PTEN inhibition promotes robust growth of bulbospinal respiratory axons and partial recovery of diaphragm function in a chronic model of cervical contusion spinal cord injury.

High spinal cord injury (SCI) leads to persistent and debilitating compromise in respiratory function. Cervical SCI not only causes the death of phrenic motor neurons (PhMNs) that innervate the diaphragm, but also damages descending respiratory pathways originating in the rostral ventral respiratory group (rVRG) located in the brainstem, resulting in denervation and consequent silencing of spared PhMNs located caudal to injury. It is imperative to determine whether interventions targeting rVRG axon growth and respiratory neural circuit reconnection are efficacious in chronic cervical contusion SCI, given that the vast majority of individuals are chronically-injured and most cases of SCI involve contusion-type damage to the cervical region. We therefore employed a rat model of chronic cervical hemicontusion to test therapeutic manipulations aimed at reconstructing damaged rVRG-PhMN-diaphragm circuitry to achieve recovery of respiratory function. At a chronic time point post-injury, we systemically administered: an antagonist peptide directed against phosphatase and tensin homolog (PTEN), a central inhibitor of neuron-intrinsic axon growth potential; an antagonist peptide directed against receptor-type protein tyrosine phosphatase sigma (PTPσ), another important negative regulator of axon growth capacity; or a combination of these two peptides. PTEN antagonist peptide (PAP4) promoted partial recovery of diaphragm motor activity out to nine months post-injury (though this effect depended on the anesthetic regimen used during recording), while PTPσ peptide did not impact diaphragm function after cervical SCI. Furthermore, PAP4 promoted robust growth of descending bulbospinal rVRG axons caudal to the injury within the denervated portion of the PhMN pool, while PTPσ peptide did not affect rVRG axon growth at this location that is critical to control of diaphragmatic respiratory function. In conclusion, we find that, when PTEN inhibition is targeted at a chronic time point following cervical contusion, our non-invasive PAP4 strategy can successfully promote significant regrowth of damaged respiratory neural circuitry and also partial recovery of diaphragm motor function.

Cancer-associated point mutations within the extracellular domain of PTPRD affect protein stability and HSPG interaction.

PTPRD, a well-established tumor suppressor gene, encodes the protein tyrosine phosphatase-type D. This protein consists of three immunoglobulin-like (Ig) domains, four to eight fibronectin type 3 (FN) domains, a single transmembrane segment, and two cytoplasmic tandem tyrosine phosphatase domains. PTPRD is known to harbor various cancer-associated point mutations. While it is assumed that PTPRD regulates cellular functions as a tumor suppressor through the tyrosine phosphatase activity in the intracellular region, the function of its extracellular domain (ECD) in cancer is not well understood. In this study, we systematically examined the impact of 92 cancer-associated point mutations within the ECD. We found that 69.6% (64 out of 92) of these mutations suppressed total protein expression and/or plasma membrane localization. Notably, almost all mutations (20 out of 21) within the region between the last FN domain and transmembrane segment affected protein expression and/or localization, highlighting the importance of this region for protein stability. We further found that some mutations within the Ig domains adjacent to the glycosaminoglycan-binding pocket enhanced PTPRD's binding ability to heparan sulfate proteoglycans (HSPGs). This interaction is proposed to suppress phosphatase activity. Our findings therefore suggest that HSPG-mediated attenuation of phosphatase activity may be involved in tumorigenic processes through PTPRD dysregulation.

The mechanism of covalent inhibition of LAR phosphatase by illudalic acid.

Leukocyte antigen-related (LAR) phosphatase is a receptor-type protein tyrosine phosphatase involved in cellular signaling and associated with human disease including cancer and metabolic disorders. Selective inhibition of LAR phosphatase activity by well characterized and well validated small molecules would provide key insights into the roles of LAR phosphatase in health and disease, but identifying selective inhibitors of LAR phosphatase activity has been challenging. Recently, we described potent and selective inhibition of LAR phosphatase activity by the fungal natural product illudalic acid. Here we provide a detailed biochemical characterization of the adduct formed between LAR phosphatase and illudalic acid. A mass spectrometric analysis indicates that two cysteine residues are covalently labeled by illudalic acid and a related analog. Mutational analysis supports the hypothesis that inhibition of LAR phosphatase activity is due primarily to the adduct with the catalytic cysteine residue. A computational study suggests potential interactions between the illudalic acid moiety and the enzyme active site. Taken together, these data offer novel insights into the mechanism of inhibition of LAR phosphatase activity by illudalic acid.

