Developmental control of cell fate and dysregulation in cancer
Our lab is broadly interested in stem/progenitor cell biology, and how studies of these cells might improve therapies in cancer and regenerative medicine. Our research is divided into two programs.
Dissecting regulatory networks that control growth factor signaling. The long-term goal of this program is to elucidate the mechanisms that regulate growth factor signaling during development and to understand how the integration of multiple signaling pathways leads to cell fate decisions by stem/progenitor cells. This work is fundamentally important: fine regulation of growth factor signaling and signal integration are crucial for proper cell fate decisions, coordinated development of organs, and for environmental and physiological cues to alter cellular responses. In humans, dysregulation of growth factor signaling is linked to developmental syndromes and many forms of cancer. We study regulation of signaling by the epidermal growth factor receptor (EGFR), an evolutionarily conserved receptor that is implicated in a wide number of human cancers. With many key components of the EGFR pathway defined, the greatest challenges lie in understanding the extensive regulatory inputs and how they are coordinated to achieve specific outputs. For these studies, we focus on genetic approaches in the nematode C. elegans, which allows us to identify regulatory mechanisms that operate in the context of a whole animal. Precise patterning of the nematode vulva requires multiple levels of regulation of EGFR signaling and involves cross-talk with Wnt signaling, another growth factor signaling pathway involved in human cancer. Small deviations from this regulation result in quantifiable changes in vulval patterning. By studying vulval development, we have identified a number of new regulatory mechanisms. Current work is aimed at studying how neuromuscular activity controls the response of vulval progenitor cells to growth factors and determining how a specific receptor protein tyrosine phosphatase regulates EGFR signaling. In addition, we have isolated a number of mutations that cause excessive responses to growth factor signaling, whose molecular identities we are trying to determine.
Stem/progenitor cell biology in human lung. The long-term goal of this new program is to determine how self-renewal and differentiation is regulated in the epithelium of adult human central airways (trachea and mainstem bronchi), and to understand how perturbations in these processes lead to diseases like lung cancer. This work is fundamentally important because diseases of the central airways are some of the most common and lethal diseases affecting humans. For example, millions of North Americans suffer from asthma and cystic fibrosis, and lung cancer is the deadliest form of cancer worldwide. The molecular identities of the progenitor cells and their progeny, the number of steps involved in self-renewal and differentiation, and the specific signals that control these processes are largely unknown, especially in humans. To begin to address these questions, we have established an in vitro culture system for the isolation, expansion, and differentiation of normal human bronchial epithelial (NHBE) stem/progenitor cells. Current work is aimed at developing complementary in vivo xenograft assays and developing tools for real time imaging and high-throughput screening for regulators of self-renewal and differentiation. In addition, we are pursuing a number of projects in which we are already interrogating the contributions of specific signaling pathways.
- Monica Clifford
- Bo Ram Kim
Selected References:Link to Pubmed Publications
Modzelewska, K*, Elgort, MG*, Huang, J, Jongeward, G, Lauritzen, A, Yoon, CH, Sternberg, PW, Moghal, N. An activating mutation in sos-1 identifies its Dbl domain as a critical inhibitor of the EGFR pathway during C. elegans vulval development. (*These authors contributed equally.) Mol Cell Biol 2007; 27(10): 3695-3707.
Moghal N*, Garcia LR*, Iwasaki K, Khan L, Sternberg PW. Modulation of EGF receptor-mediated vulva development by the heterotrimeric G-protein Galpha q and excitable cells in C. elegans. Development 2003; 130(19): 4553-4566. (*These authors contributed equally.) [Comment in Science. 301(5639): 1447.]
Moghal N and Sternberg PW. Extracellular domain determinants of LET-23 (EGF) receptor tyrosine kinase activity in C. elegans. Oncogene 2003; 22(35): 5471-5480.
Moghal N and Sternberg PW. A component of the transcriptional mediator complex inhibits RAS-dependent vulval fate specification in C. elegans. Development 2003;130(1): 57-69.
Moghal N and Sternberg PW. The EGF system in C. elegans. Exp Cell Res 2003; 284(1): 150-159.
Moghal N and Neel BG. Integration of growth factor, extracellular matrix, and retinoid signals during bronchial epithelial cell differentiation. Mol Cell Biol.1998;18(11): 6666-6678.
Moghal N and Neel BG. Evidence for impaired retinoic acid receptor-thyroid hormone receptor AF-2 cofactor activity in human lung cancer. Mol Cell Biol 1995; 15(7): 3945-3959.