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Brain tumors are the most common cause of cancer-related death in children. Better cancer therapy can only come from improved understanding of the molecular mechanisms driving growth of tumors. Our laboratory strives to better understand the biology of brain tumors and thus contribute to development of novel treatments based on tumor biology.
Not long ago we came across a little-known gene called PID1 (Phosphotyrosine Interaction Domain containing 1; also called NYGGF4), which surfaced in a colleague’s microarray dataset as one of the genes that was highly correlated with survival of children with medulloblastoma (the most common malignant brain tumor in children). Online tools revealed that mRNA of PID1 was also highly correlated with survival in gliomas, such that higher PID1 mRNA level correlated with longer survival, leading us to test its effect in cell culture: we found remarkable inhibitory effects of PID1 on growth of three types of brain tumor cell lines: medulloblastomas, glioblastomas, and atypical teratoid rhabdoid (ATRT) tumors. This work was published in Clinical Cancer Research in 2014 (Erdreich-Epstein et al) and was the first peer-reviewed publication to link PID1 to cancer. This work suggested that PID1 is a novel candidate tumor inhibitor in brain cancer.
Not much is known about PID1 to date, with only about 20 peer reviewed papers published on it. Other than its effects in brain tumors, PID1 has mostly been studied in adipocytes and muscle cells. It is known as an inhibitor of insulin receptor signaling and thought to play a role in insulin resistance in obesity. PID1 strongly inhibits mitochondrial function and is known to directly bind to the Low Density lipoprotein receptor-related Protein 1, LRP1, although the function of this interaction remains unknown. PID1 has also been found to vary in brains of Alzheimer’s patients compared to healthy ones, although here too, its function is not clear. Clearly, the molecular mechanism by which PID1 functions and a link to explain its effect in these diverse conditions remains unknown.
Interesting preliminary data in our lab now suggest that PID1 has a central role in a number of important biological processes. Most of the effort of our laboratory is now directed toward understanding the function and molecular mechanism of PID1, using in vitro and in vivo approaches.
Wong K, Opimo AB, Olch AJ, All S, Waxer JF, Clark D, Cheng J, Chlebik A, Erdreich-Epstein A, Krieger MD, Tamrazi B, Dhall G, Finlay JL, Chang EL. Re-irradiation of Recurrent Pineal Germ Cell Tumors with Radiosurgery: Report of Two Cases and Review of Literature. Cureus. 2016; 8(4):e585. View in: PubMed
Shackleford GM, Shi XH, Swanson KS, Mahdi MY, Gonzalez-Gomez I, Asgharzadeh S, D'Apuzzo M, Erdreich-Epstein A, Moats RA. BarTeL, a Genetically Versatile, Bioluminescent and Granule Neuron Precursor-Targeted Mouse Model for Medulloblastoma. PLoS One. 2016; 11(6):e0156907. View in: PubMed
Blüml S, Margol AS, Sposto R, Kennedy RJ, Robison NJ, Vali M, Hung LT, Muthugounder S, Finlay JL, Erdreich-Epstein A, Gilles FH, Judkins AR, Krieger MD, Dhall G, Nelson MD, Asgharzadeh S. Molecular subgroups of medulloblastoma identification using noninvasive magnetic resonance spectroscopy. Neuro Oncol. 2016 Jan; 18(1):126-31. View in: PubMed
Chakravadhanula M, Hampton CN, Chodavadia P, Ozols V, Zhou L, Catchpoole D, Xu J, Erdreich-Epstein A, Bhardwaj RD. Wnt pathway in atypical teratoid rhabdoid tumors. Neuro Oncol. 2015 Apr; 17(4):526-35. View in: PubMed
Margol AS, Robison NJ, Gnanachandran J, Hung LT, Kennedy RJ, Vali M, Dhall G, Finlay JL, Erdreich-Epstein A, Krieger MD, Drissi R, Fouladi M, Gilles FH, Judkins AR, Sposto R, Asgharzadeh S. Tumor-Associated Macrophages in SHH Subgroup of Medulloblastomas. Clin Cancer Res. 2015 Mar 15; 21(6):1457-65. View in: PubMed
