Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology
Abstract
Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that often develop in patients with neurofibromatosis type 1 (NF1). To address the critical need for novel therapeutics in MPNST, we aimed to establish an ex vivo 3D platform that accurately captured the genomic diversity of MPNST and could be utilized in a medium-throughput manner for drug screening studies to be validated in vivo using patient-derived xenografts (PDX). Genomic analysis was performed on all PDX-tumor pairs. Selected PDX were harvested for assembly into 3D microtissues. Based on prior work in our labs, we evaluated drugs (trabectedin, olaparib, and mirdametinib) ex vivo and in vivo. For 3D microtissue studies, cell viability was the endpoint as assessed by Zeiss Axio Observer. For PDX drug studies, tumor volume was measured twice weekly. Bulk RNA sequencing was performed to identify pathways enriched in cells. We developed 13 NF1-associated MPNST-PDX and identified mutations or structural abnormalities in NF1 (100%), SUZ12 (85%), EED (15%), TP53 (15%), CDKN2A (85%), and chromosome 8 gain (77%). We successfully assembled PDX into 3D microtissues, categorized as robust (>90% viability at 48 h), good (>50%), or unusable (<50%). We evaluated drug response to “robust” or “good” microtissues, namely MN-2, JH-2-002,more »
- Authors:
-
more »
- Univ. of Minnesota, Minneapolis, MN (United States)
- Washington Univ., St. Louis, MO (United States)
- Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine
- Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
- Johns Hopkins Univ., Baltimore, MD (United States)
- Publication Date:
- Research Org.:
- Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 2305670
- Report Number(s):
- PNNL-ACT-SA-10646
Journal ID: ISSN 1522-8517
- Grant/Contract Number:
- AC05-76RL01830
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Neuro-Oncology
- Additional Journal Information:
- Journal Volume: 25; Journal Issue: 11; Journal ID: ISSN 1522-8517
- Publisher:
- Oxford University Press
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; drug therapy; genomic variants; MPNST; microtissues; PDX; drug screening, NF1; drug response; genome; nerve sheath tumors; neoplasms; olaparib; trabectedin
Citation Formats
Larsson, Alex T., Bhatia, Himanshi, Calizo, Ana, Pollard, Kai, Zhang, Xiaochun, Conniff, Eric, Tibbitts, Justin F., Rono, Elizabeth, Cummins, Katherine, Osum, Sara H., Williams, Kyle B., Crampton, Alexandra L., Jubenville, Tyler, Schefer, Daniel, Yang, Kuangying, Lyu, Yang, Pino, James C., Bade, Jessica, Gross, John M., Lisok, Alla, Dehner, Carina A., Chrisinger, John S. A., He, Kevin, Gosline, Sara J. C., Pratilas, Christine A., Largaespada, David A., Wood, David K., and Hirbe, Angela C. Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology. United States: N. p., 2023.
Web. doi:10.1093/neuonc/noad097.
Larsson, Alex T., Bhatia, Himanshi, Calizo, Ana, Pollard, Kai, Zhang, Xiaochun, Conniff, Eric, Tibbitts, Justin F., Rono, Elizabeth, Cummins, Katherine, Osum, Sara H., Williams, Kyle B., Crampton, Alexandra L., Jubenville, Tyler, Schefer, Daniel, Yang, Kuangying, Lyu, Yang, Pino, James C., Bade, Jessica, Gross, John M., Lisok, Alla, Dehner, Carina A., Chrisinger, John S. A., He, Kevin, Gosline, Sara J. C., Pratilas, Christine A., Largaespada, David A., Wood, David K., & Hirbe, Angela C. Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology. United States. https://doi.org/10.1093/neuonc/noad097
Larsson, Alex T., Bhatia, Himanshi, Calizo, Ana, Pollard, Kai, Zhang, Xiaochun, Conniff, Eric, Tibbitts, Justin F., Rono, Elizabeth, Cummins, Katherine, Osum, Sara H., Williams, Kyle B., Crampton, Alexandra L., Jubenville, Tyler, Schefer, Daniel, Yang, Kuangying, Lyu, Yang, Pino, James C., Bade, Jessica, Gross, John M., Lisok, Alla, Dehner, Carina A., Chrisinger, John S. A., He, Kevin, Gosline, Sara J. C., Pratilas, Christine A., Largaespada, David A., Wood, David K., and Hirbe, Angela C. Mon .
"Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology". United States. https://doi.org/10.1093/neuonc/noad097. https://www.osti.gov/servlets/purl/2305670.
@article{osti_2305670,
title = {Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology},
author = {Larsson, Alex T. and Bhatia, Himanshi and Calizo, Ana and Pollard, Kai and Zhang, Xiaochun and Conniff, Eric and Tibbitts, Justin F. and Rono, Elizabeth and Cummins, Katherine and Osum, Sara H. and Williams, Kyle B. and Crampton, Alexandra L. and Jubenville, Tyler and Schefer, Daniel and Yang, Kuangying and Lyu, Yang and Pino, James C. and Bade, Jessica and Gross, John M. and Lisok, Alla and Dehner, Carina A. and Chrisinger, John S. A. and He, Kevin and Gosline, Sara J. C. and Pratilas, Christine A. and Largaespada, David A. and Wood, David K. and Hirbe, Angela C.},
abstractNote = {Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that often develop in patients with neurofibromatosis type 1 (NF1). To address the critical need for novel therapeutics in MPNST, we aimed to establish an ex vivo 3D platform that accurately captured the genomic diversity of MPNST and could be utilized in a medium-throughput manner for drug screening studies to be validated in vivo using patient-derived xenografts (PDX). Genomic analysis was performed on all PDX-tumor pairs. Selected PDX were harvested for assembly into 3D microtissues. Based on prior work in our labs, we evaluated drugs (trabectedin, olaparib, and mirdametinib) ex vivo and in vivo. For 3D microtissue studies, cell viability was the endpoint as assessed by Zeiss Axio Observer. For PDX drug studies, tumor volume was measured twice weekly. Bulk RNA sequencing was performed to identify pathways enriched in cells. We developed 13 NF1-associated MPNST-PDX and identified mutations or structural abnormalities in NF1 (100%), SUZ12 (85%), EED (15%), TP53 (15%), CDKN2A (85%), and chromosome 8 gain (77%). We successfully assembled PDX into 3D microtissues, categorized as robust (>90% viability at 48 h), good (>50%), or unusable (<50%). We evaluated drug response to “robust” or “good” microtissues, namely MN-2, JH-2-002, JH-2-079-c, and WU-225. Drug response ex vivo predicted drug response in vivo, and enhanced drug effects were observed in select models. These data support the successful establishment of a novel 3D platform for drug discovery and MPNST biology exploration in a system representative of the human condition.},
doi = {10.1093/neuonc/noad097},
journal = {Neuro-Oncology},
number = 11,
volume = 25,
place = {United States},
year = {Mon May 29 00:00:00 EDT 2023},
month = {Mon May 29 00:00:00 EDT 2023}
}
Works referenced in this record:
Organotypic three-dimensional cancer cell cultures mirror drug responsesin vivo: lessons learned from the inhibition of EGFR signaling
journal, November 2017
- Jacobi, Nico; Seeboeck, Rita; Hofmann, Elisabeth
- Oncotarget, Vol. 8, Issue 64
SARC023: Phase I/II trial of ganetespib in combination with sirolimus for refractory sarcomas and malignant peripheral nerve sheath tumors (MPNST).
journal, May 2014
- Kim, AeRang; Reinke, Denise K.; Cichowski, Karen
- Journal of Clinical Oncology, Vol. 32, Issue 15_suppl
A High-Throughput Screening Platform Identifies Novel Combination Treatments for Malignant Peripheral Nerve Sheath Tumors
journal, May 2022
- Fernández-Rodríguez, Juana; Creus-Bachiller, Edgar; Zhang, Xiaohu
- Molecular Cancer Therapeutics, Vol. 21, Issue 7
A clinically and genomically annotated nerve sheath tumor biospecimen repository
journal, June 2020
- Pollard, Kai; Banerjee, Jineta; Doan, Xengie
- Scientific Data, Vol. 7, Issue 1
Subdiaphragmatic and intrathoracic paraspinal malignant peripheral nerve sheath tumors
journal, June 1998
- Kourea, Helen P.; Bilsky, Mark H.; Leung, Denis H. Y.