Loss of PTPRS elicits potent metastatic capability and resistance to temozolomide in glioblastoma.

Glioblastoma (GBM) is the most aggressive brain tumor type with worse clinical outcome due to the hallmarks of strong invasiveness, high rate of recurrence, and therapeutic resistance to temozolomide (TMZ), the first-line drug for GBM, representing a major challenge for successful GBM therapeutics. Understanding the underlying mechanisms that drive GBM progression will shed novel insight into therapeutic strategies. Receptor-type tyrosine-protein phosphatase S (PTPRS) is a frequently mutated gene in human cancers, including GBM. Its role in GBM has not yet been clarified. Here, inactivating PTPRS mutation or deficiency was frequently found in GBM, and deficiency in PTPRS significantly induced defects in the G2M checkpoint and limited GBM cells proliferation, leading to potent resistance to TMZ treatment in vitro and in vivo. Surprisingly, loss of PTPRS triggered an unexpected mesenchymal phenotype that markedly enhances the migratory capabilities of GBM cells through upregulating numerous matrix metalloproteinases via MAPK-MEK-ERK signaling. Therefore, this work provides a therapeutic window for precisely excluding PTPRS-mutated patients who do not respond to TMZ.

Downregulation of PTPRT elevates the expression of survivin and promotes the proliferation, migration, and invasion of lung adenocarcinoma.

BACKGROUND: Receptor-type tyrosine-protein phosphatase T (PTPRT) is a transmembrane protein that is involved in cell adhesion. We previously found that PTPRT was downregulated in multiple cancer types and the mutation of PTPRT was associated with cancer early metastasis. However, the impacts of PTPRT downregulation on tumour proliferation, invasion, and clinical interventions such as immune checkpoint inhibitor (ICI) therapies remained largely unknown. METHODS: Gene expression data of non-small cell lung cancer (NSCLC) samples from The Cancer Genome Atlas database were downloaded and used to detect the differential expressed genes between PTPRT-high and PTPRT-low subgroups. Knockdown and overexpress of PTPRT in lung cancer cell lines were performed to explore the function of PTPRT in vitro. Western blot and qRT-PCR were used to evaluate the expression of cell cycle-related genes. CCK-8 assays, wound-healing migration assay, transwell assay, and colony formation assay were performed to determine the functional impacts of PTPRT on cell proliferation, migration, and invasion. KM-plotter was used to explore the significance of selected genes on patient prognosis. RESULTS: PTPRT was found to be downregulated in tumours and lung cancer cell lines compared to normal samples. Cell cycle-related genes (BIRC5, OIP5, and CDCA3, etc.) were specifically upregulated in PTPRT-low lung adenocarcinoma (LUAD). Modulation of PTPRT expression in LUAD cell lines affected the expression of BIRC5 (survivin) significantly, as well as the proliferation, migration, and invasion of tumour cells. In addition, low PTPRT expression level was correlated with worse prognosis of lung cancer and several other cancer types. Furthermore, PTPRT downregulation was associated with elevated tumour mutation burden and tumour neoantigen burden in lung cancer, indicating the potential influence on tumour immunogenicity. CONCLUSION: Our findings uncovered the essential roles of PTPRT in the regulation of proliferation, migration, and invasion of LUAD, and highlighted the clinical significance of PTPRT downregulation in lung cancer.

A novel binding pocket in the D2 domain of protein tyrosine phosphatase mu (PTPmu) guides AI screen to identify small molecules that modulate tumour cell adhesion, growth and migration.

