals generation of an autocrine loop by a mutant EGFR in glioma cells. Cancer Res. 66, 867-874. 2006
Ramnarain DB, Park S, Paulmurugan R, Asaithamby A, Mickey BE, Saha D, Kelliher MA, Mukhopadhyay P, Banani F, Madden CJ, and *Habib AA. The death domain containing kinase receptor interacting protein (RIP1) links inflammatory and growth factor signaling pathways by regulating expression of the epidermal growth factor receptor. Cell Death and Differ. 15, 344-353. 2008
Park S, Ramnarain DB, Hatanpaa KJ, Mickey BE, Saha D, Paulmurugan R, Madden CJ, Wright P, Bhai S, Ali M, Puttaparthi K, Hu W, Elliott JL, Stuve O, and *Habib AA. The death domain-containing Kinase RIPI regulates p27 Kip1 levels through the PI3K-Akt-forkhead pathway. EMBO Rep., 9, 766-783. 2008
Park S, Hatanpaa KJ, Xie Y, Mickey BE, Madden CJ, Raisanen J, Ramnarain DB, Xiao G, Saha D, Boothman DA, Zhao D, Bachoo RM, Pieper RO, and *Habib AA. The receptor interacting protein (RIP1) inhibits p53 induction through NF-kappa B activation and confers a worse prognosis in glioblastoma. Cancer Research 69, 69: 2809-2816, 2009
Park S, Zhao D, Hatanpaa KJ, Mickey BE, Saha D, Boothman DA, Story MD, Wong ET, Burma S, Georgescu MM, Rangnekar V, Chauncey SS, and *Habib AA. RIP1 activates PI3K-Akt via a dual mechanism involving NF-kappa B mediated inhibition of the mTOR-S6K-IRS1 negative feedback loop and downregulation of PTEN. Cancer Research 69, 4107-4111, 2009