- Cancer, Vol. 82, Issue 11
Induction of Abnormal Proliferation by Nonmyelinating Schwann Cells Triggers Neurofibroma Formation
journal, February 2008
- Zheng, Huarui; Chang, Lou; Patel, Neha
- Cancer Cell, Vol. 13, Issue 2
A high-throughput molecular data resource for cutaneous neurofibromas
journal, April 2017
- Gosline, Sara J. C.; Weinberg, Hubert; Knight, Pamela
- Scientific Data, Vol. 4, Issue 1
Rapid generation of collagen-based microtissues to study cell–matrix interactions
journal, June 2016
- Brett, Marie-Elena; Crampton, Alexandra L.; Wood, David K.
- TECHNOLOGY, Vol. 04, Issue 02
NF1 Deletion Generates Multiple Subtypes of Soft-Tissue Sarcoma That Respond to MEK Inhibition
journal, September 2013
- Dodd, Rebecca D.; Mito, Jeffrey K.; Eward, William C.
- Molecular Cancer Therapeutics, Vol. 12, Issue 9
Trimmomatic: a flexible trimmer for Illumina sequence data
journal, April 2014
- Bolger, Anthony M.; Lohse, Marc; Usadel, Bjoern
- Bioinformatics, Vol. 30, Issue 15
Loss of NF1 in Cutaneous Melanoma Is Associated with RAS Activation and MEK Dependence
journal, February 2014
- Nissan, Moriah H.; Pratilas, Christine A.; Jones, Alexis M.
- Cancer Research, Vol. 74, Issue 8
Mouse Models of Tumor Development in Neurofibromatosis Type 1
journal, December 1999
- Cichowski, K.
- Science, Vol. 286, Issue 5447
Trabectedin
journal, September 2009
- Dubois, Eline A.; Cohen, Adam F.
- British Journal of Clinical Pharmacology, Vol. 68, Issue 3
Spheroid three-dimensional culture enhances Notch signaling in cardiac progenitor cells
journal, September 2017
- Mauretti, Arianna; Rossi, Fabrizio; Bax, Noortje A. M.
- MRS Communications, Vol. 7, Issue 3
Transposon Mutagenesis-Guided CRISPR/Cas9 Screening Strongly Implicates Dysregulation of Hippo/YAP Signaling in Malignant Peripheral Nerve Sheath Tumor Development
journal, March 2021
- Vélez-Reyes, Germán L.; Koes, Nicholas; Ryu, Ji Hae
- Cancers, Vol. 13, Issue 7
Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts
journal, September 2013
- Li, Shunqiang; Shen, Dong; Shao, Jieya
- Cell Reports, Vol. 4, Issue 6
MUC12 mRNA expression is an independent marker of prognosis in stage II and stage III colorectal cancer
journal, February 2010
- Matsuyama, Takatoshi; Ishikawa, Toshiaki; Mogushi, Kaoru
- International Journal of Cancer, Vol. 127, Issue 10
Salmon provides fast and bias-aware quantification of transcript expression
journal, March 2017
- Patro, Rob; Duggal, Geet; Love, Michael I.
- Nature Methods, Vol. 14, Issue 4
Human Organ-Specific 3D Cancer Models Produced by the Stromal Self-Assembly Method of Tissue Engineering for the Study of Solid Tumors
journal, April 2020
- Roy, Vincent; Magne, Brice; Vaillancourt-Audet, Maude
- BioMed Research International, Vol. 2020
A genetic mouse model with postnatalNf1andp53loss recapitulates the histology and transcriptome of human malignant peripheral nerve sheath tumor
journal, January 2021
- Inoue, Akira; Janke, Laura J.; Gudenas, Brian L.
