Notch signaling defines a fundamental cell signaling pathway controlling cell fate acquisition. Notch signals control the development of a very broad spectrum of tissues and experimental modulation of such signals results in cell fate changes throughout the development of multicellular organisms including man. Given the pleiotropy of Notch signals and their potency in controlling the developmental state of cells, as well as the established direct involvement of Notch in carcinogenesis, we wish to explore the consequences of Notch signal modulation in tumors and its potential to influence the fate of specific cell lineages. We will focus our attention to the mammary gland, a tissue with a well characterized developmental profile as well as established mouse cancer models. Our working hypothesis is that changes in Notch signaling activity will result in changes in cell fates, including the fate of specific oncogenic conditions.
The aims proposed will examine the consequences of Notch signal modulation in the mouse mammary epithelium with the help of transgenic mice. We expect that these studies will provide a firm basis to analyze the action of Notch signals in mammary tissue, including the involvement of these signals in both the onset and maintenance of mammary tumors as well as evaluate the capacity of those signals to influence the kinetics of oncogenesis. In order to supplement our understanding of how Notch signaling influences oncogenesis, we will also study the involvement of Notch in proliferative events using cell culture systems.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Pathology B Study Section (PTHB)
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Yassin, Rihab R,
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Massachusetts General Hospital
United States
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Ho, Diana M; Pallavi, S K; Artavanis-Tsakonas, Spyros (2015) The Notch-mediated hyperplasia circuitry in Drosophila reveals a Src-JNK signaling axis. Elife 4:e05996
Hori, Kazuya; Sen, Anindya; Artavanis-Tsakonas, Spyros (2014) Genetic circuitry modulating notch signals through endosomal trafficking. Methods Enzymol 534:283-99
Fleming, Robert J; Hori, Kazuya; Sen, Anindya et al. (2013) An extracellular region of Serrate is essential for ligand-induced cis-inhibition of Notch signaling. Development 140:2039-49
Oh, Philmo; Lobry, Camille; Gao, Jie et al. (2013) In vivo mapping of notch pathway activity in normal and stress hematopoiesis. Cell Stem Cell 13:190-204
Hori, Kazuya; Sen, Anindya; Artavanis-Tsakonas, Spyros (2013) Notch signaling at a glance. J Cell Sci 126:2135-40
ล ale, Sanja; Lafkas, Daniel; Artavanis-Tsakonas, Spyros (2013) Notch2 genetic fate mapping reveals two previously unrecognized mammary epithelial lineages. Nat Cell Biol 15:451-60
Hori, Kazuya; Sen, Anindya; Kirchhausen, Tom et al. (2012) Regulation of ligand-independent Notch signal through intracellular trafficking. Commun Integr Biol 5:374-6
Guruharsha, K G; Kankel, Mark W; Artavanis-Tsakonas, Spyros (2012) The Notch signalling system: recent insights into the complexity of a conserved pathway. Nat Rev Genet 13:654-66
Louvi, Angeliki; Artavanis-Tsakonas, Spyros (2012) Notch and disease: a growing field. Semin Cell Dev Biol 23:473-80
Pallavi, S K; Ho, Diana M; Hicks, Chindo et al. (2012) Notch and Mef2 synergize to promote proliferation and metastasis through JNK signal activation in Drosophila. EMBO J 31:2895-907

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