Approximately 40% of people will get cancer in their lifetime in the US, and 20% are predicted to die from the condition when it is invasive and metastatic. Targeted screening for drugs that interact with proteins that drive cancer cell growth and migration can lead to new therapies. We screened molecular libraries with the AtomNet® AI-based drug design tool to identify compounds predicted to interact with the cytoplasmic domain of protein tyrosine phosphatase mu. Protein tyrosine phosphatase mu (PTPmu) is proteolytically downregulated in cancers such as glioblastoma generating fragments that stimulate cell survival and migration. Aberrant nuclear localization of PTPmu intracellular fragments drives cancer progression, so we targeted a predicted drug-binding site between the two cytoplasmic phosphatase domains we termed a D2 binding pocket. The function of the D2 domain is controversial with various proposed regulatory functions, making the D2 domain an attractive target for the development of allosteric drugs. Seventy-five of the best-scoring and chemically diverse computational hits predicted to interact with the D2 binding pocket were screened for effects on tumour cell motility and growth in 3D culture as well as in a direct assay for PTPmu-dependent adhesion. We identified two high-priority hits that inhibited the migration and glioma cell sphere formation of multiple glioma tumour cell lines as well as aggregation. We also identified one activator of PTPmu-dependent aggregation, which was able to stimulate cell migration. We propose that the PTPmu D2 binding pocket represents a novel regulatory site and that inhibitors targeting this region may have therapeutic potential for treating cancer.

Inhibition of the proteoglycan receptor PTPσ promotes functional recovery on a rodent model of preterm hypoxic-ischemic brain injury.

BACKGROUND: Preterm white matter injury (WMI) is the most common brain injury in preterm infants and is associated with long-term adverse neurodevelopmental outcomes. Protein tyrosine phosphatase sigma (PTPσ) was discovered as chondroitin sulfate proteoglycan (CSPG) receptor that played roles in inhibiting myelin regeneration in spinal injury, experimental autoimmune encephalomyelitis, and stroke models. However, the role of PTPσ in perinatal WMI is not well understood. AIMS: This study examines the effect of PTPσ inhibition on neurodevelopmental outcomes, myelination, and neuroinflammation in a mouse model of preterm WMI. MATERIALS AND METHODS: Modified Rice-Vannucci model was performed on postnatal day 3 (P3) C57BL/6 mice. Intracellular Sigma Peptide (ISP) or vehicle was administrated subcutaneously one hour after injury for an additional 14 consecutive days. A battery of behavioral tests was performed to evaluate the short- and long-term effects of ISP on neurobehavioral deficit. Real time qPCR, western blot, immunofluorescence, and transmission electron microscopy were performed to assess white matter development. qPCR and flow cytometry were performed to evaluate neuroinflammation and microglia/macrophage phenotype. RESULTS: The expression of PTPσ was increased after preterm WMI. ISP improved short-term neurological outcomes and ameliorated long-term motor and cognitive function of mice after preterm WMI. ISP promoted oligodendrocyte differentiation, maturation, myelination, and improved microstructure of myelin after preterm WMI. Furthermore, ISP administration fostered a beneficial inflammatory response in the acute phase after preterm WMI, inhibited the infiltration of peripheral macrophages, and promoted anti-inflammatory phenotype of microglia/macrophages. CONCLUSION: PTPσ inhibition can ameliorate neurofunctional deficit, promote white matter development, modulate neuroinflammation and microglia/macrophage phenotype after preterm WMI. Thus, ISP administration may be a potential therapeutic strategy to improve neurodevelopmental outcomes of perinatal WMI.

Manipulating PTPRD function with ectodomain antibodies.

Protein tyrosine phosphatases (PTPs) are critical regulators of signal transduction but have yet to be exploited fully for drug development. Receptor protein tyrosine phosphatase δ (RPTPδ/PTPRD) has been shown to elicit tumor-promoting functions, including elevating SRC activity and promoting metastasis in certain cell contexts. Dimerization has been implicated in the inhibition of receptor protein tyrosine phosphatases (RPTPs). We have generated antibodies targeting PTPRD ectodomains with the goal of manipulating their dimerization status ectopically, thereby regulating intracellular signaling. We have validated antibody binding to endogenous PTPRD in a metastatic breast cancer cell line, CAL51, and demonstrated that a monoclonal antibody, RD-43, inhibited phosphatase activity and induced the degradation of PTPRD. Similar effects were observed following chemically induced dimerization of its phosphatase domain. Mechanistically, RD-43 triggered the formation of PTPRD dimers in which the phosphatase activity was impaired. Subsequently, the mAb-PTPRD dimer complex was degraded through lysosomal and proteasomal pathways, independently of secretase cleavage. Consequently, treatment with RD-43 inhibited SRC signaling and suppressed PTPRD-dependent cell invasion. Together, these findings demonstrate that manipulating RPTP function via antibodies to the extracellular segments has therapeutic potential.

