A Spontaneous Murine Model for the Study of CD44 in Glioma Progression.
Postdoctoral Associate, Baylor College of Medicine
Undergraduate Institution and Major/Degree:
Gustavus Adolphus College, BA in Biochemistry and Chemistry, 2005
John Olhfest, Ph.D.
CD44 is a transmembrane receptor for hyaluronan that coordinates intracellular signaling and cytoskeleton rearrangements in response to cues from the extracellular matrix. As brain tumors develop in a hyaluronan rich environment, overexpression of CD44 can lead to the enhancement of proliferation, migration, and survival facilitated by CD44. My lab has developed a murine model of gliomas that is uniquely suited for CD44 loss of function studies. Malignant gliomas are induced in mice by transfecting plasmids encoding oncogenes, SV40LgT and NRasG12V, into the lateral ventricle of wildtype (CD44+/+) and knockout (CD44-/-) mice. In CD44+/+ mice, grade 3-4 gliomas advance rapidly as assessed by steadily increasing bioluminescent imaging and a median survival of 39 days. In contrast to CD44+/+ rapid tumor growth, CD44-/- tumors have a significant delay in progression (median survival=50 days). Importantly, a subset of tumors in CD44-/- mice spontaneously regresses as measured by bioimaging. CD44 loss of function can be rescued by expressing murine CD44 cDNA in cis on the NrasG12V plasmid. The significant extension of survival in CD44-/- mice is abolished when CD44 expression is rescued exclusively in the tumor cells. Therefore, glioma cells require CD44 to facilitate tumor initiation and progression.
- John Olhfest
- Guiseppe Pellizzer
- Donald Simone
Courses Taken Beyond the Core Courses:
- CMB 8361 Neuro-Immune Interactions
- NSC 5667 Neurobiology in Disease
- MICA 8003 Immunity & Immunopathology
- MICA 8004 Cellular & Cancer Biology
- GCD 8181 Stem Cell Biology
- CMB 5910 Grantwriting
- Decker SA*, Wiesner SM*, Larson JD, Ericson K, Forster C, Gallardo JL, Long C, Demorest ZL, Zamora EA, Low WC, SantaCruz K, Largaespada DA, Ohlfest JR. De novo induction of genetically engineered brain tumors in mice using plasmid DNA. Cancer Res. 2009 Jan 15;69(2):431-9. PMID:19147555.
- Fujita M, Scheurer ME, Decker SA, McDonald HA, Kohanbash G, Kastenhuber ER, Kato H, Bondy ML, Ohlfest JR, Okada H. Role of type 1 IFNs in antiglioma immunosurveillance—using mouse studies to guide examination of novel prognostic markers in humans. Clin Cancer Res. 2010 Jul 1;16(13):3409-19. PMID:20472682
- Fujita M, Kohanbash G, Fellows-Mayle W, Hamilton RL, Komohara Y, Decker SA, Ohlfest JR, Okada H. COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells. Cancer Res. 2011 Apr 1;71(7):2664-74. PMID:21324923
- Agarwal S, Mittapalli R, Zellmer DM, Gallardo JL, Donelson R, Seiler C, Decker SA, SantaCruz KS, Pokorny JL, Sarkaria JN, Elmquist WF, Ohlfest JR. Active efflux of dasatinib from the brain limits efficacy against murine glioblastoma: broad implications for the clinical use of molecularly-targeted agents. Mol Can Ther. In Press. PMID: 22891038
- Murphy KA, Lechner MG, Popescu FE, Bedi J, Decker SA, Hu P, Erickson JR, O’Sullivan MG, Swier L, Salazar AM, Olin MR, Epstein AL, Ohlfest JR. An in vivo immunotherapy screen of costimulatory molecules identifies Fc-OX40L as a potent reagent for the treatment of established murine gliomas. Clin Cancer Res. 2012 Sep 1;18(17):4657-68. PMID: 22781551
Awards and Honors:
- Brain Tumor Program Travel Award 2008, 2009, 2010
- Milne/Brandenburg Award 2009
- Brain Tumor Biology and Progression Award 2010
- Stark Award 2010
- Society for Neuroscience annual meeting - Fall 2006
- Society for Neuro-Oncology, Annual Meeting – 2007
- Crystal, MN