The Hu Lab for Brain Tumor Evolution and Therapy

Modeling the Evolution and Diversity of Brain Tumors using Human-in-mouse Systems

Intratumor genetic heterogeneity and phenotypic diversity are the hallmarks of glioma and medulloblastoma, which predict the risk of tumor development, progression, and response to treatment. To delineate crosstalk mechanisms of these factors, the Hu Lab has developed human-in-mouse model systems based on malignant transformation of human neural/cerebellar stem cells driven by subtype-specific genetic/epigenetic alterations. These models can faithfully recapitulate the molecular diversity, cellular heterogeneity, and histology seen in patient tumors. In addition, these models enable precise system-level comparisons of premalignant and malignant states of these stem cells, which deepens our understanding of tumor evolutionary dynamics in the molecular and cellular level. The key regulators in this process are validated as diagnostic biomarkers and therapeutic targets for clinical application.

Interrogating Consequences of Stem Cells Plasticity within the Brain Tumor Microenvironment

Emerging evidence suggests that glioma/medulloblastoma stem cells may contribute to tumor evolution and anti-therapy. We previously found that glioblastoma stem cells (GSCs) differentiate into endothelial-like cells (GdECs), which recruit host endothelial cells (ECs) to form an invasive niche, resulting in tumor invasiveness and recurrence. We are continuing our efforts to gain a better understanding of the molecular mechanisms of these cancer stem cells, and how they communicate with their surrounding cells (e.g. endothelial cells, microglia/macrophages, astrocytes, etc.), which allows us to develop novel and more effective therapies by targeting critical components of the tumor microenvironment.

The invasive niche is comprised of GSCs, GdECs, ECs, and other types of cells in glioblastoma tumors. Representative images show the close proximity of GdEC (yellow) and host ECs (green) compared with GSCs (red). (Hu, et al., Cell, 22 Feb 2016)

Illuminating Mechanisms Governing Cancer Cell Invasion and Dissemination in the Brain

The major challenge in the clinical management of glioblastoma is that cancer cells extensively infiltrate into the surrounding tissue, leading to nearly universal recurrence. Group 3 medulloblastoma is characterized by frequent metastasis at diagnosis and the worst prognosis among all the subgroups. We aim to elucidate molecular mechanisms of de novo invasion and treatment-induced invasion (e.g. temozolomide, bevacizumab, etc.), which enables us to identify the “drivers” mediating invasion by cancer cells and to disseminate and aid in the development of new therapies.

Suppression of tumor invasiveness by depleting WNT5A-mediated GdECs using HSVTK/ganciclovir (GCV) cell ablation system. Representative images for tumor appearance (left) and peritumoral satellite lesions (right) in PDX mouse model. (Hu, et al., Cell, 22 Feb 2016)

Baoli Hu, PhD

Principal Investigator
baolihu@pitt.edu
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Rashmi Srivastava, PhD
Post-doctoral Fellow

Han Zou, medical student
International Scholar

Evridiki Asimakidou, MD
Visiting Scholar

Contact Us

The Hu Lab
UPMC Children’s Hospital of Pittsburgh
John G. Rangos Sr. Research Center, Suite 7127
4401 Penn Avenue
Pittsburgh, PA 15224
412-692-9457

Lab Activities and Achievements

2021

The Hu Lab received R21 funding from the National Institute of Neurological Disorders and Stroke (NINDS) to investigate the role of SMARCD3/BAF60C in neurodevelopment and medulloblastoma.

2020

The Hu Lab received the 2020 Walter L. Copeland Fund of the Pittsburgh Foundation to study the role of CHI3L1 in reprogramming of the tumor immune microenvironment of glioblastoma.

2018-2019

The Hu Lab received two awards to study new epigenetic alterations in medulloblastoma, funded by the Matthew Larson Foundation and the Connor’s Cure fund from the V Foundation for Cancer Research.