PTPRD mutation is a prognostic biomarker for sensitivity to ICIs treatment in advanced non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have become the standard treatment for advanced non-small cell lung cancer (NSCLC). ICIs can provide durable responses and prolong survival for some patients. With the increasing routine of next-generation sequencing (NGS) in clinical practice, it is essential to integrate prognostic factors to establish novel nomograms to improve clinical prediction ability in NSCLC with ICIs treatment. METHODS: Clinical information, response data, and genome data of advanced NSCLC treated ICIs were obtained from cBioPortal. The top 20 gene alterations in durable clinical benefit (DCB) were compared with those genes in no durable benefit (NDB). Survival analyses were performed using the Kaplan-Meier plot method and selected clinical variables to develop a novel nomogram. RESULTS: The mutation of PTPRD was significantly related to progression free survival (PFS) and overall survival (OS) in advanced NSCLC with ICIs treatment (PFS: p = 0.0441, OS: p = 0.0086). The PTPRD mutation was closely related to tumor mutational burden (TMB) and tumor-infiltrating immune cells (TIICs). Two novel nomograms were built to predict the PFS and OS of advanced NSCLC patients with ICIs treatment. CONCLUSIONS: Our study suggested that PTPRD mutations could serve as a predictive biomarker for the sensitivity to ICIs treatment and PFS and OS in advanced NSCLC with ICIs. Our systematic nomograms showed great potential value in clinical application to predict the PFS and OS for advanced NSCLC patients with ICIs.

Small molecule antagonists of PTPmu identified by artificial intelligence-based computational screening block glioma cell migration and growth.

PTPmu (PTPµ) is a member of the receptor protein tyrosine phosphatase IIb family that participates in both homophilic cell-cell adhesion and signaling. PTPmu is proteolytically downregulated in glioblastoma generating extracellular and intracellular fragments that have oncogenic activity. The intracellular fragments, in particular, are known to accumulate in the cytoplasm and nucleus where they interact with inappropriate binding partners/substrates generating signals required for glioma cell migration and growth. Thus, interfering with these fragments is an attractive therapeutic strategy. To develop agents that target these fragments, we used the AI-based AtomNetⓇ model, a drug design and discovery tool, to virtually screen molecular libraries for compounds able to target a binding pocket bordered by the wedge domain, a known regulatory motif located within the juxtamembrane portion of the protein. Seventy-four high-scoring and chemically diverse virtual hits were then screened in multiple cell-based assays for effects on glioma cell motility (scratch assays) and growth in 3D culture (sphere assays), and PTPmu-dependent adhesion (Sf9 aggregation). We identified three inhibitors (247678835, 247682206, 247678791) that affected the motility of multiple glioma cell lines (LN229, U87MG, and Gli36delta5), the growth of LN229 and Gli36 spheres, and PTPmu-dependent Sf9 aggregation. Compound 247678791 was further shown to suppress PTPmu enzymatic activity in an in vitro phosphatase assay, and 247678835 was able to inhibit the growth of human glioma tumors in mice. We propose that these three compounds are PTPmu-targeting agents with therapeutic potential for treating glioblastoma.

Metastasis suppressor 1 interacts with protein tyrosine phosphatase receptor-δ to regulate adipogenesis.