Weingart MF, Roth JJ, Hutt-Cabezas M, Busse TM, Kaur H, Price A, Maynard R, Rubens J, Taylor I, Mao XG, Xu J, Kuwahara Y, Allen SJ, Erdreich-Epstein A, Weissman BE, Orr BA, Eberhart CG, Biegel JA, Raabe EH. Disrupting LIN28 in atypical teratoid rhabdoid tumors reveals the importance of the mitogen activated protein kinase pathway as a therapeutic target. Oncotarget. 2015 Feb 20; 6(5):3165-77. View in: PubMed
Kaur H, Hütt-Cabezas M, Weingart MF, Xu J, Kuwahara Y, Erdreich-Epstein A, Weissman BE, Eberhart CG, Raabe EH. The Chromatin-Modifying Protein HMGA2 Promotes Atypical Teratoid/Rhabdoid Cell Tumorigenicity. J Neuropathol Exp Neurol. 2015 Feb; 74(2):177-85. View in: PubMed
Xu J, Margol A, Asgharzadeh S, Erdreich-Epstein A. Pediatric brain tumor cell lines. J Cell Biochem. 2015 Feb; 116(2):218-24. View in: PubMed
Xu J, Margol AS, Shukla A, Ren X, Finlay JL, Krieger MD, Gilles FH, Couch FJ, Aziz M, Fung ET, Asgharzadeh S, Barrett MT, Erdreich-Epstein A. Disseminated Medulloblastoma in a Child with Germline BRCA2 6174delT Mutation and without Fanconi Anemia. Front Oncol. 2015; 5:191. View in: PubMed
Nandhu MS, Hu B, Cole SE, Erdreich-Epstein A, Rodriguez-Gil DJ, Viapiano MS. Novel Paracrine Modulation of Notch-DLL4 Signaling by Fibulin-3 Promotes Angiogenesis in High-Grade Gliomas. Cancer Res. 2014 Oct 1; 74(19):5435-48. View in: PubMed
Antony R, Wong KE, Patel M, Olch AJ, McComb G, Krieger M, Gilles F, Sposto R, Erdreich-Epstein A, Dhall G, Gardner S, Finlay JL. A retrospective analysis of recurrent intracranial ependymoma. Pediatr Blood Cancer. 2014 Jul; 61(7):1195-201. View in: PubMed
Erdreich-Epstein A, Robison N, Ren X, Zhou H, Xu J, Davidson TB, Schur M, Gilles FH, Ji L, Malvar J, Shackleford GM, Margol AS, Krieger MD, Judkins AR, Jones DT, Pfister SM, Kool M, Sposto R, Asgharazadeh S. PID1 (NYGGF4), a New Growth-Inhibitory Gene in Embryonal Brain Tumors and Gliomas. Clin Cancer Res. 2014 Feb 15; 20(4):827-36. View in: PubMed
Lee JS, Xiao J, Patel P, Schade J, Wang J, Deneen B, Erdreich-Epstein A, Song HR. A novel tumor-promoting role for nuclear factor IA in glioblastomas is mediated through negative regulation of p53, p21, and PAI1. Neuro Oncol. 2014 Jan; 16(2):191-203. View in: PubMed
Gozali AE, Britt B, Shane L, Gonzalez I, Gilles F, McComb JG, Krieger MD, Lavey RS, Shlien A, Villablanca JG, Erdreich-Epstein A, Dhall G, Jubran R, Tabori U, Malkin D, Finlay JL. Choroid plexus tumors; management, outcome, and association with the Li-Fraumeni syndrome: The Children's Hospital Los Angeles (CHLA) experience, 1991-2010. Pediatr Blood Cancer. 2012 Jun; 58(6):905-9. View in: PubMed
Ridgway LD, Wetzel MD, Ngo JA, Erdreich-Epstein A, Marchetti D. Heparanase-Induced GEF-H1 Signaling Regulates the Cytoskeletal Dynamics of Brain Metastatic Breast Cancer Cells. Mol Cancer Res. 2012 Jun; 10(6):689-702. View in: PubMed
Xu J, Erdreich-Epstein A, Gonzalez-Gomez I, Melendez EY, Smbatyan G, Moats RA, Rosol M, Biegel JA, Reynolds CP. Novel cell lines established from pediatric brain tumors. J Neurooncol. 2012 Apr; 107(2):269-80. View in: PubMed
Ren X, Xu J, Cooper JP, Kang MH, Erdreich-Epstein A. c-Abl Is an Upstream Regulator of Acid Sphingomyelinase in Apoptosis Induced by Inhibition of Integrins avß3 and avß5. PLoS One. 2012; 7(8):e42291. View in: PubMed
Davidson TB, Sanchez-Lara PA, Randolph LM, Krieger MD, Wu SQ, Panigrahy A, Shimada H, Erdreich-Epstein A. Microdeletion del(22)(q12. 2) encompassing the facial development-associated gene, MN1 (meningioma 1) in a child with Pierre-Robin sequence (including cleft palate) and neurofibromatosis 2 (NF2): a case report and review of the literature. BMC Med Genet. 2012; 13:19. View in: PubMed
Parekh C, Jubran R, Erdreich-Epstein A, Panigrahy A, Bluml S, Finlay J, Dhall G. Treatment of children with recurrent high grade gliomas with a bevacizumab containing regimen. J Neurooncol. 2011 Jul; 103(3):673-80. View in: PubMed
