Li Lab - PDOX models & experimental neuro-oncology

Current Research Projects

Pre-clinical Cancer Model System

We have a specific interest in developing pre-clinical animal models for drug screening as well as biological studies of human malignant brain tumors. Since traditional subcutaneous xenograft models do not faithfully reproduce the biology of human brain tumors and are often associated with failure or reduced efficacy of the drug/therapy in clinical trials, we are actively engaged in the development of novel patient tumor derived orthotopic xenograft (PDOX or orthotopic PDX) mouse models by implanting a patient’s tumor cells directly into matched location in mouse brains.

 

Since the transplanted brain tumor cells grow in a biological and anatomic environment that is close to their native habitat, the developed xenograft tumors recapitulate the biology of human cancer much better than the traditional subcutaneous models. Therefore, the antitumor effects obtained in these models are more predictable of future clinical applications. Our laboratory has developed >120 PDOX models of 8 pediatric brain tumor pathologies as well as several models of adult GBM and meningioma. We have also developed models from patient autopsy tumor samples, which represent refractory/relapsed tumors most in need of novel therapies.

 

 

Once established, all the models are subjected to detailed histopathological examination and comprehensive molecular characterization during serial in vivo subtransplantations to ensure that these patient-specific PDOX models look like human tumor and behave like human cancers. 

 

Recognizing the need of in vitro model system and the difficulties of developing cell lines from patient tumors, we are also utilizing our PDOX model system to develop long term cultures/cell lines as monolayer, 3D neurospheres and organoids.

 

Understanding of Tumor Biology

Our PDOX model system has provided us a unique opportunity to understand tumor biology. We are actively examining the mechanisms of high grade glioma tumor invasion and medulloblastoma metastasis, analyzing the regulation of cell cycle progression (particularly from quiescent G0 to active G1 phase), and identifying new markers of cancer stem cells responsible for therapy resistance and tumor relapse.

Pre-clinical Translation to Clinical Studies

We are particularly interested in establishing a pre-clinical rationale for clinical trials of various antitumor compounds. We have optimized systems of both in vitro and in vivo assays to evaluate the antitumor effects of novel compounds on cell proliferation, apoptosis, differentiation, cellular senescence, colony forming efficiency, and tumorigenicity. In addition to collaborating with various pharmaceutical companies for examination of therapeutic efficacies in our PDOX animal models, we also conduct high-througput drug screening by examining ~8,000 drugs at same time. Our laboratory works closely with clinical investigators to quickly translate our pre-clinical findings into clinical trials; 4 clinical trials for pediatric brain tumors patients have resulted directly from our laboratory research.

Tumor Tissue Donations

Requesting of PDOX Models

We are committed to share our established PDOX models and PDOX derived cell lines with other investigators through a fully executed material transfer agreement. For those interested in obtaining our PDOX models, please contact the PI, Dr. Xiao-Nan Li, at xli@luriechildrens.org or xiaonan.li@northwestern.edu.

Laboratory Members

• Yuchen Du, PhD, Research Assistant Professor
• Lin Qi, PhD, Research Assistant Professor
• Joon Won Yoon, PhD, Research Assistant Professor
• Sophie Xiao, Research Associate III

Funding Agencies

NIH/NCI Patient-Derived Models of Cancer (UO1) (2020-2025)
NIH/NCI Pediatric Preclinical Testing Consortium (UO1)(2015-2020)
NIH/NCI RO1 (2014-2018)
Cancer Prevention & Research Institute of Texas (CPRIT) RP-1801312, 2018
The Cure Starts Now Foundation (2017-2019)
Cancer Prevention & Research Institute of Texas (CPRIT) RP-170169, 2016
Cancer Prevention & Research Institute of Texas (CPRIT) RP150032, 2014
Golfers Against Cancer (2016-2018)
The Cure Starts Now Foundation (2015-2017)
DIANA HELIS HENRY AND ADRIENNE HELIS MALVIN MEDICAL RESEARCH FOUNDATIONS (2015-2018)
Golfers Against Cancer (2015-2016)
The Cure Starts Now Foundation (2014)
Congressionally Directed Medical Research Programs (CDMRP) DOD (2011-2012)
Accelerate Brain Cancer Cure (2009-2010)
Cancer Fighters of Houston (2008)
National Brain Tumor Society (2004-2005)
Children's Brain Tumor Foundation (2003-2005)