Adipogenesis is a finely controlled process and its dysfunction may contribute to metabolic disorders such as obesity. Metastasis suppressor 1 (MTSS1) is a player in tumorigenesis and metastasis of various types of cancers. To date, it is not known whether and how MTSS1 plays a role in adipocyte differentiation. In the current study, we found that MTSS1 was upregulated during adipogenic differentiation of established mesenchymal cell lines and primary cultured bone marrow stromal cells. Gain-of-function and loss-of-function experiments uncovered that MTSS1 facilitated adipocyte differentiation from mesenchymal progenitor cells. Mechanistic explorations revealed that MTSS1 bound and interacted with FYN, a member of Src family of tyrosine kinases (SFKs), and protein tyrosine phosphatase receptor-δ (PTPRD). We demonstrated that PTPRD was capable of inducing the differentiation of adipocytes. Overexpression of PTPRD attenuated the impaired adipogenesis induced by the siRNA targeting MTSS1. Both MTSS1 and PTPRD activated SFKs by suppressing the phosphorylation of SFKs at Tyr530 and inducing the phosphorylation of FYN at Tyr419. Further investigation showed that MTSS1 and PTPRD were able to activate FYN. Collectively, our study has for the first time unraveled that MTSS1 plays a role in adipocyte differentiation in vitro through interacting with PTPRD and thereby activating SFKs such as FYN tyrosine kinase.

Artificial Intelligence-Based Computational Screening and Functional Assays Identify Candidate Small Molecule Antagonists of PTPmu-Dependent Adhesion.

PTPmu (PTPµ) is a member of the receptor protein tyrosine phosphatase IIb family that participates in cell-cell adhesion and signaling. PTPmu is proteolytically downregulated in glioblastoma (glioma), and the resulting extracellular and intracellular fragments are believed to stimulate cancer cell growth and/or migration. Therefore, drugs targeting these fragments may have therapeutic potential. Here, we used the AtomNet® platform, the first deep learning neural network for drug design and discovery, to screen a molecular library of several million compounds and identified 76 candidates predicted to interact with a groove between the MAM and Ig extracellular domains required for PTPmu-mediated cell adhesion. These candidates were screened in two cell-based assays: PTPmu-dependent aggregation of Sf9 cells and a tumor growth assay where glioma cells grow in three-dimensional spheres. Four compounds inhibited PTPmu-mediated aggregation of Sf9 cells, six compounds inhibited glioma sphere formation/growth, while two priority compounds were effective in both assays. The stronger of these two compounds inhibited PTPmu aggregation in Sf9 cells and inhibited glioma sphere formation down to 25 micromolar. Additionally, this compound was able to inhibit the aggregation of beads coated with an extracellular fragment of PTPmu, directly demonstrating an interaction. This compound presents an interesting starting point for the development of PTPmu-targeting agents for treating cancer including glioblastoma.

Generation of an Aptamer Targeting Receptor-Type Tyrosine-Protein Phosphatase F.

Cell-SELEX is a powerful tool to generate aptamers that specifically bind the native molecules on living cells. Here, we report an aptamer ZAJ4a generated by cell-SELEX. The molecular target of ZAJ4a was pulled down by the enriched cell-SELEX pool and identified to be the receptor-type tyrosine-protein phosphatase F (PTPRF) through a stable isotope labeling using amino acids in cell culture (SILAC)-based quantitative proteomic method. ZAJ4a showed high binding affinity with nanomolar range to cancer cells expressing PTPRF. Meanwhile, PTPRF was proven to highly express on several cancer cell lines using ZAJ4a as a molecular probe and to highly express in many kinds of cancer samples using gene expression profiling interactive analysis (GEPIA2) from the TCGA and GTEx databases. These results indicate that the aptamer generated by cell-SELEX showed good specificity at the molecular level. This cell-SELEX and target identification strategies show great potential for identifying biomarkers on the cell surface.

Comparison of Near-Infrared Imaging Agents Targeting the PTPmu Tumor Biomarker.

