Project title: Understanding the genetic and cellular origins of carcinoid cancer

General Description

Dr. Shivdasani’s research focuses on the mechanisms of cell differentiation for carcinoid and other cancers. Dr. Shivdasani is determining, for example, what makes gastrointestinal cells in the first place and what drives their specific differentiation toward enteroendocrine cells, the type present in carcinoid tumors. Specifically, Dr. Shivdasani is pursuing four lines of carcinoid research:

1. Investigating the biology of the gastrointestinal cell type that dominates in carcinoid tumors
2. Mapping all chromosomal abnormalities that characterize gastrointestinal neuroendocrine malignancies and integrating that information with genes that are significantly dysregulated in this class of tumors
3. Analyzing the results within the larger context of interrelated cell activity to create a conceptual framework that integrates genetics with tumor and normal cell biology
4. Evaluating specific hypotheses in rigorous and physiologically relevant experimental models

This research will help Dr. Shivdasani decode the rules that govern the fates of different categories of gastrointestinal cells, specifically neuroendocrine cells. Dr. Shivdasani’s goal is to discover the key pathways of carcinoid cells. This missing piece of the carcinoid puzzle should unlock a new platform from which to launch an investigation into new therapeutic targets and test selected targeted therapies.

Publications

Kim TH1, Kim BM, Mao J, Rowan S, Shivdasani RA. Endodermal Hedgehog signals modulate Notch pathway activity in the developing digestive tract mesenchyme. Development. 2011 Aug;138(15):3225-33. doi: 10.1242/dev.066233.
Kim TH, Shivdasani RA. Notch signaling in stomach epithelial stem cell homeostasis. J Exp Med. 2011 Apr 11;208(4):677-88. doi: 10.1084/jem.20101737. Epub 2011 Mar 14.

Kim TH, Shivdasani RA. Genetic evidence that intestinal Notch functions vary regionally and operate through a common mechanism of Math1 repression. J Biol Chem. 2011 Apr 1;286(13):11427-33. doi: 10.1074/jbc.M110.188797. Epub 2011 Jan 31.

Verzi MP, Shin H, He HH, Sulahian R, Meyer CA, Montgomery RK, Fleet JC, Brown M, Liu XS, Shivdasani RA. Differentiation-specific histone modifications reveal dynamic chromatin interactions and partners for the intestinal transcription factor CDX2. Dev Cell. 2010 Nov 16;19(5):713-26. doi: 10.1016/j.devcel.2010.10.006.

Verzi MP, Hatzis P, Sulahian R, Philips J, Schuijers J, Shin H, Freed E, Lynch JP, Dang DT, Brown M, Clevers H, Liu XS, Shivdasani RA. TCF4 and CDX2, major transcription factors for intestinal function, converge on the same cis-regulatory regions. Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15157-62. doi: 10.1073/pnas.1003822107. Epub 2010 Aug 9.

Hafler BP, Choi MY, Shivdasani RA, Rowitch DH. Expression and function of Nkx6.3 in vertebrate hindbrain. Brain Res. 2008 Jul 30;1222:42-50. doi: 10.1016/j.brainres.2008.04.072. Epub 2008 May 6.

Choi MY, Romer AI, Wang Y, Wu MP, Ito S, Leiter AB, Shivdasani RA. Requirement of the tissue-restricted homeodomain transcription factor Nkx6.3 in differentiation of gastrin-producing G cells in the stomach antrum. Mol Cell Biol. 2008 May;28(10):3208-18. doi: 10.1128/MCB.01737-07. Epub 2008 Mar 17.

 

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