Selected Publications

Yao M, Ventura PB, Jiang Y, Rodriguez FJ, Wang L, Perry JSA, Yang Y, Wahl K, Crittenden RB, Bennett ML, Qi L, Gong CC, Li XN, Barres BA, Bender TP, Ravichandran KS, Janes KA, Eberhart CG, Zong H. Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth. Cell. 2020 Feb 6;180(3):502-520.e19. doi: 10.1016/j.cell.2019.12.024. Epub 2020 Jan 23. PMID: 31983537

Lambo S, Gröbner SN, Rausch T, Waszak SM, Schmidt C, Gorthi A, Romero JC, Mauermann M, Brabetz S, Krausert S, Buchhalter I, Koster J, Zwijnenburg DA, Sill M, Hübner JM, Mack N, Schwalm B, Ryzhova M, Hovestadt V, Papillon-Cavanagh S, Chan JA, Landgraf P, Ho B, Milde T, Witt O, Ecker J, Sahm F, Sumerauer D, Ellison DW, Orr BA, Darabi A, Haberler C, Figarella-Branger D, Wesseling P, Schittenhelm J, Remke M, Taylor MD, Gil-da-Costa MJ, Łastowska M, Grajkowska W, Hasselblatt M, Hauser P, Pietsch T, Uro-Coste E, Bourdeaut F, Masliah-Planchon J, Rigau V, Alexandrescu S, Wolf S, Li XN, Schüller U, Snuderl M, Karajannis MA, Giangaspero F, Jabado N, von Deimling A, Jones DTW, Korbel JO, von Hoff K, Lichter P, Huang A, Bishop AJR, Pfister SM, Korshunov A, Kool M. The molecular landscape of ETMR at diagnosis and relapse. Nature. 2019 Dec;576(7786):274-280. doi: 10.1038/s41586-019-1815-x. Epub 2019 Dec 4. PMID: 31802000

Rokita JL, Rathi KS, Cardenas MF, Upton KA, Jayaseelan J, Cross KL, Pfeil J, Egolf LE, Way GP, Farrel A, Kendsersky NM, Patel K, Gaonkar KS, Modi A, Berko ER, Lopez G, Vaksman Z, Mayoh C, Nance J, McCoy K, Haber M, Evans K, McCalmont H, Bendak K, Böhm JW, Marshall GM, Tyrrell V, Kalletla K, Braun FK, Qi L, Du Y, Zhang H, Lindsay HB, Zhao S, Shu J, Baxter P, Morton C, Kurmashev D, Zheng S, Chen Y, Bowen J, Bryan AC, Leraas KM, Coppens SE, Doddapaneni H, Momin Z, Zhang W, Sacks GI, Hart LS, Krytska K, Mosse YP, Gatto GJ, Sanchez Y, Greene CS, Diskin SJ, Vaske OM, Haussler D, Gastier-Foster JM, Kolb EA, Gorlick R, Li XN, Reynolds CP, Kurmasheva RT, Houghton PJ, Smith MA, Lock RB, Raman P, Wheeler DA, Maris JM. Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design. Cell Rep. 2019 Nov 5;29(6):1675-1689.e9. doi: 10.1016/j.celrep.2019.09.071. PMID: 31693904 Free PMC Article

Hovestadt V, Smith KS, Bihannic L, Filbin MG, Shaw ML, Baumgartner A, DeWitt JC, Groves A, Mayr L, Weisman HR, Richman AR, Shore ME, Goumnerova L, Rosencrance C, Carter RA, Phoenix TN, Hadley JL, Tong Y, Houston J, Ashmun RA, DeCuypere M, Sharma T, Flasch D, Silkov A, Ligon KL, Pomeroy SL, Rivera MN, Rozenblatt-Rosen O, Rusert JM, Wechsler-Reya RJ, Li XN, Peyrl A, Gojo J, Kirchhofer D, Lötsch D, Czech T, Dorfer C, Haberler C, Geyeregger R, Halfmann A, Gawad C, Easton J, Pfister SM, Regev A, Gajjar A, Orr BA, Slavc I, Robinson GW, Bernstein BE, Suvà ML, Northcott PA. Resolving medulloblastoma cellular architecture by single-cell genomics. Nature. 2019 Aug;572(7767):74-79. doi: 10.1038/s41586-019-1434-6. Epub 2019 Jul 24. PMID: 31341285 Free PMC Article