- Neuro-Oncology Advances, Vol. 3, Issue 1
Phase II study of erlotinib in metastatic or unresectable malignant peripheral nerve sheath tumors (MPNST)
journal, June 2006
- Albritton, K. H.; Rankin, C.; Coffin, C. M.
- Journal of Clinical Oncology, Vol. 24, Issue 18_suppl
Engaging a community to enable disease-centric data sharing with the NF Data Portal
journal, December 2019
- Allaway, Robert J.; La Rosa, Salvatore; Verma, Sharad
- Scientific Data, Vol. 6, Issue 1
Low mutation burden and frequent loss of CDKN2A/B and SMARCA2, but not PRC2, define premalignant neurofibromatosis type 1–associated atypical neurofibromas
journal, February 2019
- Pemov, Alexander; Hansen, Nancy F.; Sindiri, Sivasish
- Neuro-Oncology, Vol. 21, Issue 8
New Model Systems and the Development of Targeted Therapies for the Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors
journal, April 2020
- Williams, Kyle B.; Largaespada, David A.
- Genes, Vol. 11, Issue 5
Genomic Patterns of Malignant Peripheral Nerve Sheath Tumor (MPNST) Evolution Correlate with Clinical Outcome and Are Detectable in Cell-Free DNA
journal, January 2023
- Cortes-Ciriano, Isidro; Steele, Christopher D.; Piculell, Katherine
- Cancer Discovery, Vol. 13, Issue 3
Systematic Review of Patient-Derived Xenograft Models for Preclinical Studies of Anti-Cancer Drugs in Solid Tumors
journal, May 2019
- Koga, Yoshikatsu; Ochiai, Atsushi
- Cells, Vol. 8, Issue 5
PDX
models recapitulate the genetic and epigenetic landscape of pediatric T‐cell leukemia
journal, November 2018
- Richter‐Pechańska, Paulina; Kunz, Joachim B.; Bornhauser, Beat
- EMBO Molecular Medicine, Vol. 10, Issue 12
3D tumor microtissues as an in vitro testing platform for microenvironmentally-triggered drug delivery systems
journal, July 2017
- Brancato, Virginia; Gioiella, Filomena; Profeta, Martina
- Acta Biomaterialia, Vol. 57
Genomic Profiling in Patients With Malignant Peripheral Nerve Sheath Tumors Reveals Multiple Pathways With Targetable Mutations
journal, August 2018
- Kaplan, Henry G.; Rostad, Steven; Ross, Jeffrey S.
- Journal of the National Comprehensive Cancer Network, Vol. 16, Issue 8
Tumor-Stroma Interactions Alter the Sensitivity of Drug in Breast Cancer
journal, June 2020
- Brancato, Virginia; Kundu, Banani; Oliveira, Joaquim Miguel
- Frontiers in Materials, Vol. 7
The Arf-GAP and protein scaffold Cat1/Git1 as a multifaceted regulator of cancer progression
journal, December 2017
- Yoo, Sungsoo M.; Cerione, Richard A.; Antonyak, Marc A.
- Small GTPases, Vol. 11, Issue 2
A High-Throughput Workflow to Study Remodeling of Extracellular Matrix-Based Microtissues
journal, January 2019
- Crampton, Alexandra L.; Cummins, Katherine A.; Wood, David K.
- Tissue Engineering Part C: Methods, Vol. 25, Issue 1
PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors
journal, September 2014
- Lee, William; Teckie, Sewit; Wiesner, Thomas
- Nature Genetics, Vol. 46, Issue 11
KRAS and PIK3CA Mutation Frequencies in Patient-derived Xenograft Models of Pancreatic and Colorectal Cancer Are Reflective of Patient Tumors and Stable Across Passages
journal, September 2014
- Tignanelli, Christopher J.; Loeza, Silvia G. Herrera; Yeh, Jen Jen
- The American Surgeon, Vol. 80, Issue 9
Nf1-Dependent Tumors Require a Microenvironment Containing Nf1+/−- and c-kit-Dependent Bone Marrow
journal, October 2008
- Yang, Feng-Chun; Ingram, David A.; Chen, Shi
- Cell, Vol. 135, Issue 3
Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer
journal, December 2021
- Raghavan, Srivatsan; Winter, Peter S.; Navia, Andrew W.