PURPOSE: Maximal, safe resection of solid tumors is considered a critical first step in successful cancer treatment. The advent of fluorescence image-guided surgery (FIGS) using non-specific agents has improved patient outcomes, particularly in the case of glioblastoma. Molecularly targeted agents that recognize specific tumor biomarkers have the potential to augment these gains. Identification of the optimal combination of targeting moiety and fluorophore is needed prior to initiating clinical trials. PROCEDURES: A 20-amino acid peptide (SBK2) recognizing the receptor protein-tyrosine phosphatase mu (PTPmu)-derived tumor-specific biomarker, with or without a linker, was conjugated to three different near-infrared fluorophores: indocyanine green (ICG), IRDye® 800CW, and Tide Fluor™ 8WS. The in vivo specificity, time course, and biodistribution were evaluated for each using mice with heterotopic human glioma tumors that express the PTPmu biomarker to identify component combinations with optimal properties for FIGS. RESULTS: SBK2 conjugated to ICG demonstrated excellent specificity for gliomas in heterotopic tumors. SBK2-ICG showed significantly higher in vivo tumor labeling compared to the Scram-ICG control from 10 min to 24 h, p < 0.01 at all timepoints, following injection, as well as a significantly higher ex vivo tumor signal at 24 h, p < 0.001. Inserting a six-amino acid linker between the targeting peptide and ICG increased the clearance rate and resulted in significantly higher in vivo tumor signal relative to its linker-containing Scrambled control from 10 min to 8 h, p < 0.05 at all timepoints, after dosing. Agents made with the more hydrophilic IRDye® 800CW and Tide Fluor™ 8WS showed no specific tumor labeling relative to the controls. The IRDye 800CW-conjugated agents cleared within 1 h, while the non-specific fluorescent tumor signal generated by the Tide Fluor 8WS-conjugated agents persists beyond 24 h. CONCLUSIONS: The SBK2 PTPmu-targeting peptide conjugated to ICG specifically labels heterotopic human gliomas grown in mice between 10 min and 24 h following injection. Similar molecules constructed with more hydrophilic dyes demonstrated no specificity. These studies present a promising candidate for use in FIGS of PTPmu biomarker-expressing tumors.

Genomic Characterization of Prostatic Basal Cell Carcinoma.

Basal cell carcinoma (BCC) of the prostate is a rare tumor. Compared with the more common acinar adenocarcinoma (AAC) of the prostate, BCCs show features of basal cell differentiation and are thought to be biologically distinct from AAC. The spectrum of molecular alterations of BCC has not been comprehensively described, and genomic studies are lacking. Herein, whole genome sequencing was performed on archival formalin-fixed, paraffin-embedded specimens of two cases with BCC. Prostatic BCCs were characterized by an overall low copy number and mutational burden. Recurrent copy number loss of chromosome 16 was observed. In addition, putative driver gene alterations in KIT, DENND3, PTPRU, MGA, and CYLD were identified. Mechanistically, depletion of the CYLD protein resulted in increased proliferation of prostatic basal cells in vitro. Collectively, these studies show that prostatic BCC displays distinct genomic alterations from AAC and highlight a potential role for loss of chromosome 16 in the pathogenesis of this rare tumor type.

PTPRU, a quiescence-induced receptor tyrosine phosphatase negatively regulates osteogenic differentiation of human mesenchymal stem cells.

Bone marrow mesenchymal stem cells (MSCs) are heterogeneous osteo-progenitors that are mainly responsible for bone regeneration and homeostasis. In vivo, a subpopulation of bone marrow MSCs persists in a quiescent state, providing a source of new cells for repair. Previously, we reported that induction of quiescence in hMSCs in vitro skews their differentiation potential in favour of osteogenesis while suppressing adipogenesis. Herein, we uncover a new role for a protein tyrosine phosphatase, receptor type U (PTPRU) in repressing osteogenesis during quiescence. A 75 kD PTPRU protein isoform was found to be specifically induced during quiescence and down-regulated during cell cycle reactivation. Using siRNA-mediated knockdown, we report that in proliferating hMSC, PTPRU preserves self-renewal, while in quiescent hMSC, PTPRU not only maintains reversibility of cell cycle arrest but also suppresses expression of osteogenic lineage genes. Knockdown of PTPRU in proliferating or quiescent hMSC de-represses osteogenic markers, and enhances induced osteogenic differentiation. We also show that PTPRU positively regulates a ß-catenin-TCF transcriptional reporter. Taken together, our study suggests a role for a quiescence-induced 75kD PTPRU isoform in modulating bone differentiation in hMSC, potentially involving the Wnt pathway.

PTPRD/PTPRT mutation as a predictive biomarker of immune checkpoint inhibitors across multiple cancer types.

