Neurofibromatosis-1 Heterozygosity Increases Microglia in a Spatially and Temporally Restricted Pattern Relevant to Mouse Optic Glioma Formation and Growth

Simmons, Grant W.; Pong, Winnie W.; Emnett, Ryan J.; White, Crystal; Gianino, Scott M.; Rodríguez, Fausto J.; Gutmann, David H.

doi:10.1097/nen.0b013e3182032d37

Cited by 112 publications

(110 citation statements)

References 58 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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“…In addition, NF1 haploinsufficiency in the cellular environment of a tumor promotes its progression in vivo. That observation was made in Nf1 mouse models in both plexiform neurofibromas [Yang et al, 2008;Staser et al, 2012] and optic gliomas [Daginakatte and Gutmann, 2007;Simmons et al, 2011], e.g. via hyperactivated Nf1 +/-mast cells as critical mediators [Khalaf et al, 2007;Parrinello and Lloyd, 2009;Staser et al, 2010].…”

mentioning

confidence: 99%

Partial Blindness to Submicron Topography in <b><i>NF1</i></b> Haploinsufficient Cultured Fibroblasts Indicates a New Function of Neurofibromin in Regulation of Mechanosensoric

Kaufmann

Hoesch

Su³

et al. 2012

Mol Syndromol

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Cells sense physical properties of their extracellular environment and translate them into biochemical signals. In this study, cell responses to surfaces with submicron topographies were investigated in cultured human NF1 haploinsufficient fibroblasts. Age-matched fibroblasts from 8 patients with neurofibromatosis type 1 (NF1^+/–) and 9 controls (NF1^+/+) were cultured on surfaces with grooves of 200 nm height and lateral distance of 2 µm. As cellular response indicator, the mean cell orientation along microstructured grooves was systematically examined. The tested NF1 haploinsufficient fibroblasts were significantly less affected by the topography than those from healthy donors. Incubation of the NF1^+/– fibroblasts with the farnesyltransferase inhibitor FTI-277 and other inhibitors of the neurofibromin pathway ameliorates significantly the cell orientation. These data indicate that NF1 haploinsufficiency results in an altered response to specific surface topography in fibroblasts. We suggest a new function of neurofibromin in the sensoric mechanism to topographies and a partial mechanosensoric blindness by NF1 haploinsufficiency.

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“…3B), where 35%-55% of the cells in these PA tumors were microglia/macrophages. This level of stromal contamination with microglia/macrophages is similar to that observed in both sporadic low-grade and high-grade gliomas (Simmons et al 2011). Next, we evaluated that possibility of large-scale somatic rearrangements in other genes potentially cooperate with NF1 loss during PA formation or growth by performing copy number alteration analysis of WGS read data using the cnvHMM algorithm (Chen et al 2012).…”

Section: Resultsmentioning

confidence: 99%

“…The importance of these stromal cells to NF1 glioma growth is further supported by several studies using Nf1 GEM strains. In these experiments, pharmacologic or genetic silencing of microglia reduces glioma growth and proliferation Daginakatte et al 2008;Simmons et al 2011). The mechanism underlying their glioma-promoting properties has not been fully elucidated, but likely involves the generation of growth factors and chemokines Warrington et al 2007;Wesolowska et al 2008;Zhai et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma

et al. 2012

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Low-grade brain tumors (pilocytic astrocytomas) arising in the neurofibromatosis type 1 (NF1) inherited cancer predisposition syndrome are hypothesized to result from a combination of germline and acquired somatic NF1 tumor suppressor gene mutations. However, genetically engineered mice (GEM) in which mono-allelic germline Nf1 gene loss is coupled with bi-allelic somatic (glial progenitor cell) Nf1 gene inactivation develop brain tumors that do not fully recapitulate the neuropathological features of the human condition. These observations raise the intriguing possibility that, while loss of neurofibromin function is necessary for NF1-associated low-grade astrocytoma development, additional genetic changes may be required for full penetrance of the human brain tumor phenotype. To identify these potential cooperating genetic mutations, we performed whole-genome sequencing (WGS) analysis of three NF1-associated pilocytic astrocytoma (PA) tumors. We found that the mechanism of somatic NF1 loss was different in each tumor (frameshift mutation, loss of heterozygosity, and methylation). In addition, tumor purity analysis revealed that these tumors had a high proportion of stromal cells, such that only 50%-60% of cells in the tumor mass exhibited somatic NF1 loss. Importantly, we identified no additional recurrent pathogenic somatic mutations, supporting a model in which neuroglial progenitor cell NF1 loss is likely sufficient for PA formation in cooperation with a proper stromal environment.

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Neurofibromatosis-1 Heterozygosity Increases Microglia in a Spatially and Temporally Restricted Pattern Relevant to Mouse Optic Glioma Formation and Growth

Cited by 112 publications

References 58 publications

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

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

Partial Blindness to Submicron Topography in <b><i>NF1</i></b> Haploinsufficient Cultured Fibroblasts Indicates a New Function of Neurofibromin in Regulation of Mechanosensoric

Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma

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