5103-Ivan, Mircea

Mircea Ivan, MD, PhD

Associate Professor of Medicine

Associate Professor of Microbiology & Immunology

Address
Joseph E. Walther Hall, Room C225
980 W. Walnut St.
Indianapolis , IN 46202
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Bio

We are interested in specific molecular responses to hypoxia and their relevance for cancer biology. My postdoctoral work in Dr. William Kaelin's laboratory elucidated the key signaling event that allows metazoan cells to monitor ambient O2 tension. In 2016 my first-author Science and PNAS papers were highlighted in connection to the annual Lasker Foundation awards. Furthermore, the Nobel Assembly chose my 2001 Science paper as essential for their decision to award the 2019 Nobel Prize in Medicine or Physiology to my former mentor Dr. William Kaelin.

In 2007 my group was the first to identify microRNAs induced by decreased oxygen tension, including miR-210, now widely recognized as universal “hypoxia-miR.” Hypoxia-regulated noncoding RNAs are integrated into our broader interest in metabolic responses to oxygen deprivation. 

We are developing new combinatorial therapeutic approaches based on rational interference with tumor metabolism, focusing on glioma and glioblastoma. In 2013 we generated proof of concept showing that blockade of pyruvate dehydrogenase kinase using dichloroacetate (DCA) significantly increases antiangiogenic agents' efficacy in xenografts. With the support of the IU Brain Tumor Working group, we continue to refine this strategy, aiming to open the road for clinical trials.

In 2019, we characterized a novel long noncoding RNA generated by the mir193bhg locus on chr16. We termed this lincRNA lincNORS and demonstrated that it modulated the sterol and steroid homeostatic programs in the cells. Interestingly, lincNORS is "tagged" by more than 20 genome-wide association studies, and we provide early evidence for its roles in human growth phenotypes, in particular puberty onset timing in males and females. 

Key Publications

  • Ivan, M., Fishel, M. L., Tudoran, O. M., Pollok, K. E., Wu, X., & Smith, P. J. (2021). Hypoxia signaling: Challenges and opportunities for cancer therapy. Seminars in Cancer Biology. https://doi.org/10.1016/j.semcancer.2021.10.002

  • Wu, X., Niculite, C.M., Preda, M.B. et al. Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincNORS. Nat Commun 11, 4755 (2020). https://doi.org/10.1038/s41467-020-18411-x

  • Kreuzer, M., Banerjee, A., Birts, C. N., Darley, M., Tavassoli, A., Ivan, M., & Blaydes, J. P. (Accepted/In press). Glycolysis, via NADH-dependent dimerisation of CtBPs, regulates hypoxia-induced expression of CAIX and stem-like breast cancer cell survival. FEBS Letters. https://doi.org/10.1002/1873-3468.13874

  • Moreno Leon, L., Gautier, M., Allan, R. et al. The nuclear hypoxia-regulated NLUCAT1 long non-coding RNA contributes to an aggressive phenotype in lung adenocarcinoma through regulation of oxidative stress. Oncogene 38, 7146–7165 (2019). https://doi.org/10.1038/s41388-019-0935-y

  • Ivan M, Kaelin WG Jr. The EGLN-HIF O(2)-Sensing System: Multiple Inputs and Feedbacks. Mol Cell. 2017 Jun 15;66(6):772-779. doi:10.1016/j.molcel.2017.06.002. Review. PubMed PMID: 28622522; PubMed Central PMCID: PMC5613951

  • Brady LK, Wang H, Radens CM, Bi Y, Radovich M, Maity A, Ivan C, Ivan M, Barash Y, Koumenis C. Transcriptome analysis of hypoxic cancer cells uncovers intron retention in EIF2B5 as a mechanism to inhibit translation. PLoS Biol. 2017 Sep 29;15(9):e2002623. doi: 10.1371/journal.pbio.2002623. eCollection 2017 Sep. PubMed PMID: 28961236

  • Mantel CR, O’Leary HA,  Chitteti BR, Huang X, Cooper S, Hangoc G, Brustovetsky N, Srour EF, Lee MR, Messina-Graham S, Haas DM, Falah N, Kapur R, Pelus LM, Bardeesy N, Fitamant J, Ivan M, Kim K-S, Broxmeyer HE. Enhancing hematopoietic stem cell transplantation efficacy by mitigating oxygen shock. Cell 2015 Jun 9. pii: S0092-8674(15)00574-7. doi: 10.1016/j.cell.2015.04.054; PMID:26073944.

  • Fishel ML, Wu X, Devlin CM, Logsdon DP, Jiang Y, Luo M, He Y, Yu Z, Tong Y, Lipking KP, Maitra A, Rajeshkumar NV, Scandura G, Kelley MR, Ivan M. Apurinic/Apyrimidinic Endonuclease/ Redox Factor-1 (APE1/Ref-1) Redox Function Negatively Regulates NRF2. J Biol Chem. 2015 Jan 30; 290(5):3057-68. doi:10.1074/jbc.M114.621995 pii: jbc.M114.621995 PMID: 25492865

  • Ferdin J, Nishida N, Wu X, Nicoloso MS, Shah MY, Devlin C, Ling H, Shimizu M, Kumar K, Cortez MA, Ferracin M, Bi Y, Yang D, Czerniak B, Zhang W, Schmittgen TD, Voorhoeve MP, Reginato MJ, Negrini M, Davuluri RV, Kunej T, Ivan M, Calin GA. HINCUTs in Cancer: Hypoxia-Induced Non-Coding Ultraconserved Transcripts. Cell Death Differ, 2013 Dec;20(12):1675-87. doi: 10.1038/cdd.2013.119. PMID: 24037088; PMCID: PMC3824588

  • Kumar K, Wigfield S, Gee HE, Devlin CM, Singleton D, Li JL,  Buffa F, Huffman M,  Sinn AL, Silver J, Turley H, Leek R, Harris AL, Ivan M. Dichloroacetate Reverses the Hypoxic Adaptation to Bevacizumab and Enhances its Antitumor Effects in Mouse Xenografts. J Mol Med, June 2013, 91(6): 749-758

  • Devlin CM, Tim Lahm T, Hubbard WC, Van Demark M, Wang K, Wu X, Bielawska A, Obeid L, Ivan M, Petrache I. A Dihydroceramide-Based Response to Hypoxia. J Biol Chem, 2011 Nov 4;286(44):38069-78 PMID: 21914808; PMCID: PMC320748

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