Cdkn2a loss in a model of neurofibroma demonstrates stepwise tumor progression to atypical neurofibroma and mpnst

Katherine E. Chaney, Melissa R. Perrino, Leah J. Kershner, Ami V. Patel, Jianqiang Wu, Kwangmin Choi, Tilat A. Rizvi, Eva Dombi, Sara Szabo, David A. Largaespada, Nancy Ratner

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Plexiform neurofibromas are benign nerve sheath Schwann cell tumors characterized by biallelic mutations in the neurofibroma-tosis type 1 (NF1) tumor suppressor gene. Atypical neurofibromas show additional frequent loss of CDKN2A/Ink4a/Arf and may be precursor lesions of aggressive malignant peripheral nerve sheath tumors (MPNST). Here we combined loss of Nf1 in developing Schwann cells with global Ink4a/Arf loss and identified paraspinal plexiform neurofibromas and atypical neurofibromas. Upon transplantation, atypical neurofibromas generated genetically engineered mice (GEM)-PNST similar to human MPNST, and tumors showed reduced p16INK4a protein and reduced senescence markers, confirming susceptibility to transformation. Superficial GEM-PNST contained regions of nerve-associated plexiform neurofibromas or atypical neurofibromas and grew rapidly on transplantation. Transcriptome analyses showed similarities to corresponding human tumors. Thus, we recapitulated nerve tumor progression in NF1 and provided preclinical platforms for testing therapies at each tumor grade. These results support a tumor progression model in which loss of NF1 in Schwann cells drives plexiform neurofibromas formation, additional loss of Ink4a/Arf contributes to atypical neurofibromas formation, and further changes underlie transformation to MPNST.

Original languageEnglish (US)
Pages (from-to)4720-4730
Number of pages11
JournalCancer Research
Volume80
Issue number21
DOIs
StatePublished - Nov 1 2020

Bibliographical note

Funding Information:
K.E. Chaney reports grants from NIH (R01 ns086219 to N. Ratner) during the conduct of the study. L.J. Kershner reports grants from NIH (R01 NS086219 to N. Ratner) and NIH (Ruth L. Kirschstein NRSA; 2T32CA117846-11A1 to self) during the conduct of the study; grants from NIH (Ruth L. Kirschstein NRSA;

Funding Information:
This work was supported by R01 NS086219 (to D.A. Largaespada and N. Ratner) and American Cancer Society, ACS Research Professor Award #123939 (to D.A. Largaespada). L.J. Kershner is supported by NIH Ruth L. Kirschstein NRSA (2T32CA117846-11A1).

Funding Information:
2T32CA117846-11A1 to self) outside the submitted work. J. Wu reports grants from NIH during the conduct of the study. T.A. Rizvi reports grants from NIH (RO1 NS086219 to N. Ratner) during the conduct of the study. S. Szabo reports grants from NIH and DOD during the conduct of the study; personal fees and nonfinancial support from Parkview Mirro Cancer Center, IN (symposium speaker) and Michigan State University, MI (lecturer) outside the submitted work. D.A. Largaespada reports personal fees from B-MoGen Biotechnologies (chair of the board; sold to Bio-Teche summer 2019); grants from Genentech; other compensation from NeoClone Biotechnology (ownership interest), ImmuSoft (previously Discovery Genomics, Inc.; ownership interest), B-MoGen Biotechnologies (ownership interest, sold to Bio-Teche summer 2019), and Recombinetics, Inc. (ownership interest) outside the submitted work; and acted as Chief Science Officer for Surrogen, Inc. (uncompensated position). N. Ratner reports sponsored research contracts with Revolution Medicine and Boehringer Ingelheim outside the submitted work. No potential conflicts of interest were disclosed by the other authors.

Publisher Copyright:
© 2020 American Association for Cancer Research.

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