Jeremy T. Miyauchi
B.S. Cornell University, 2009
PhD Stony Brook University 2017
8th Year MSTP
4th Year Medical Student
Advisor:
Styliani E. Tsirka, PhD
Department: Pharmacological Sciences, Stony Brook University
Graduate Program: Molecular & Cellular Pharmacology
Title:
The role of Neuropilin 1 in glioma associated
microglia and macrophages
Abstract:
Gliomas are the most commonly diagnosed primary tumors of the central nervous
system (CNS). Median times of survival are dismal regardless of the treatment
approach, underlying the need to develop more effective therapies. Modulation
of the immune system is a promising strategy as innate and adaptive immunity
play important roles in cancer progression. Glioma associated microglia and
macrophages (GAMs) can comprise over 30% of the cells in glioma biopsies.
Gliomas secrete cytokines that suppress the anti-tumorigenic properties of
GAMs, causing them to secrete factors that support the tumor’s spread and
growth. Neuropilin 1 (Nrp1) is a transmembrane receptor that in mice both amplifies
pro-angiogenic signaling in the tumor microenvironment and affects behavior of
innate immune cells. Using a Cre-lox system, we generated mice that lacked
expression of Nrp1 in GAMs. We demonstrated, using an in vivo orthotopic glioma
model, that tumors in mice with Nrp1-deficient GAMs exhibited less vascularity,
grew at a slower pace, and were populated by increased numbers of
anti-tumorigenic GAMs. Moreover, glioma survival times in mice with
Nrp1-deficient GAMs were significantly longer. Treating wild-type mice with a
small molecule inhibitor of Nrp1’s b1 domain, EG00229, which we showed was
selective for Nrp1 over Nrp2, yielded an identical outcome. Transplanting bone
marrow from mice with Nrp1-deficient macrophages to wild type recipient mice
led to reductions in tumor growth, al-be-it not to the extent seen in knockout
mice. Additionally, mice with only Nrp1-deficient microglia but wild type BMDMs
had a slower disease course with microglia making up a higher percentage of
overall GAM infiltrate, relative to wild type mice which received wild type
allografts. In both cases, Nrp1-deficient microglia or BMDMs exhibited an
increased anti-tumorigenic phenotype relative to wild type macrophages or
microglia within the vicinity. Nrp1-deficient or EG00229-treated wild-type
microglia exhibited a shift towards anti-tumorigenicity as evident by altered
inflammatory marker profiles in vivo and decreased SMAD2/3 activation when
conditioned in the presence of glioma-derived factors. These results provide
support for the proposal that pharmacological inhibition of Nrp1 constitutes a
potential strategy for suppressing glioma progression.
Awards
ASPET Graduate Student Travel Award (2015)
AACR Scholar in Training Award (2016)
Kirschstein-NRSA Fellowship Award for Predoctoral MD/PhD Fellows F30CA196110 (2016-2019)
ASPET Graduate Student Travel Award (2016)
ASPET 2nd Place Best Abstract Award for Translational and Clinical Pharmacology at EB 2016 (2016)
ASPET Graduate Student Travel Award (2017)
ASPET 2nd Place Young Investigator Award for Best Oral Presentation at EB2017 (2017)
Publications:
(MSTP-supported publications indicated with an *)
*Steadman D, Crosby S, Jarvis A, Powell J, Miyauchi JT, Reisinger T, Winfield N, Milagre C, Filipa M, Yelland T, Chan AW, O’Leary A, Liu D, Fotinou D, Jia H, Frankel P, Zachary IC, Djordevic S, Tsirka SE, Selwood D. (2018) Structure-based design of a potent class of neuropilin-1 antagonists reveals a new, anti-angiogenic, anti-tumour compound with therapeutic potential. JMC. 61(9): 4135-4154.
*Caponegro MD, Miyauchi JT and Tsirka SE. (2018) Contributions of Immune Cell Populations in the Maintenance, Progression, and Therapeutic Modalities of Glioma. AIMS Allergy and Immunology. 2(1): 24-44.
*Haj-Dahmane S, Elmes MW, Studholme K, Kanjiya MP, Dilger JP, Hotamisligil GS, Miyauchi JT, Tsirka SE, Deutsch DG, Thanos PK, Kaczocha M. (2018) Fatty Acid binding protein 5 Controls Retrograde Endocannabinoid Signaling at Central Glutamate Synapses. PNAS. 115(13): 3482-3487.
*Miyauchi JT, Caponegro M, Chen D, Choi M, Li M, Tsirka SE. (2018) Deletion of neuropilin 1 from microglia or bone marrow-derived macrophages slows glioma progression. Cancer Research. 78(3): 685-694.
*Miyauchi JT and Tsirka SE. (2017) Advances in the Implementation and Evaluation of Glioma Immunotherapy. Journal of Neurology. 265(4): 741-756.
*Miyauchi JT and Tsirka SE. (2016) Defining differential roles for microglia and infiltrating macrophages in the growth and neovascularization of glioma. Translational Cancer Research. 5(Suppl 4): S648-S651.
*Lewis CS*, Torres L*, Miyauchi JT*, Rastegar C, Patete JM, Smith JM, Wong SS, Tsirka SE. (2016) Absence of Cytotoxicity towards Microglia of Iron Oxide (α-Fe2O3) Nanorhombohedra. Toxicology Research. 5: 836-847.
*Miyauchi JT, Chen D, Choi M, Nissen JC, Shroyer KR, Djordevic S, Zachary IC, Selwood D, Tsirka SE. (2016) Ablation of Neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression. Oncotarget. 7(9): 9801-9814.
*Elmes MW, Kaczocha M, Berger WT, Leung KN, Ralph BP, Wang L, Miyauchi JT, Ji K, Tsirka SE, Ojima I, Deutsch DG. (2015) Fatty Acid Binding Proteins (FABPs) are Intracellular Carriers for Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD). J. Biol. Chem. 290(14): 8711-8721.
*Torres L, Danver J, Ji K, Miyauchi JT, Chen D, Anderson ME, West BL, Robinson JK, Tsirka SE. (2015) Dynamic microglial modulation of spatial learning and social behavior. Brain Behav Immun. http://dx.doi.org/10.1016/j.bbi.2015.09.001
*Ji K, Miyauchi J, Tsirka SE. (2013) Microglia: an active player in the regulation of synaptic activity. Neural Plasticity 2013: 627325.
Miyauchi JT, Piermarini PM, Yang JD, Gilligan DM, Beyenbach KW. (2013) Roles of PKC and phosphoadducin in transepithelial fluid secretion by Malphigian tubules of the yellow fever mosquito. Tissue Barriers 1(1): e23120.
Piermarini PM, Hine RM, Schepel M, Miyauchi J, Beyenbach KW. (2011). Role of an apical K,Cl cotransporter in urine formation by renal tubules of the yellow fever mosquito (Aedes aegypti). Am J Physiol Regul Integr Comp Physiol. 301(5):R1318-37.
Schepel SA, Fox AJ, Miyauchi JT, Sou T, Yang JD, Lau K, Blum AW, Nicholson LK, Tiburcy F, Nachman RJ, Piermarini PM, Beyenbach KW. (2010). The single kinin receptor signals to separate and independent physiological pathways in Malpighian tubules of the yellow fever mosquito. Am J Reg Integr CompPhys.299(2): R612-622.