The Hu Lab received three awards to investigate the role of WNT5A in glioblastoma therapy resistance, including UPMC Competitive Medical Research Fund Award, B*CURED Brain Cancer Research Investigator Award, and the Walter L. Copeland Fund Award.

Presentations at Scientific Meetings

2021

Baoli Hu, PhD, delivered a virtual presentation, “Understanding and Targeting CHI3L1/YKL-40 Signaling in Glioblastoma,” by invitation for OncoArendi Therapeutics, Warsaw, Poland.

Dr. Hu delivered a virtual presentation, “Glioblastoma Therapy: Targeting Intracellular or Intercellular Signaling?” for the University of Pittsburgh School of Pharmacy fall seminar series.

A Resource of High-quality and Versatile Nanobodies for Drug Delivery
Shen Z, Xiang Y, Vergara S, Chen A, Xiao Z, Santiago U, Jin C, Sang Z, Luo J, Chen K, Schneidman-Duhovny D, Camacho C, Calero G, Hu B, Shi Y
iScience
2021 Aug 21

Chitinase-3-like 1 Protein Complexes Modulate Macrophage-mediated Immune Suppression in Glioblastoma
Chen A, Jiang Y, Li Z, Wu L, Santiago U, Zou H, Cai C, Sharma V, Guan Y, McCarl LH, Ma J, Wu YL, Michel J, Shi Y, Konnikova L, Amankulor NM, Zinn PO, Kohanbash G, Agnihotri S, Lu S, Lu X, Sun D, Gittes GK, Wang Q, Xiao X, Yimlamai D, Pollack IF, Camacho CJ, Hu B
The Journal of Clinical Investigation
2021 Aug 16

ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma
Arabzade A, Zhao Y, Varadharajan S, Chen HC, Jessa S, Rivas B, Stuckert AJ, Solis M, Kardian A, Tlais D, Golbourn BJ, Stanton AJ, Chan YS, Olson C, Karlin KL, Kong K, Kupp R, Hu B, Injac SG, Ngo M, Wang PR, De León LA, Sahm F, Kawauchi D, Pfister SM, Lin CY, Hodges HC, Singh I, Westbrook TF, Chintagumpala MM, Blaney SM, Parsons DW, Pajtler KW, Agnihotri S, Gilbertson RJ, Yi J, Jabado N, Kleinman CL, Bertrand KC, Deneen B, Mack SC
Cancer Discovery
2021 Sep 11

Therapy-Induced Transdifferentiation Promotes Glioma Growth Independent of EGFR Signaling
Oh H, Hwang I, Jang JY, Wu L, Cao D, Yao J, Ying H, Li JY, Yao Y, Hu B, Wang Q, Zheng H, Paik J
Cancer Research
2021 Mar 15

Telomere Dysfunction Activates YAP1 to Drive Tissue Inflammation
Chakravarti D, Hu B, Mao X, Rashid A, Li J, Li J, Liao WT, Whitley EM, Dey P, Hou P, LaBella KA, Chang A, Wang G, Spring DJ, Deng P, Zhao D, Liang X, Lan Z, Lin Y, Sarkar S, Terranova C, Deribe YL, Blutt SE, Okhuysen P, Zhang J, Vilar E, Nielsen OH, Dupont A, Younes M, Patel KR, Shroyer NF, Rai K, Estes MK, Wang YA, Bertuch AA, DePinho RA
Nature Communications
2020 Sep 21

Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment
Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L, deCarvalho AC, Lyu S, Li P, Li Y, Barthel F, Cho HJ, Lin YH, Satani N, Martinez-Ledesma E, Zheng S, Chang E, Sauvé CG, Olar A, Lan ZD, Finocchiaro G, Phillips JJ, Berger MS, Gabrusiewicz KR, Wang G, Eskilsson E, Hu J, Mikkelsen T, DePinho RA, Muller F, Heimberger AB, Sulman EP, Nam DH, Verhaak RGW
Cancer Cell
2017 Jul 10

