PLX3397 treatment inhibits constitutive CSF1R-induced oncogenic ERK signaling, reduces tumor growth, and metastatic burden in osteosarcoma

Branden A. Smeester, Nicholas J. Slipek, Emily J. Pomeroy, Kanut Laoharawee, Sara H. Osum, Alex T. Larsson, Kyle B. Williams, Natalie Stratton, Kenta Yamamoto, Joseph J. Peterson, Susan K. Rathe, Lauren J. Mills, Wendy A. Hudson, Margaret R. Crosby, Minjing Wang, Eric P. Rahrmann, Branden S. Moriarity, David A. Largaespada

Research output: Contribution to journalArticlepeer-review

Abstract

Osteosarcoma (OSA) is a heterogeneous and aggressive solid tumor of the bone. We recently identified the colony stimulating factor 1 receptor (Csf1r) gene as a novel driver of osteosarcomagenesis in mice using the Sleeping Beauty (SB) transposon mutagenesis system. Here, we report that a CSF1R-CSF1 autocrine/paracrine signaling mechanism is constitutively activated in a subset of human OSA cases and is critical for promoting tumor growth and contributes to metastasis. We examined CSF1R and CSF1 expression in OSAs. We utilized gain-of-function and loss-of-function studies (GOF/LOF) to evaluate properties of cellular transformation, downstream signaling, and mechanisms of CSF1R-CSF1 action. Genetic perturbation of CSF1R in immortalized osteoblasts and human OSA cell lines significantly altered oncogenic properties, which were dependent on the CSF1R-CSF1 autocrine/paracrine signaling. These functional alterations were associated with changes in the known CSF1R downstream ERK effector pathway and mitotic cell cycle arrest. We evaluated the recently FDA-approved CSF1R inhibitor Pexidartinib (PLX3397) in OSA cell lines in vitro and in vivo in cell line and patient-derived xenografts. Pharmacological inhibition of CSF1R signaling recapitulated the in vitro genetic alterations. Moreover, in orthotopic OSA cell line and subcutaneous patient-derived xenograft (PDX)-injected mouse models, PLX3397 treatment significantly inhibited local OSA tumor growth and lessened metastatic burden. In summary, CSF1R is utilized by OSA cells to promote tumorigenesis and may represent a new molecular target for therapy.

Original languageEnglish (US)
Article number115353
JournalBone
Volume136
DOIs
StatePublished - Jul 2020

Bibliographical note

Funding Information:
Dr. Largaespada is the co-founder and co-owner of several biotechnology companies including NeoClone Biotechnologies, Inc., Discovery Genomics, Inc. (recently acquired by Immunsoft, Inc.), and B-MoGen Biotechnologies, Inc. (recently acquired by bio-techne corporation). He consults for Genentech, Inc., which is funding some of his research. Dr. Largaespada holds equity in and serves as the Chief Scientific Officer of Surrogen, a subsidiary of Recombinetics, a genome-editing company. The business of all these companies is unrelated to the contents of this manuscript. Other authors have no conflicts of interest to disclose.The authors would like to thank Plexxikon for their gift of PLX3397 formulated rodent chow. The authors acknowledge the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing resources that contributed to the research results reported within this paper. URL: http://www.msi.umn.edu. Author B.A.S. was previously supported by an NIH NIAMS T32 AR050938 Musculoskeletal Training Grant and is currently supported by a Doctoral Dissertation Fellowship (DDF) through the Graduate School at the University of Minnesota. Author E.J.P. is supported by an NIH NIAID T32 AI997313 Immunology Training Grant. Author S.H.O. is supported by an NIHT32 OD0100993 Comparative Medicine and Pathology Training Grant. Author K.B.W. is supported by a Children's Tumor Foundation Young Investigator Award from the NF Research Initiative at Boston Children's Hospital made possible by an anonymous gift. This work was made possible through funding from the Zach Sobiech OSA Fund Award, Randy Shaver Cancer Research and Community Fund, Aflac-AACR Career Development Award, and the Children's Cancer Research Fund to author B.S.M. and American Cancer Society (ACS) Professor award to author D.A.L.

Funding Information:
The authors would like to thank Plexxikon for their gift of PLX3397 formulated rodent chow. The authors acknowledge the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing resources that contributed to the research results reported within this paper. URL: http://www.msi.umn.edu . Author B.A.S. was previously supported by an NIH NIAMS T32 AR050938 Musculoskeletal Training Grant and is currently supported by a Doctoral Dissertation Fellowship (DDF) through the Graduate School at the University of Minnesota . Author E.J.P. is supported by an NIH NIAID T32 AI997313 Immunology Training Grant. Author S.H.O. is supported by an NIH T32 OD0100993 Comparative Medicine and Pathology Training Grant. Author K.B.W. is supported by a Children's Tumor Foundation Young Investigator Award from the NF Research Initiative at Boston Children's Hospital made possible by an anonymous gift. This work was made possible through funding from the Zach Sobiech OSA Fund Award , Randy Shaver Cancer Research and Community Fund , Aflac-AACR Career Development Award, and the Children's Cancer Research Fund to author B.S.M. and American Cancer Society (ACS) Professor award to author D.A.L.

Publisher Copyright:
© 2020

Keywords

  • CSF1R
  • Osteosarcoma
  • PLX3397

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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