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Foxr2 promotes formation of CNS-embryonal tumors in a Trp53-deficient background.

ABSTRACT: BACKGROUND:Embryonal tumors in the central nervous system (CNS) are primary, aggressive, and poorly differentiated pediatric brain tumors. We identified forkhead box R2 (FOXR2) as an oncogene for medulloblastoma through a transposon-based insertional mutagenesis screen. FOXR2 translocation has been identified in a subset of human embryonal tumors of the CNS, designated as CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2); however, the in vivo functions of FOXR2 remain elusive. METHODS:We analyzed the effect of Foxr2 overexpression in the mouse brain by generating a transgenic strain that expresses Foxr2 in the entire brain under the Trp53 deficient background. We performed histological analysis of tumors and characterized tumor-derived sphere-forming cells. We investigated gene expression profiles of tumor-derived cells. RESULTS:Foxr2 and Trp53 loss promoted tumor formation in the olfactory bulb (OB) and brainstem (BS). The tumors showed the common morphological features of small round blue cell tumors, exhibiting divergent, mainly neuronal and glial, patterns of differentiation, which corresponds to the definition of CNS-embryonal tumors. Importantly, all mice developed CNS-embryonal tumors. In the OB, early proliferative lesions consisting of Olig2+ cells were observed, indicating that Foxr2 expression expanded Olig2+ cells in the OB. Tumor-derived cells formed spheres in vitro and induced tumors that recapitulated the parental tumor upon transplantation, indicating the presence of tumor-initiating cells. Gene expression profiling revealed that OB and BS tumor cells were enriched for the expression of the genes specific to CNS NB-FOXR2. CONCLUSIONS:Our data demonstrate that Foxr2 plays a causative role in the formation of CNS-embryonal tumors.

SUBMITTER: Poh B

PROVIDER: S-EPMC6682215 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Foxr2 promotes formation of CNS-embryonal tumors in a Trp53-deficient background.

Poh Boonmin B Koso Hideto H Momota Hiroyuki H Komori Takashi T Suzuki Yutaka Y Yoshida Nobuaki N Ino Yasushi Y Todo Tomoki T Watanabe Sumiko S

Neuro-oncology 20190801 8

<h4>Background</h4>Embryonal tumors in the central nervous system (CNS) are primary, aggressive, and poorly differentiated pediatric brain tumors. We identified forkhead box R2 (Foxr2) as an oncogene for medulloblastoma through a transposon-based insertional mutagenesis screen. Foxr2 translocation has been identified in a subset of human embryonal tumors of the CNS, designated as CNS neuroblastoma with Foxr2 activation (CNS NB-Foxr2); however, the in vivo functions of Foxr2 remain elusive.<h4>Me ...[more]

PMID: 30976792

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Project description:Tremendous progress has recently been made in both molecular subgrouping, and the establishment of prognostic biomarkers for embryonal brain tumors, particularly medulloblastoma. Several prognostic biomarkers that were initially identified in retrospective cohorts of medulloblastoma, including MYC and MYCN amplification, nuclear ?-catenin accumulation, and chromosome 17 aberrations have now been validated in clinical trials. Moreover, molecular subgroups based on distinct transcriptome profiles have been consistently reported from various groups on different platforms demonstrating that the concept of distinct medulloblastoma subgroups is very robust. Well-described subgroups of medulloblastomas include tumors showing wingless signaling pathway (Wnt) activation, and another characterized by sonic hedgehog pathway activity. Two or more additional subgroups were consistently reported to contain the vast majority of high-risk tumors, including most tumors with metastatic disease at diagnosis and/or large cell/anaplastic histology. Several years ago, atypical teratoid rhabdoid tumor (AT/RT) was recognized as a separate entity based on its distinct biology and particularly aggressive clinical behavior. These tumors may occur supra or infratentorially and are usually found to have genetic alterations of SMARCB1 (INI1/hSNF5), a tumor suppressor gene located on chromosome 22q. Subsequent loss of SMARCB1 protein expression comprises a relatively specific and sensitive diagnostic marker for AT/RT. For CNS primitive neuroectodermal tumors (CNS PNETs), a consistent finding has been that they are molecularly distinct from medulloblastoma. Furthermore, a distinct fraction of CNS PNETs with particularly poor prognosis only occurring in young children was delineated, which was previously labeled ependymoblastoma or embryonal tumor with abundant neuropil and true rosettes (ETANTR) and which is morphologically characterized by the presence of multilayered "ependymoblastic" rosettes. This group of tumors shows a unique cytogenetic abnormality not seen in other brain tumors: focal amplification of a micro-RNA cluster at chromosome 19q13.42, which has never been found to be amplified in other CNS PNETs, medulloblastoma or AT/RT. In summary, these consistent findings have significantly contributed to our ability to sub-classify embryonal brain tumors into clinically and biologically meaningful strata and, for some of the subgroups, have led to the identification of specific targets for future development of molecularly targeted therapies.

Dataset Information

Foxr2 promotes formation of CNS-embryonal tumors in a Trp53-deficient background.

Publications

Foxr2 promotes formation of CNS-embryonal tumors in a Trp53-deficient background.

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