- Cell, Vol. 184, Issue 25
Targeting Sporadic and Neurofibromatosis Type 1 (NF1) Related Refractory Malignant Peripheral Nerve Sheath Tumors (MPNST) in a Phase II Study of Everolimus in Combination with Bevacizumab (SARC016)
journal, July 2019
- Widemann, Brigitte C.; Lu, Yao; Reinke, Denise
- Sarcoma, Vol. 2019
Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis
journal, May 2013
- Rahrmann, Eric P.; Watson, Adrienne L.; Keng, Vincent W.
- Nature Genetics, Vol. 45, Issue 7
Human organoids: model systems for human biology and medicine
journal, July 2020
- Kim, Jihoon; Koo, Bon-Kyoung; Knoblich, Juergen A.
- Nature Reviews Molecular Cell Biology, Vol. 21, Issue 10
The Ensembl Variant Effect Predictor
journal, June 2016
- McLaren, William; Gil, Laurent; Hunt, Sarah E.
- Genome Biology, Vol. 17, Issue 1
Maftools: efficient and comprehensive analysis of somatic variants in cancer
journal, October 2018
- Mayakonda, Anand; Lin, De-Chen; Assenov, Yassen
- Genome Research, Vol. 28, Issue 11
PTEN and NF1 Inactivation in Schwann Cells Produces a Severe Phenotype in the Peripheral Nervous System That Promotes the Development and Malignant Progression of Peripheral Nerve Sheath Tumors
journal, July 2012
- Keng, Vincent W.; Rahrmann, Eric P.; Watson, Adrienne L.
- Cancer Research, Vol. 72, Issue 13
A high-throughput microtissue platform to probe endothelial function in vitro
journal, January 2018
- Crampton, Alexandra L.; Cummins, Katherine A.; Wood, David K.
- Integrative Biology, Vol. 10, Issue 9
Evaluation of molecular subtypes and clonal selection during establishment of patient-derived tumor xenografts from gastric adenocarcinoma
journal, July 2020
- Peille, Anne-Lise; Vuaroqueaux, Vincent; Wong, Swee-Seong
- Communications Biology, Vol. 3, Issue 1
Diagnosis and management of malignant peripheral nerve sheath tumors: Current practice and future perspectives
journal, November 2019
- Prudner, Bethany C.; Ball, Tyler; Rathore, Richa
- Neuro-Oncology Advances, Vol. 2, Issue Supplement_1
Chromosome 8 gain is associated with high-grade transformation in MPNST
journal, March 2021
- Dehner, Carina; Moon, Chang In; Zhang, Xiyuan
- JCI Insight, Vol. 6, Issue 6
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
journal, December 2014
- Love, Michael I.; Huber, Wolfgang; Anders, Simon
- Genome Biology, Vol. 15, Issue 12
Three-Dimensional Culture Systems for Dissecting Notch Signalling in Health and Disease
journal, November 2021
- Marconi, Guya Diletta; Porcheri, Cristina; Trubiani, Oriana
- International Journal of Molecular Sciences, Vol. 22, Issue 22
Establishment and characterization of patient-derived cancer models of malignant peripheral nerve sheath tumors
journal, February 2020
- Oyama, Rieko; Kito, Fusako; Takahashi, Mami
- Cancer Cell International, Vol. 20, Issue 1
Neurofibromatosis Type 1–Associated MPNST State of the Science: Outlining a Research Agenda for the Future
journal, August 2017
- Reilly, Karlyne M.; Kim, AeRang; Blakely, Jaishri
- JNCI: Journal of the National Cancer Institute, Vol. 109, Issue 8