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Ian  Macara

Ian Macara, Ph.D.

Co-Leader, Signal Transduction and Chemical Biology Research Program
Louise B. McGavock Professor and Chair of Cell and Developmental Biology
Researcher

Contact Information:

Dept. of Cell and Developmental Biology
Vanderbilt University Medical Center
465 21st Avenue S., U 3209 MRB III
Nashville, TN 37232-8240
615-875-5565
Fax: 615-322-5060

Profile

Dr. Macara studies the development of the ducts that form breast tissue, and the mechanisms that can result in the initiation and spread of breast cancer. Most types of cancer arise from epithelial cells. These cells form many of the organs in the body, and arrange themselves into either sheets (such as the skin) or branching ducts (such as kidney, or mammary glands).
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Dr. Macara studies the development of the ducts that form breast tissue, and the mechanisms that can result in the initiation and spread of breast cancer. Most types of cancer arise from epithelial cells. These cells form many of the organs in the body, and arrange themselves into either sheets (such as the skin) or branching ducts (such as kidney, or mammary glands). Epithelial cells are polarized - they have a top and bottom, which differ from one another in form and function. Dr. Macara is studying how polarization occurs, how this process might be disrupted in breast cancer, and how defects in polarization contribute to invasive behavior and metastasis.

Education
  • BSc - University of Sheffield, UK
  • PhD - University of Sheffield, UK
  • Postdoctoral training - Harvard University, MA
Research Description

Our lab is interested in the ways in which cells break symmetry, and initiate and maintain spatial asymmetries. Asymmetries can form as cells polarize, or can occur within cells, for instance during mitosis. Gradients of proteins or other molecules can create asymmetries that the cell uses to specify orientations and subcellular locations. Carcinomas arise from epithelial cells, and tumor progression involves a loss of polarity, so an understanding of cell polarity is important in the identification of novel therapeutic approaches to cancer. Cell polarity is usually lost early during tumor progression, and several polarity proteins have been identified as tumor suppressors.
We have four major research programs on (a) the mechanisms that determine the polarization of mammalian epithelial cells; (b) the control of mammary gland morphogenesis and breast cancer initiation and metastasis; (c) the role of stem cells and mechanisms contrling stemness in mammary gland morphogenesis; and (d) the role of a novel exonuclease in DNA repair of interstrand crosslinks.
We use a range of approaches to study these cell processes, including a mammary gland regeneration model in which mammary stem cells are transduced with lentivirus then transplanted into the cleared fat pads of recipient mice, where the cells regenerate an entire new mammary ductal tree. In vitro studies include 3D culture of mammary gland organoids, human breast tissue organotypic cultures, and renal epithelial cysts. We are using these systems to explore the mechanisms that control spindle orientation during mitosis; the roles of small GTPases in cell polarization; and the mechanisms that underlie multipotency versus unipotency in mammary stem cells.

