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Timothy L. Ratliff

Timothy L.  Ratliff Profile Picture

Distinguished Professor Department of Comparative Pathobiology and the Robert Wallace Miller Director of the Purdue Cancer Center
MS 1984-Texas A & M, PhD 1977-University of Arkansas


Contact Info:

tlratlif@purdue.edu
765-494-9129


Training Group(s):
Molecular Signaling and Cancer Biology
Immunology and Infectious Diseases


Current Research Interests:

Dr. Ratliff’s laboratory focuses on understanding immune regulation and the development of alternative approaches to treating urologic cancers, primarily bladder and prostate cancers, through the modulation of anti-cancer immunity.  Current studies focus on prostate inflammation, its immune regulation and its impact on prostate stem cells, gene expression in prostate tissue, and cancer development.  The intent is to develop a better understanding of the inflammatory factors contributing to cancer development and to use the information gained to develop novel approaches to treating prostate cancer through modulation of the immune response.  Genetically modified mouse models are used to probe inflammation, immune regulation, the development of autoimmunity and anticancer effector mechanisms.  Regulatory cells termed myeloid-derived suppressor cells have been linked to regulation of prostate inflammation and are observed early in genetically modified mouse spontaneous prostate tumor models.  Determining how to control myeloid-derived suppressor cell function is a focus that is anticipated to provide a new approach to augmenting antitumor immunity.  Likewise, understanding the impact of inflammation on prostate stem cells is anticipated to advance knowledge about the mechanisms of prostate growth and cancer development.

Studies to understand aspects of cholesterol metabolism on prostate cancer growth are an active component of our research activities.  Cholesterol sulfate is an important metabolite of cholesterol in prostate cancer.  Cholesterol is converted to cholesterol sulfate by the sulfotransferase enzyme, SULT2B1b.  We observe the induction of apoptosis if SULT2B1b is eliminated from prostate cancer cells.  The apoptotic cascade appears to be initiated through the androgen receptor.  Current studies are focused on understanding the mechanisms by which elimination of SULT2B1b initiates apoptosis.

Studies to improve the treatment of bladder cancer through the development of nano-delivery approaches for intravesical therapy are in progress.  The fibronectin binding protein, previously identified as an important attachment protein for mycobacteria, was observed to mediate antitumor activity in a bladder tumor model and alter the bladder inflammatory process.  The fibronectin binding protein has the capacity to deliver nanoparticles to bladder cancer cells is being tested as a new approach for delivery of therapeutic agents for the treatment of superficial bladder cancer.  The approach has the potential to not only treat superficial bladder cancer but also to treat a bladder inflammatory condition termed interstitial cystitis. 

More basic studies focus on the impact of platelet-derived immunomodulatory molecules on the adaptive immune response.  Precursor frequency of antigen specific T and B lymphocytes is very low prior to antigenic recognition and clonal expansion of the reactive cells. Control of pathogenic microbes early in the infection period is linked to innate immunity prior to clonal expansion of antigen specific adaptive immunity.  Studies in the Ratliff laboratory implicate platelet-derived ligands as mediators of the early amplification of the adaptive immune compartment.  Ratliff’s team hypothesizes that platelet-derived ligands are the earliest signals to the adaptive immune compartment that enables rapid and ultimately optimal expansion of the adaptive immune response to the invading microbe.  Studies are in progress to fully characterize the role of platelets in the modulation of adaptive immunity.



Selected Publications:

Cimen Bozkus C, Elzey BD, Crist SA, Ellies LG, Ratliff TL. Expression of Cationic Amino Acid Transporter 2 is Required for Myeloid-derived Suppressor Cell-Medicated Control of T Cell Immunity. J Immunol. 2015 Dec 1;195(11):5237-50. Epub 2015 Oct 21. PMID:26491198

Li J, Karki A, Hodges KB, Ahmad N, Zoubeidi A, Strebhardt K, Ratliff TL, Konieczny SF, Liu X. Cotargeting Polo-Like Kinase 1 and the Wnt/ß-Catenin Signaling Pathway in Castration-Resistant Prostate Cancer. Mol Cell Biol. 2015 Dec 15;35(24):4185-98. doi: 10.1128/MCB.00825-15. Epub 2015 Oct 5. PMID:26438599

Wang HH, Wang L, Jerde TJ, Chan BD, Savran CA, Burcham GN, Crist S, Ratliff TL. Characterization of autoimmune inflammation induced prostate stem cell expansion. Prostate. 2015 Oct;75(14):1620-31. Epub 2015 Jul 14. PMID:26174474

Lee SS, Li J, Tai JN, Ratliff TL, Park K, Cheng JX. Avasimibe encapsulated in human serum albumin blocks cholesterol esterification for selective cancer treatment. ACS Nano. 2015 Mar 24;9(3):2420-32. Epub 2015 Feb 16. PMID:25662106

Burcham GN, Cresswell GM, Snyder PW, Chen L, Liu X, Crist SA, Henry MD, Ratliff TL. Impact of prostate inflammation on lesion development in the POET3(+)Pten (+/1) mouse model of prostate carcinogenesis. Am J Pathol. 2014 Dec;184(12):3176-91. doi: 10.1016/j.ajpath.2014.08.021. Epub 2014 Nov 22. PMID: 25455686

Yue S, Li J, Lee, SY, Lee HJ, Shao T, Song B, Cheng L, Masterson TA, Liu X, Ratliff TL, Cheng JX Cholesteryl Ester Accumulation Induced by PTEN Loss and PI3K/AKT Activation Underlies Human Prostate Cancer Aggressiveness. Cell Metabol. 2014 19:393-406. PMID: 24606897

Zhang W, Lee S, McNear KL, Chung TF, Lee S, Lee K, Crist SA, Ratliff TL, Zhong Z, Chen YP, Yang C. Sci Rep. 2014 Feb 14;4:4097. doi: 10.1038/srep04097. PMID: 24526127

Crist SA, Elzey BD, Ahmann MT, Ratliff TL. Early growth response-1 (EGR-1) and nuclear factor of activated T cells (NFAT) cooperate to mediate CD40L expression in megakaryocytes and platelets. J Biol Chem. 2013;288:33985-96. PubMed PMID: 24106272; PubMed Central PMCID: PMCPmc3837138.

