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 of glioma   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 growth factor signaling pathways.  For example, RIP 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.

Recent Publications:

*Habib A. A., Chun S. J., Neel B. G., and Vartanian T.  Increased expression of the epidermal growth  factor receptor induces sequestration of extracellular signal-related kinases (ERKs) and selective attenuation of   specific EGF-mediated signal transduction pathways.  Mol Cancer Res.  1, 219-233.  2003

Chun SJ, Rasband MN, Sidman RL, Habib AA, and Vartanian T.  Integrin-Linked kinase is required for Laminin-2 induced oligodendrocyte cell spreading and CNS myelination.  J. Cell Biol.  163, 397-408.  2003

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

Ali MA, Choy H, Habib AA, and Saha D. SNS-032 prevents tumor cell induced angiogenesis by inhibiting vascular endothelial growth factor.  Neoplasia 9, 370-381. 2007

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., Published online June 20, 2008.