NF1 +/- Hematopoietic Cells Accelerate Malignant Peripheral Nerve Sheath Tumor Development without Altering Chemotherapy Response

Rebecca D Dodd; Chang-Lung Lee; Tess Overton; Wesley Huang; William C Eward; Lixia Luo; Yan Ma; Davis R Ingram; Keila E Torres; Diana M Cardona; Alexander J Lazar; David G Kirsch

doi:10.1158/0008-5472.CAN-16-2643

Back

NF1 +/- Hematopoietic Cells Accelerate Malignant Peripheral Nerve Sheath Tumor Development without Altering Chemotherapy Response

Journal article

Open access

Peer reviewed

NF1 +/- Hematopoietic Cells Accelerate Malignant Peripheral Nerve Sheath Tumor Development without Altering Chemotherapy Response

Rebecca D Dodd, Chang-Lung Lee, Tess Overton, Wesley Huang, William C Eward, Lixia Luo, Yan Ma, Davis R Ingram, Keila E Torres, Diana M Cardona, …

Cancer research (Chicago, Ill.), Vol.77(16), pp.4486-4497

08/15/2017

DOI: 10.1158/0008-5472.CAN-16-2643

PMCID: PMC5839126

PMID: 28646022

Files and links (1)

url

https://doi.org/10.1158/0008-5472.CAN-16-2643View

Published (Version of record) Open Access

Abstract

Haploinsufficiency in the tumor suppressor NF1 contributes to the pathobiology of neurofibromatosis type 1, but a related role has not been established in malignant peripheral nerve sheath tumors (MPNST) where NF1 mutations also occur. Patients with NF1-associated MPNST appear to have worse outcomes than patients with sporadic MPNST, but the mechanism underlying this correlation is not understood. To define the impact of stromal genetics on the biology of this malignancy, we developed unique mouse models that reflect the genetics of patient-associated MPNST. Specifically, we used adenovirus-Cre injections to generate MPNST in Nf1 ; Ink4a/Arf and Nf1 ; Ink4a/Arf paired littermate mice to model tumors from NF1-wild-type and NF1-associated patients, respectively. In these models, Nf1 haploinsufficiency in hematopoietic cells accelerated tumor onset and increased levels of tumor-infiltrating immune cells comprised of CD11b cells, monocytes, and mast cells. We observed that mast cells were also enriched in human NF1-associated MPNST. In a coclinical trial to examine how the tumor microenvironment influences the response to multiagent chemotherapy, we found that stromal Nf1 status had no effect. Taken together, our results clarify the role of the NF1-haploinsufficient tumor microenvironment in MPNST. .

Animals

Disease Models, Animal

Hematopoietic Stem Cells - metabolism

Hematopoietic Stem Cells - pathology

Humans

Mice

Nerve Sheath Neoplasms - drug therapy

Nerve Sheath Neoplasms - genetics

Nerve Sheath Neoplasms - pathology

Neurofibromatosis 1 - drug therapy

Neurofibromatosis 1 - genetics

Neurofibromatosis 1 - metabolism

Neurofibromatosis 1 - pathology

Details

Title: Subtitle: NF1 +/- Hematopoietic Cells Accelerate Malignant Peripheral Nerve Sheath Tumor Development without Altering Chemotherapy Response
Creators: Rebecca D Dodd - Duke Medical Center
Chang-Lung Lee - Duke Medical Center
Tess Overton - Duke Medical Center
Wesley Huang - Duke Medical Center
William C Eward - Duke University Hospital
Lixia Luo - Duke Medical Center
Yan Ma - Duke Medical Center
Davis R Ingram - The University of Texas MD Anderson Cancer Center
Keila E Torres - The University of Texas MD Anderson Cancer Center
Diana M Cardona - Duke University
Alexander J Lazar - The University of Texas MD Anderson Cancer Center
David G Kirsch - Duke Medical Center
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.77(16), pp.4486-4497
DOI: 10.1158/0008-5472.CAN-16-2643
PMID: 28646022
PMCID: PMC5839126
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Grant note: P30 CA086862 / NCI NIH HHS R35 CA197616 / NCI NIH HHS
Language: English
Date published: 08/15/2017
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984359573802771

Metrics

4 Record Views

25 Times Cited - Web of Science

See more details