Children and adults with NF1 are prone to develop brain tumors. In children, most of these tumors are low-grade gliomas involving the optic nerve, called an optic pathway glioma (OPG), while adults can develop more aggressive (malignant) gliomas.
Using a variety of different methods and approaches, investigators in the Washington University NF Center are focused on creating small animal and tissue culture models of NF1-associated brain tumors. These preclinical models are employed to discover new anti-cancer drugs and evaluate their safety and efficacy prior to clinical trials in people with NF1.
- Cellular origins of brain tumors
- Role of immune cells in brain tumor formation and growth
- Role of nerves in brain tumor development
- Identification and preclinical evaluation of new brain tumor therapies
Cellular origins of brain tumors
Research over the past decade has shown that brain tumors arise from a number of different types of cells in the brain. Determining where these tumors come from in children and adults with NF1 may yield new insights into how best to prevent their formation.
To understand the cellular origins of NF1-associated gliomas, Dr. David Gutmann, Dr. Nicole Brossier, Dr. Corina Anastasaki and their colleagues are using novel mouse strains and patient-derived tumor models. These studies aim to identify which cells in the developing brain give rise to low-grade gliomas in children and malignant brain tumors in young adults with NF1.
Anastasaki C, Chatterjee J, Cobb O, Sanapala S, Scheaffer SM, De Andrade Costa A, Wilson AF, Kernan CM, Zafar AH, Ge X, Garbow JR, Rodriguez FJ, Gutmann DH. Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling. Acta Neuropathol Commun. 2022 Aug 19;10(1):120. doi: 10.1186/s40478-022-01428-2. PMID: 35986378
Brossier NM, Thondapu S, Cobb OM, Dahiya S, Gutmann DH. Temporal, spatial, and genetic constraints contribute to the patterning and penetrance of murine neurofibromatosis-1 optic glioma. Neuro Oncol. 2021 Apr 12;23(4):625-637. doi: 10.1093/neuonc/noaa237. PMID: 33080011
Lee DY, Gianino SM, Gutmann DH. Innate neural stem cell heterogeneity determines the patterning of glioma formation in children. Cancer Cell. 2012 Jul 10;22(1):131-8. doi: 10.1016/j.ccr.2012.05.036. PMID: 22789544.
Role of immune cells in brain tumor formation and growth
Brain tumors contain both cancerous and non-cancerous cells, specifically immune system cells called T lymphocytes (T cells) and monocytes (microglia). Studies in the Washington University NF Center have revealed that these immune cells play critical roles in the development and growth of optic gliomas.
Studies ongoing in Dr. Gutmann’s laboratory are focused on understanding how these immune cells support brain tumor growth, how they are recruited into the developing tumor, and how they could be modified using immune therapies to block optic glioma development and growth.
Guo X, Pan Y, Xiong M, Sanapala S, Anastasaki C, Cobb O, Dahiya S, Gutmann DH. Midkine activation of CD8+ T cells establishes a neuron-immune-cancer axis responsible for low-grade glioma growth. Nat Commun. 2020 May 1;11(1):2177. doi: 10.1038/s41467-020-15770-3. PMID: 32358581
De Andrade Costa A, Chatterjee J, Cobb O, Cordell E, Chao A, Schaeffer S, Goldstein A, Dahiya S, Gutmann DH. Immune deconvolution and temporal mapping identifies stromal targets and developmental intervals for abrogating murine low-grade optic glioma formation. Neurooncol Adv. 2021 Dec 31;4(1):vdab194. doi: 10.1093/noajnl/vdab194. eCollection 2022 Jan-Dec. PMID: 35187488
Pan Y, Xiong M, Chen R, Ma Y, Corman C, Maricos M, Kindler U, Semtner M, Chen YH, Dahiya S, Gutmann DH. Athymic mice reveal a requirement for T-cell-microglia interactions in establishing a microenvironment supportive of Nf1 low-grade glioma growth. Genes Dev. 2018 Apr 1;32(7-8):491-496. doi: 10.1101/gad.310797.117. Epub 2018 Apr 9. PMID: 29632086.
Role of nerve cells in brain tumor formation and growth
Brain tumors form and grow in an environment rich in nerves. While not conventionally thought to control tumor development and progression, recent studies have revealed that nerve cells are important drivers of optic glioma initiation and continued growth.
Studies in the laboratories of Dr. Gutmann, Dr. Anastasaki and Dr. Pan are focused on understanding how mutations in the NF1 gene cause nerve cells (neurons) to be hyperexcitable, defining the mechanisms by which nerves control tumor growth, and identifying therapies that safely block neuron activity-driven tumor expansion.
Anastasaki C, Gao Y, Gutmann DH. Neurons as stromal drivers of nervous system cancer formation and progression. Dev Cell. 2023 Jan 23;58(2):81-93. doi: 10.1016/j.devcel.2022.12.011. PMID: 36693322
Anastasaki C, Mo J, Chen JK, Chatterjee J, Pan Y, Scheaffer SM, Cobb O, Monje M, Le LQ, Gutmann DH. Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1. Nat Commun. 2022 May 19;13(1):2785. doi: 10.1038/s41467-022-30466-6. PMID: 35589737
Pan Y, Hysinger JD, Barron T, Schindler NF, Cobb O, Guo X, Yalçın B, Anastasaki C, Mulinyawe SB, Ponnuswami A, Scheaffer S, Ma Y, Chang KC, Xia X, Toonen JA, Lennon JJ, Gibson EM, Huguenard JR, Liau LM, Goldberg JL, Monje M, Gutmann DH. NF1 mutation drives neuronal activity-dependent initiation of optic glioma. Nature. 2021 Jun;594(7862):277-282. doi: 10.1038/s41586-021-03580-6. Epub 2021 May 26. PMID: 34040258
Identification and preclinical evaluation of new brain tumor therapies
After the identification of the NF1 gene and its protein (neurofibromin), several promising drugs have been identified that are currently being evaluated as potential therapies for children and adults with NF1. However, these treatments do not work in all individuals and are often associated with serious side effects. To provide alternatives to our currently available therapies, investigators in the Washington University NF Center are identifying and evaluating new drugs for the treatment of optic glioma, brain tumors, neurofibromas, and malignant peripheral nerve sheath tumors using mice and patient-derived tumor specimens.
These studies are designed to rapidly test the most promising candidate drugs prior to their evaluation in children and adults with NF1. Additional compounds are also currently being evaluated for their ability restore or prevent vision loss from NF1-OPG.
Toonen JA, Ma Y, Gutmann DH. Defining the temporal course of murine neurofibromatosis-1 optic gliomagenesis reveals a therapeutic window to attenuate retinal dysfunction. Neuro Oncol. 2017 Jun 1;19(6):808-819. doi: 10.1093/neuonc/now267. PMID: 28039362.
Toonen JA, Solga AC, Ma Y, Gutmann DH. Estrogen activation of microglia underlies the sexually dimorphic differences in Nf1 optic glioma-induced retinal pathology. J Exp Med. 2017 Jan;214(1):17-25. doi: 10.1084/jem.20160447. Epub 2016 Dec 6. PMID: 27923908.
Kaul A, Toonen JA, Cimino PJ, Gianino SM, Gutmann DH. Akt- or MEK-mediated mTOR inhibition suppresses Nf1 optic glioma growth. Neuro Oncol. 2015 Jun;17(6):843-53. doi: 10.1093/neuonc/nou329. Epub 2014 Dec 21. PMID: 25534823.