Hou X, Li Z, Huang W, Li J, Staiger C, Kuang S, Ratliff TL, Liu X. Plk1-dependent microtubule dynamics promotes androgen receptor signaling in prostate cancer. Prostate. 2013 Sep;73(12):1352-63. doi: 10.1002/pros.22683. Epub 2013/05/11. doi: 10.1002/pros.22683. PubMed PMID: 23661607; PubMed Central PMCID: PMCPmc3720713.

Coon BG, Crist S, Gonzalez-Bonet AM, Kim HK, Sowa J, Thompson DH, Ratliff TL,      Aguilar RC. Fibronectin attachment protein from bacillus Calmette-Guerin as targeting agent for bladder tumor cells. International journal of cancer Journal international du cancer. 2012;131(3):591-600. Epub 2011/09/09. doi: 10.1002/ijc.26413. PMCID: PMC3276703.

Chou CK, Schietinger A, Liggitt HD, Tan X, Funk S, Freeman GJ, Ratliff TL, Greenberg NM, Greenberg PD. Cell-intrinsic abrogation of TGF-beta signaling delays but does not prevent dysfunction of self/tumor-specific CD8 T cells in a murine model of autochthonous prostate cancer. Journal of immunology (Baltimore, Md : 1950). 2012;189(8):3936-46. Epub 2012/09/18. doi: 10.4049/jimmunol.1201415. PMCID: PMC3466379.  Â

Wang X, Zhao M, Nolte DD, Ratliff TL. Prostate specific antigen detection in patient sera by fluorescence-free BioCD protein array. Biosensors & bioelectronics. 2011;26(5):1871-5. Epub 2010/03/20. doi: 10.1016/j.bios.2010.02.009.Â

Svensson RU, Haverkamp JM, Thedens DR, Cohen MB, Ratliff TL, Henry MD. Slow disease progression in a C57BL/6 pten-deficient mouse model of prostate cancer. The American journal of pathology. 2011;179(1):502-12. Epub 2011/06/28. doi: 10.1016/j.ajpath.2011.03.014. PMCID: PMC3123867.

Haverkamp JM, Crist SA, Elzey BD, Cimen C, Ratliff TL. In vivo suppressive function of myeloid-derived suppressor cells is limited to the inflammatory site. European journal of immunology. 2011;41(3):749-59. Epub 2011/02/03. doi: 10.1002/eji.201041069. PMCID: PMC3089902.

Elzey BD, Ratliff TL, Sowa JM, Crist SA. Platelet CD40L at the interface of adaptive immunity. Thrombosis research. 2011;127(3):180-3. Epub 2010/11/16. doi: 10.1016/j.thromres.2010.10.011. PMCID: PMC3073541.

Eberlin LS, Dill AL, Costa AB, Ifa DR, Cheng L, Masterson T, Koch M, Ratliff TL, Cooks RG. Cholesterol sulfate imaging in human prostate cancer tissue by desorption electrospray ionization mass spectrometry. Analytical chemistry. 2010;82(9):3430-4. Epub 2010/04/09. doi: 10.1021/ac9029482. PMCID: PMC2872194.  Â

Lubaroff DM, Konety BR, Link B, Gerstbrein J, Madsen T, Shannon M, Howard J, Paisley J, Boeglin D, Ratliff TL, Williams RD. Phase I clinical trial of an adenovirus/prostate-specific antigen vaccine for prostate cancer: safety and immunologic results. Clinical cancer research : an official journal of the American Association for Cancer Research. 2009;15(23):7375-80. Epub 2009/11/19. doi: 10.1158/1078-0432.ccr-09-1910. PMCID: PMC2787649.  Â

Sprague DL, Elzey BD, Crist SA, Waldschmidt TJ, Jensen RJ, Ratliff TL. Platelet-mediated modulation of adaptive immunity: unique delivery of CD154 signal by platelet-derived membrane vesicles. Blood. 2008;111(10):5028-36. Epub 2008/01/17. doi: 10.1182/blood-2007-06-097410. PMCID: PMC2384131.

Sinn HW, Elzey BD, Jensen RJ, Zhao X, Zhao W, Ratliff TL. The fibronectin attachment protein of bacillus Calmette-Guerin (BCG) mediates antitumor activity. Cancer immunology, immunotherapy : CII. 2008;57(4):573-9. Epub 2007/09/06. doi: 10.1007/s00262-007-0397-x.

Haverkamp J, Charbonneau B, Ratliff TL. Prostate inflammation and its potential impact on prostate cancer: a current review. Journal of cellular biochemistry. 2008;103(5):1344-53. Epub 2007/10/24. doi: 10.1002/jcb.21536

Elzey BD, Schmidt NW, Crist SA, Kresowik TP, Harty JT, Nieswandt B, Ratliff TL. Platelet-derived CD154 enables T-cell priming and protection against Listeria monocytogenes challenge. Blood. 2008;111(7):3684-91. Epub 2008/02/08. doi: 10.1182/blood-2007-05-091728. PMCID: PMC2275027.  Â

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