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

Abstract

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...

The Genetics of Nodal Marginal Zone Lymphoma

“…61,63 At variance with solid cancers arising in ptprd knockout mice, lymphomas arising in these animal models do not carry any clue of Y705-phospho STAT3 activation, 63 which is consistent with our observation in human NMZL patients and indicates that other yet unknown PTPRD substrates and oncogenic signaling are affected by its deletion or mutations in lymphomas. The observation that PTPRD lesions associate with proliferation in NMZL prompts investigations aimed at characterizing the biochemical mechanisms linking PTPRD mutations to the cell-cycle program in this lymphoma and its clinical implications.…”

“…PTPRD encodes a receptor-type protein tyrosine phosphatase that has not been previously described as recurrently mutated in indolent and aggressive lymphomas, with the exception of a few cases of primary central nervous system DLBCL. 52 In NMZL, PTPRD lesions either remove the entire PTPRD gene or damage the tyrosine phosphatase 61 However, NMZL, including PTPRD-affected cases, carry neither Y705-phospho STAT3 nor any other phenotypic or genetic clue of cytokine-signaling deregulation, thus indicating that PTPRD genetic lesions do not act through STAT3 constitutive activation in NMZL. The observation that PTPRD missense substitutions interfere with Y705-phospho STAT3 dephosphorylation by PTPRD in a biochemical assay confirms the deleterious effect of these variants and supports the notion that they are not passenger events.…”

“…Phospho-STAT3 (Y705) is an experimentally validated substrate of PTPRD used as functional readout of its phosphatase activity. 56,61,62 Therefore, to evaluate how phosphatase activity was affected by the missense PTPRD mutations identified in NMZL, we expressed wild-type PTPRD or mutant PTPRD with p.C1844S, p.Y1903H, p.E440K, and p.W1729R substitutions in HEK 293 cells engineered to express the human interleukin 6 (IL-6) receptor (HEK 293-IL6) (Figure 6). In this system, stimulation with increasing doses of IL-6 led to dose-dependent phosphorylation of STAT6 Y705, which was markedly reduced in the presence of the exogenous wild-type PTPRD phosphatase (Figure 6).…”

Identification of Subsets of Genetic Alterations in KRAS-mutant Lung Cancer using Association Rule Mining

“…The role of PTPRs in lung 17, 2017; cancer is yet to be unraveled. However, phospho-STAT3 is a substrate for these phosphatases [40,41] and frequent loss of function mutations in PTPRT and PTPRD have been linked to hyperphosphorylation of STAT3 in head and neck squamous carcinoma and in gliomagenesis [42][43][44]. STAT3 is hyperactive in some lung cancers [45].…”

“…Mutations in PTPRs can lead to constitutive activation of STAT3 which is associated with many lung cancer [42][43][44]. PTPRs alterations were collectively altered in at least 50% of KRASmutant tumors (Table 1).…”