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School of Medicine
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Barry D. Nelkin, Ph.D.
Professor of Oncology
Research Interests: Molecular Mechanisms of Thyroid and Lung Cancers; Signal transduction; kinase inhibitors; RAS pathway
- Professor of Oncology
Centers & Institutes
Research & Publications
For the past two decades, this laboratory has explored the control of growth and differentiation of MTC cells. The initial impetus for this research was the finding by Dr. Stephen Baylin that loss of expression of a well-known differentiation marker for MTC, calcitonin, was correlated with poor disease prognosis. This laboratory isolated the human calcitonin gene and, using a cell culture model of MTC, showed that a coordinated program of cell differentiation and growth arrest could be induced by several signal transduction pathways. Subsequent research has focused on the ability of the ras/raf signal transduction pathway to induce irreversible growth arrest and differentiation in these cells. This has resulted in the identification of two ras/raf-responsive transcription factors, RREB and BARX2, and the demonstration that the RET oncogene is silenced during raf-mediated MTC cell differentiation. Raf activation also induces growth arrest and differentiation in small cell lung cancer (SCLC) cells.
Recently, this laboratory has shown that ras/raf-induced differentiation and cell arrest in MTC cells involves two parallel signal transduction pathways, either of which is sufficient to elicit the cell response. One of these pathways is intracellular. The other pathway involves ras/raf-induced expression and autocrine/paracrine signaling by a cytokine, leukemia inhibitory factor (LIF). Thus, in these cells, the ras/raf signal transduction pathway can activate the JAK/STAT signal transduction pathway. SCLC cells are also induced by ras/raf to activate LIF expression and JAK/STAT signaling; however, ras/raf activation arrests SCLC only by the intracellular pathway but not by the autocrine/paracrine LIF-mediated pathway. The significance of these findings is that neuroendocrine cancers, which rarely, if ever, have ras mutations, are actually arrested by such activation of the ras/raf signal transduction pathway. This cell arrest in response to ras/raf activation has been described previously in normal cells, where it may serve as a defense mechanism against ras/raf-mediated growth dysregulation. For ras-associated carcinogenesis, these mechanisms must be inactivated. The findings indicate that, in neuroendocrine cancer cells, some of these growth inhibitory mechanisms are still intact, suggesting that activation of these growth regulatory mechanisms, e.g., by LIF in MTC, may be a potential approach for therapy in neuroendocrine cancers.
Hayes TK, Neel NF, Hu C, Gautam P, Chenard M, Long B, Aziz M, Kassner M, Bryant KL, Pierobon M, Marayati R, Kher S, George SD, Xu M, Wang-Gillam A,Samatar AA, Maitra A, Wennerberg K, Petricoin EF 3rd, Yin HH, Nelkin B, Cox AD,
Yeh JJ, Der CJ. Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression. Cancer Cell. 2016 29:75-89. PubMed PMID: 26725216; PubMed Central PMCID: PMC4816652.
Feldmann G, Mishra A, Hong SM, Bisht S, Strock CJ, Ball DW, Goggins M, Maitra A, Nelkin BD. Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling. Cancer Res. 2010 70:4460-9. PubMed PMID: 20484029; PubMed Central PMCID: PMC3071300.
Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A. 1996 93:9821-6. PubMed PMID: 8790415; PubMed Central PMCID:
Ball DW, Azzoli CG, Baylin SB, Chi D, Dou S, Donis-Keller H, Cumaraswamy A, Borges M, Nelkin BD. Identification of a human achaete-scute homolog highly expressed in neuroendocrine tumors. Proc Natl Acad Sci U S A. 1993 90:5648-52. PubMed PMID: 8390674; PubMed Central PMCID: PMC46778.
Baylin SB, Höppener JW, de Bustros A, Steenbergh PH, Lips CJ, Nelkin BD. DNA methylation patterns of the calcitonin gene in human lung cancers and lymphomas. Cancer Res. 1986 46:2917-22. PubMed PMID: 3009002.