Publications
  • Archibald A, Mihai C, Macara IG, McCaffrey L. Oncogenic suppression of apoptosis uncovers a Rac1/JNK proliferation pathway activated by loss of Par3. Oncogene [print-electronic]. 2015 Jun 6/11/2015; 34(24): 3199-206. PMID: 25109337, PMCID: PMC4324374, PII: onc2014242, DOI: 10.1038/onc.2014.242, ISSN: 1476-5594.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/25109337.
  • Guyer RA, Macara IG. Loss of the polarity protein PAR3 activates STAT3 signaling via an atypical protein kinase C (aPKC)/NF-¿B/interleukin-6 (IL-6) axis in mouse mammary cells. J. Biol. Chem [print-electronic]. 2015 Mar 3/27/2015; 290(13): 8457-68. PMID: 25657002, PMCID: PMC4375497, PII: M114.621011, DOI: 10.1074/jbc.M114.621011, ISSN: 1083-351X.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/25657002.
  • Iioka H, Macara IG. Detection of RNA-Protein Interactions Using Tethered RNA Affinity Capture. Methods Mol. Biol. 2015; 1316: 67-73. PMID: 25967053, DOI: 10.1007/978-1-4939-2730-2_6, ISSN: 1940-6029.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/25967053.
  • Macara IG, Guyer R, Richardson G, Huo Y, Ahmed SM. Epithelial homeostasis. Curr. Biol. 2014 Sep 9/8/2014; 24(17): R815-25. PMID: 25202877, PMCID: PMC4196707, PII: S0960-9822(14)00785-4, DOI: 10.1016/j.cub.2014.06.068, ISSN: 1879-0445.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/25202877.
  • Huo Y, Macara IG. The Par3-like polarity protein Par3L is essential for mammary stem cell maintenance. Nat. Cell Biol [print-electronic]. 2014 Jun; 16(6): 529-37. PMID: 24859006, PMCID: PMC4083567, PII: ncb2969, DOI: 10.1038/ncb2969, ISSN: 1476-4679.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/24859006.
  • Rodriguez-Boulan E, Macara IG. Organization and execution of the epithelial polarity programme. Nat. Rev. Mol. Cell Biol. 2014 Apr; 15(4): 225-42. PMID: 24651541, PMCID: PMC4211427, PII: nrm3775, DOI: 10.1038/nrm3775, ISSN: 1471-0080.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/24651541.
  • Baschieri F, Confalonieri S, Bertalot G, Di Fiore PP, Dietmaier W, Leist M, Crespo P, Macara IG, Farhan H. Spatial control of Cdc42 signalling by a GM130-RasGRF complex regulates polarity and tumorigenesis. Nat Commun. 2014; 5: 4839. PMID: 25208761, PMCID: PMC4449154, PII: ncomms5839, DOI: 10.1038/ncomms5839, ISSN: 2041-1723.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/25208761.
  • McCaffrey LM, Macara IG. Signaling pathways in cell polarity. Cold Spring Harb Perspect Biol. 2012 Jun; 4(6): PMID: 22553378, PMCID: PMC3367552, PII: cshperspect.a009654, DOI: 10.1101/cshperspect.a009654, ISSN: 1943-0264.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/22553378.
  • Lohia M, Qin Y, Macara IG.. The Scribble polarity protein stabilizes E-cadherin/p120-catenin binding and blocks retrieval of E-cadherin to the Golgi. 2012;
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/23226478.
  • McCaffrey LM, Montalbano J, Mihai C, Macara IG.. Loss of the Par3 polarity protein promotes breast tumorigenesis and metastasis. 2012;
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/23153534.
  • McCaffrey LM, Macara IG. Epithelial organization, cell polarity and tumorigenesis. Trends Cell Biol [print-electronic]. 2011 Dec; 21(12): 727-35. PMID: 21782440, PII: S0962-8924(11)00126-7, DOI: 10.1016/j.tcb.2011.06.005, ISSN: 1879-3088.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/21782440.
  • Pasic L, Eisinger-Mathason TS, Velayudhan BT, Moskaluk CA, Brenin DR, Macara IG, Lannigan DA. Sustained activation of the HER1-ERK1/2-RSK signaling pathway controls myoepithelial cell fate in human mammary tissue. Genes Dev. 2011 Aug 8/1/2011; 25(15): 1641-53. PMID: 21828273, PMCID: PMC3182019, PII: 25/15/1641, DOI: 10.1101/gad.2025611, ISSN: 1549-5477.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/21828273.