Sin-Chan P, Mumal I, Suwal T, Ho B, Fan X, Singh I, Du Y, Lu M, Patel N, Torchia J, Popovski D, Fouladi M, Guilhamon P, Hansford JR, Leary S, Hoffman LM, Mulcahy Levy JM, Lassaletta A, Solano-Paez P, Rivas E, Reddy A, Gillespie GY, Gupta N, Van Meter TE, Nakamura H, Wong TT, Ra YS, Kim SK, Massimi L, Grundy RG, Fangusaro J, Johnston D, Chan J, Lafay-Cousin L, Hwang EI, Wang Y, Catchpoole D, Michaud J, Ellezam B, Ramanujachar R, Lindsay H, Taylor MD, Hawkins CE, Bouffet E, Jabado N, Singh SK, Kleinman CL, Barsyte-Lovejoy D, Li XN, Dirks PB, Lin CY, Mack SC, Rich JN, Huang A. A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor. Cancer Cell. 2019 Jul 8;36(1):51-67.e7. doi: 10.1016/j.ccell.2019.06.002. PMID: 31287992 Free Article

Dobson THW, Tao RH, Swaminathan J, Maegawa S, Shaik S, Bravo-Alegria J, Sharma A, Kennis B, Yang Y, Callegari K, Haltom AR, Taylor P, Kogiso M, Qi L, Khatua S, Goldman S, Lulla RR, Fangusaro J, MacDonald TJ, Li XN, Hawkins C, Rajaram V, Gopalakrishnan V. Transcriptional repressor REST drives lineage stage-specific chromatin compaction at Ptch1 and increases AKT activation in a mouse model of medulloblastoma. Sci Signal. 2019 Jan 22;12(565). pii: eaan8680. doi: 10.1126/scisignal.aan8680. PMID: 30670636

Huang L, Garrett Injac S, Cui K, Braun F, Lin Q, Du Y, Zhang H, Kogiso M, Lindsay H, Zhao S, Baxter P, Adekunle A, Man TK, Zhao H, Li XN, Lau CC, Wong STC. Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma. Sci Transl Med. 2018 Oct 24;10(464). pii: eaat0150. doi: 10.1126/scitranslmed.aat0150. PMID: 30355798 Free PMC Article

Purzner T, Purzner J, Buckstaff T, Cozza G, Gholamin S, Rusert JM, Hartl TA, Sanders J, Conley N, Ge X, Langan M, Ramaswamy V, Ellis L, Litzenburger U, Bolin S, Theruvath J, Nitta R, Qi L, Li XN, Li G, Taylor MD, Wechsler-Reya RJ, Pinna LA, Cho YJ, Fuller MT, Elias JE, Scott MP. Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma. Sci Signal. 2018 Sep 11;11(547). pii: eaau5147. doi: 10.1126/scisignal.aau5147. PMID: 30206138 Free PMC Article

Wu F, Cheng G, Yao Y, Kogiso M, Jiang H, Li XN, Song Y. Inhibition of Mutated Isocitrate Dehydrogenase 1 in Cancer. Med Chem. 2018;14(7):715-724. doi: 10.2174/1573406414666180524093659. PMID: 29792149 Free PMC Article

Berlow NE, Svalina MN, Quist MJ, Settelmeyer TP, Zherebitskiy V, Kogiso M, Qi L, Du Y, Hawkins CE, Hulleman E, Li XN, Gultekin SH, Keller C. IL-13 receptors as possible therapeutic targets in diffuse intrinsic pontine glioma. PLoS One. 2018 Apr 5;13(4):e0193565. doi: 10.1371/journal.pone.0193565. eCollection 2018. PMID: 29621254 Free PMC Article

More publications in PubMed

Li Lab in the News

Targeting a Weak Link in Pediatric Brain Cancer

Contact Information

Xiao-Nan Li, MD, PhD, Professor of Pediatrics - Hematology, Oncology and Stem Cell Transplantation

Xiao-Nan Li Northwestern University profile