Reduced microglial <scp>CX3CR1</scp> expression delays neurofibromatosis‐1 glioma formation

Pong, Winnie W.; Higer, Samantha B.; Gianino, Scott M.; Emnett, Ryan J.; Gutmann, David H.

doi:10.1002/ana.23813

Cited by 95 publications

(78 citation statements)

References 20 publications

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“…More specifically, Ptprd +/− p16 −/− tumors had activated genes involved in up-regulation of several chemokines, all of which promote M2 polarization (23)(24)(25)(26). Macrophages can enhance tumor cell survival by promoting tumor growth, invasion, or immunosuppression (27)(28)(29)(38)(39)(40). In addition, recent work by Pyonteck et al showed that RCAS PDGFB gliomas have tumor-associated macrophages, and that inhibiting their polarization state can significantly improve survival (30).…”

Section: Discussionmentioning

confidence: 99%

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

Ortiz

Fabius²,

Wu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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PTPRD, which encodes the protein tyrosine phosphatase receptor-δ, is one of the most frequently inactivated genes across human cancers, including glioblastoma multiforme (GBM). PTPRD undergoes both deletion and mutation in cancers, with copy number loss comprising the primary mode of inactivation in GBM. However, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo, and the mechanistic basis of PTPRD function in tumors is unclear. Here, using genomic analysis and a glioma mouse model, we demonstrate that loss of Ptprd accelerates tumor formation and define the oncogenic context in which Ptprd loss acts. Specifically, we show that in human GBMs, heterozygous loss of PTPRD is the predominant type of lesion and that loss of PTPRD and the CDKN2A/p16 INK4A tumor suppressor frequently co-occur. Accordingly, heterozygous loss of Ptprd cooperates with p16 deletion to drive gliomagenesis in mice. Moreover, loss of the Ptprd phosphatase resulted in phospho-Stat3 accumulation and constitutive activation of Stat3-driven genetic programs. Surprisingly, the consequences of Ptprd loss are maximal in the heterozygous state, demonstrating a tight dependence on gene dosage. Ptprd loss did not increase cell proliferation but rather altered pathways governing the macrophage response. In total, we reveal that PTPRD is a bona fide tumor suppressor, pinpoint PTPRD loss as a cause of aberrant STAT3 activation in gliomas, and establish PTPRD loss, in the setting of CDKN2A/p16 INK4A deletion, as a driver of glioma progression.G lioblastoma multiforme (GBM) is a devastating disease. It is the most common and aggressive type of glioma and outcomes remain poor despite current treatments (1). To increase our understanding of the genetic basis of this malignancy, several mutational survey studies examining GBM have been completed and provide a detailed view of the molecular changes underlying this cancer (2-4). Because GBM is a highly heterogeneous tumor, a challenge remains to determine which molecular alterations drive tumorigenesis and to understand the underlying mechanisms of action. Recent work by our group and others have identified inactivation of protein tyrosine phosphatase receptor-δ (PTPRD) as a frequent alteration in GBM and other tumors, and showed that PTPRD copy number loss correlates with poor prognosis (5-10). Despite the high prevalence of PTPRD inactivation in human tumors, it is not known whether loss of PTPRD can promote tumorigenesis. Furthermore, the mechanisms of action and the oncogenic context in which PTPRD acts remain obscure.PTPRD belongs to a family of protein-tyrosine phosphatases that collectively have been implicated in functions, including the regulation of receptor tyrosine kinases, growth, cell migration, and angiogenesis (11). Previously, we demonstrated that phosphorylated STAT3 (p-STAT3) is a substrate of PTPRD and that cancer-specific mutations in PTPRD abrogate the ability of the phosphatase to dephosphorylate STAT3 (5). Interestingly, accumulation of phosphorylated STAT3 and STAT3 hyper...

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Section: Discussionmentioning

confidence: 99%

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis

Ortiz

Fabius²,

Wu³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Although there are no reports yet evaluating these cell types in the DIPG microenvironment, studies have shown that cells expressing microglia/macrophage markers comprise 30–50% of the cells in benign and malignant gliomas [40]. While the role of microglia/macrophages in glioma has been controversial [52], recent studies have demonstrated that pharmacologic and genetic inhibition of microglial/macrophage function reduces tumor growth in experimental rodent glioma models [25,29,37] and the inhibition of colony stimulating factor-1 receptor has been shown to block glioma progression in a transgenic mouse model of proneuronal GBM [39]. Intriguingly, it has been hypothesized that microglia/macrophages in the glioma microenvironment may be malignant cells themselves and, given their amoeboid properties, maybe capable of invading the surrounding parenchyma giving rise to tumor growth and even tumor metastasis [21].…”

Section: Discussionmentioning

confidence: 99%

Human pontine glioma cells can induce murine tumors

et al. 2014

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Diffuse intrinsic pontine glioma (DIPG), with a median survival of only nine months, is the leading cause of pediatric brain cancer mortality. Dearth of tumor tissue for research has limited progress in this disease until recently. New experimental models for DIPG research are now emerging. To develop preclinical models of DIPG, two different methods were adopted: cells obtained at autopsy 1) were directly xenografted orthotopically into the pons of immunodeficient mice without an intervening cell culture step or 2) were first cultured in vitro and, upon successful expansion, injected in vivo. Both strategies resulted in pontine tumors histopathologically similar to the original human DIPG tumors. However, following the direct transplantation method all tumors proved to be composed of murine and not of human cells. This is in contrast to the indirect method that included initial in vitro culture and resulted in xenografts comprised of human cells. Of note, direct injection of cells obtained post mortem from the pons and frontal lobe of human brains not affected by cancer did not give rise to neoplasms. The murine pontine tumors exhibited an immunophenotype similar to human DIPG, but were also positive for microglia/macrophage markers, such as CD45, CD68 and CD11b. Serial orthotopic injection of these murine cells results in lethal tumors in recipient mice. Direct injection of human DIPG cells in vivo can give rise to malignant murine tumors. This represents an important caveat for xenotransplantation models of DIPG. In contrast, an initial in vitro culture step can allow establishment of human orthotopic xenografts. The mechanism underlying this phenomenon observed with direct xenotransplantation remains an open question.

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“…In studies of NF1-associated low grade gliomas, David Gutmann (Washington University) presented evidence that human tumors are monoclonal and have no other mutations other than loss of NF1 gene expression[Gutmann et al, 2013]. However, in a genetically-engineered mouse optic glioma model, loss of Nf1 gene expression in glial cells alone is not sufficient to drive tumorigenesis but requires signals from Nf1 +/- microglia in the surrounding microenvironment [Pong et al, 2013]. …”

Section: Neurofibromatosismentioning

confidence: 99%