Chaitanya GV, Cromer WE, Wells SR, Jennings MH, Couraud PO, Romero IA, Weksler B, Erdreich-Epstein A, Mathis JM, Minagar A, Alexander JS. Gliovascular and cytokine interactions modulate brain endothelial barrier in vitro. J Neuroinflammation. 2011; 8:162. View in: PubMed
Xiong G, Husseiny MI, Song L, Erdreich-Epstein A, Shackleford GM, Seeger RC, Jäckel D, Hensel M, Metelitsa LS. Novel cancer vaccine based on genes of Salmonella pathogenicity island 2. Int J Cancer. 2010 Jun 1; 126(11):2622-34. View in: PubMed
Xu J, Millard M, Ren X, Cox OT, Erdreich-Epstein A. c-Abl mediates endothelial apoptosis induced by inhibition of integrins alphavbeta3 and alphavbeta5 and by disruption of actin. Blood. 2010 Apr 1; 115(13):2709-18. View in: PubMed
Song HR, Gonzalez-Gomez I, Suh GS, Commins DL, Sposto R, Gilles FH, Deneen B, Erdreich-Epstein A. Nuclear factor IA is expressed in astrocytomas and is associated with improved survival. Neuro Oncol. 2010 Feb; 12(2):122-32. View in: PubMed
Rosol M, Harutyunyan I, Xu J, Melendez E, Smbatyan G, Finlay JL, Krieger MD, Gonzalez-Gomez I, Reynolds CP, Nelson MD, Erdreich-Epstein A, Blüml S. Metabolism of orthotopic mouse brain tumor models. Mol Imaging. 2009 Jul-Aug; 8(4):199-208. View in: PubMed
Butturini AM, Jacob M, Aguajo J, Vander-Walde NA, Villablanca J, Jubran R, Erdreich-Epstein A, Marachelian A, Dhall G, Finlay JL. High-dose chemotherapy and autologous hematopoietic progenitor cell rescue in children with recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors: the impact of prior radiotherapy on outcome. Cancer. 2009 Jul 1; 115(13):2956-63. View in: PubMed
Rosenne E, Shakhar G, Melamed R, Schwartz Y, Erdreich-Epstein A, Ben-Eliyahu S. Inducing a mode of NK-resistance to suppression by stress and surgery: a potential approach based on low dose of poly I-C to reduce postoperative cancer metastasis. Brain Behav Immun. 2007 May; 21(4):395-408. View in: PubMed
Finlay JL, Erdreich-Epstein A, Packer RJ. Progress in the treatment of childhood brain tumors: no room for complacency. Pediatr Hematol Oncol. 2007 Jan-Feb; 24(1):79-84. View in: PubMed
Erdreich-Epstein A, Ganguly AK, Shi XH, Zimonjic DB, Shackleford GM. Androgen inducibility of Fgf8 in Shionogi carcinoma 115 cells correlates with an adjacent t(5;19) translocation. Genes Chromosomes Cancer. 2006 Feb; 45(2):169-81. View in: PubMed
Erdreich-Epstein A, Tran LB, Cox OT, Huang EY, Laug WE, Shimada H, Millard M. Endothelial apoptosis induced by inhibition of integrins alphavbeta3 and alphavbeta5 involves ceramide metabolic pathways. Blood. 2005 Jun 1; 105(11):4353-61. View in: PubMed
Sohara Y, Shimada H, Minkin C, Erdreich-Epstein A, Nolta JA, DeClerck YA. Bone marrow mesenchymal stem cells provide an alternate pathway of osteoclast activation and bone destruction by cancer cells. Cancer Res. 2005 Feb 15; 65(4):1129-35. View in: PubMed
Jubran RF, Erdreich-Epstein A, Butturini A, Murphree AL, Villablanca JG. Approaches to treatment for extraocular retinoblastoma: Children's Hospital Los Angeles experience. J Pediatr Hematol Oncol. 2004 Jan; 26(1):31-4. View in: PubMed
Stins MF, Pearce D, Di Cello F, Erdreich-Epstein A, Pardo CA, Sik Kim K. Induction of intercellular adhesion molecule-1 on human brain endothelial cells by HIV-1 gp120: role of CD4 and chemokine coreceptors. Lab Invest. 2003 Dec; 83(12):1787-98. View in: PubMed
Perelman N, Selvaraj SK, Batra S, Luck LR, Erdreich-Epstein A, Coates TD, Kalra VK, Malik P. Placenta growth factor activates monocytes and correlates with sickle cell disease severity. Blood. 2003 Aug 15; 102(4):1506-14. View in: PubMed
Erdreich-Epstein A, Tran LB, Bowman NN, Wang H, Cabot MC, Durden DL, Vlckova J, Reynolds CP, Stins MF, Groshen S, Millard M. Ceramide signaling in fenretinide-induced endothelial cell apoptosis. J Biol Chem. 2002 Dec 20; 277(51):49531-7. View in: PubMed
Erdreich-Epstein A, Monforte HL, Lavey RS, Joshi S, Phillips JD, Villablanca JG. Successful multimodality therapy of recurrent multifocal juvenile granulosa cell tumor of the ovary. J Pediatr Hematol Oncol. 2002 Mar-Apr; 24(3):229-33. View in: PubMed