PAF Promotes Stemness and Radioresistance of Glioma Stem Cells
Ong DST, Hu B, Ho YW, Sauve, GC, Bristow CA, Wang Q, Multani SA, Chen P, Nezi L, Jiang S, Gorman CE, Monasterio, MM, Koul D, Marchesini M, Colla S, Jin EJ, Sulman EP, Lang FF, Spring DJ, Yung AW, Verhaak RGW, Chin L, Wang YA, and DePinho RA
Proceedings of the National Academy of Sciences of the USA
2017 Oct 24

QKI Deficiency Maintains Stemness of Glioma Stem Cells in Suboptimal Environment by Downregulating Endolysosomal Degradation
Shingu T, Ho A, Yuan L, Zhou X, Dai C, Zheng S, Wang Q, Zhong Y, Chang, Q, Horner J, Liebelt BD, Yao Y, Hu B, Chen Y, Fuller GN, Verhaak RGW, Heimberger AM, Hu J
Nature Genetics
2017 Jan

Epigenetic Activation of WNT5A Drives Glioblastoma Stem Cell Differentiation and Invasive Growth
Hu B, Wang Q, Wang YA, Hua S, Sauve, GC, Ong DS, Zheng, DL, Chang Q, Ho YW, Monasterio, MM, Lu X, Zhong Y, Zhang J, Deng P, Tan Z, Wang G, Liao, W, Corley LJ, Yan H, Zhang J, You, Y, Liu N, Cai L, Finocchiaro G, Phillips JJ, Berger MS, Spring DJ, Hu J, Sulman EP, Fuller GN, Chin L, Verhaak RGW, DePinho RA
Cell
2016 Nov 17

Targeting YAP-Dependent MDSC Infiltration Impairs Tumor Progression
Wang G, Lu X, Dey P, Deng P, Wu CC, Jiang S, Fang Z, Zhao K, Konaparthi R, Hua S, Zhang J, Li-Ning-Tapia EM, Kapoor A, Wu CJ, Patel NB, Guo Z, Ramamoorthy V, Tieu TN, Heffernan T, Zhao D, Shang X, Khadka S, Hou P, Hu B, Jin EJ, Yao W, Pan X, Ding Z, Shi Y, Li L, Chang Q, Troncoso P, Logothetis CJ, McArthur MJ, Chin L, Wang YA, DePinho RA
Cancer Discovery
2016 Jan

From the Cover: Neutralization of Terminal Differentiation in Gliomagenesis
Hu J, Ho AL, Yuan L, Hu B, Hua S, Hwang SS, Zhang J, Hu T, Zheng H, Gan B, Wu G, Wang YA, Chin L, DePinho RA
Proceedings of the National Academy of Sciences of the USA 2013 Sep 3

Passenger Deletions Generate Therapeutic Vulnerabilities in Cancer
Muller FL, Colla S, Aquilanti E, Manzo VE, Genovese G, Lee J, Eisenson D, Narurkar R, Deng P, Nezi L, Lee MA, Hu B, Hu J, Sahin E, Ong D, Fletcher-Sananikone E, Ho D, Kwong L, Brennan C, Wang YA, Chin L, DePinho RA
Nature
2012 Aug 15

STAR RNA-binding Protein Quaking Suppresses Cancer via Stabilization of Specific miRNA
Chen AJ, Paik JH, Zhang H, Shukla SA, Mortensen R, Hu J, Ying H, Hu B, Hurt J, Farny N, Dong C, Xiao Y, Wang YA, Silver PA, Chin L, Vasudevan S, Depinho RA
Genes & Development
2012 Jul 1

We’d Like to Hear From You!

The Hu Lab is looking for talented and highly-motivated post-docs, undergraduate, and graduate students, who are interested in our research and joining us. Candidates should contact Dr. Hu via email.