  • Hao Y, Du Q, Chen X, Zheng Z, Balsbaugh JL, Maitra S, Shabanowitz J, Hunt DF, Macara IG. Par3 controls epithelial spindle orientation by aPKC-mediated phosphorylation of apical Pins. Curr. Biol [print-electronic]. 2010 Oct 10/26/2010; 20(20): 1809-18. PMID: 20933426, PMCID: PMC2963683, PII: S0960-9822(10)01150-4, DOI: 10.1016/j.cub.2010.09.032, ISSN: 1879-0445.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/20933426.
  • Tooley CE, Petkowski JJ, Muratore-Schroeder TL, Balsbaugh JL, Shabanowitz J, Sabat M, Minor W, Hunt DF, Macara IG. NRMT is an alpha-N-methyltransferase that methylates RCC1 and retinoblastoma protein. Nature. 2010 Aug 8/26/2010; 466(7310): 1125-8. PMID: 20668449, PMCID: PMC2939154, PII: nature09343, DOI: 10.1038/nature09343, ISSN: 1476-4687.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/20668449.
  • Qin Y, Meisen WH, Hao Y, Macara IG. Tuba, a Cdc42 GEF, is required for polarized spindle orientation during epithelial cyst formation. J. Cell Biol. 2010 May 5/17/2010; 189(4): 661-9. PMID: 20479467, PMCID: PMC2872902, PII: jcb.201002097, DOI: 10.1083/jcb.201002097, ISSN: 1540-8140.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/20479467.
  • McCaffrey LM, Macara IG. The Par3/aPKC interaction is essential for end bud remodeling and progenitor differentiation during mammary gland morphogenesis. Genes Dev. 2009 Jun 6/15/2009; 23(12): 1450-60. PMID: 19528321, PMCID: PMC2701573, PII: 23/12/1450, DOI: 10.1101/gad.1795909, ISSN: 1549-5477.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/19528321.
  • Macara IG, Mili S. Polarity and differential inheritance--universal attributes of life?. Cell. 2008 Nov 11/28/2008; 135(5): 801-12. PMID: 19041746, PMCID: PMC2844324, PII: S0092-8674(08)01392-5, DOI: 10.1016/j.cell.2008.11.006, ISSN: 1097-4172.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/19041746.
  • Hao Y, Macara IG. Regulation of chromatin binding by a conformational switch in the tail of the Ran exchange factor RCC1. J. Cell Biol [print-electronic]. 2008 Sep 9/8/2008; 182(5): 827-36. PMID: 18762580, PMCID: PMC2528582, PII: jcb.200803110, DOI: 10.1083/jcb.200803110, ISSN: 1540-8140.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/18762580.
  • Eisinger-Mathason TS, Andrade J, Groehler AL, Clark DE, Muratore-Schroeder TL, Pasic L, Smith JA, Shabanowitz J, Hunt DF, Macara IG, Lannigan DA. Codependent functions of RSK2 and the apoptosis-promoting factor TIA-1 in stress granule assembly and cell survival. Mol. Cell. 2008 Sep 9/5/2008; 31(5): 722-36. PMID: 18775331, PMCID: PMC2654589, PII: S1097-2765(08)00573-X, DOI: 10.1016/j.molcel.2008.06.025, ISSN: 1097-4164.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/18775331.
  • Mili S, Moissoglu K, Macara IG. Genome-wide screen reveals APC-associated RNAs enriched in cell protrusions. Nature. 2008 May 5/1/2008; 453(7191): 115-9. PMID: 18451862, PMCID: PMC2782773, PII: nature06888, DOI: 10.1038/nature06888, ISSN: 1476-4687.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/18451862.
  • Zhang H, Macara IG. The PAR-6 polarity protein regulates dendritic spine morphogenesis through p190 RhoGAP and the Rho GTPase. Dev. Cell. 2008 Feb; 14(2): 216-26. PMID: 18267090, PMCID: PMC2768076, PII: S1534-5807(07)00476-5, DOI: 10.1016/j.devcel.2007.11.020, ISSN: 1534-5807.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/18267090.
  • Goldstein B, Macara IG. The PAR proteins: fundamental players in animal cell polarization. Dev. Cell. 2007 Nov; 13(5): 609-22. PMID: 17981131, PMCID: PMC2964935, PII: S1534-5807(07)00385-1, DOI: 10.1016/j.devcel.2007.10.007, ISSN: 1534-5807.
    Available from: http://www.ncbi.nlm.nih.gov/pubmed/17981131.