Background: Immune checkpoint inhibitors (ICIs) are dramatically changing the treatment landscape of a variety of cancers. Nevertheless, the variability in ICI responses highlight the importance in identifying predictive biomarkers. PTPRD and PTPRT (PTPRD/PTPRT) are the phosphatases of JAK-STAT signaling, a critical pathway in anti-cancer immunity regulation. However, the pan-cancer association between PTPRD/PTPRT mutation and the efficacy of ICIs remains unclear across pan-cancer patients. Methods: We analyzed the association between PTPRD/PTPRT mutations and patient outcomes using clinical data and genomic mutations from TCGA pan-cancer cohort. Furthermore, the ICI-treatment cohort was used to evaluate the relationship between PTPRD/PTPRT mutation and the efficacy of ICIs. Another ICIs-treatment cohort was used to validate the findings. The TCGA pan-cancer dataset was analyzed to explore the correlation between PTPRD/PTPRT mutations and immune signatures. Moreover, we combined four factors to construct a nomogram model that could be used to predict the survival of pan-cancer patients receiving ICI treatment. The calibration curves and area under the curve were applied to assess the performance of the model. Results: PTPRD/PTPRT mutations were shown to be associated with a worse prognosis in TCGA cohort (P < 0.05). In the Samstein cohort, prolonged overall survival (OS) was observed in PTPRD/PTPRT mutant cancers, compared with wild-type cancers (mOS: 40.00 vs 16.00 months, HR = 0.570, 95%CI: 0.479-0.679, P < 0.0001). In the validation cohort, significant OS advantage was observed in PTPRD/PTPRT mutant patients (mOS: 31.32 vs 15.53 months, HR = 0.658, 95%CI: 0.464-0.934, P = 0.0292). Furthermore, PTPRD/PTPRT mutations were associated with a higher tumor mutational burden, MSI score, and TCR score (P < 0.0001). Enhanced immune signatures were found in the PTPRD/PTPRT mutant cancers (P < 0.05). Finally, we successfully established a nomogram model that could be used to predict the survival of NSCLC patients who received ICI treatment. Based on the risk score of the model, patients in the low-risk group showed a better mOS than those in the high-risk group (mOS: 2.75 vs 1.08 years, HR = 0.567, 95%CI: 0.492-0.654; P < 0.001). Conclusions: PTPRD/PTPRT mutations may be a potential biomarker for predicting ICI treatment responsiveness in multiple cancer types.

Investigation of cell signalings and therapeutic targets in PTPRK-RSPO3 fusion-positive colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) is one of the most deadly and common diseases in the world, accounting for over 881,000 casualties in 2018. The PTPRK-RSPO3 (P:R) fusion is a structural variation in CRC and well known for its ability to activate WNT signaling and tumorigenesis. However, till now, therapeutic targets and actionable drugs are limited in this subtype of cancer. MATERIALS AND METHOD: The purpose of this study is to identify key genes and cancer-related pathways specific for P:R fusion-positive CRC. In addition, we also inferred the actionable drugs in bioinformatics analysis using the Cancer Genome Atlas (TCGA) data. RESULTS: 2,505 genes were altered in RNA expression specific for P:R fusion-positive CRC. By pathway analysis based on the altered genes, ten major cancer-related signaling pathways (Apoptosis, Direct p53, EGFR, ErbB, JAK-STAT, tyrosine kinases, Pathways in Cancer, SCF-KIT, VEGFR, and WNT-related Pathway) were significantly altered in P:R fusion-positive CRC. Among these pathways, the most altered cancer genes (ALK, ACSL3, AXIN, MYC, TP53, GNAQ, ACVR2A, and FAS) specific for P:R fusion and involved in multiple cancer pathways were considered to have a key role in P:R fusion-positive CRC. Based on the drug-target network analysis, crizotinib, alectinib, lorlatinib, brigatinib, ceritinib, erdafitinib, infigratinib and pemigatinib were selected as putative therapeutic candidates, since they were already used in routine clinical practice in other cancer types and target genes of the drugs were involved in multiple cancer-pathways.

Modulation of the proteoglycan receptor PTPσ promotes white matter integrity and functional recovery after intracerebral hemorrhage stroke in mice.

BACKGROUND: Intracerebral hemorrhage (ICH) is associated with high morbidity and mortality rates. However, extant investigations have mainly focused on gray matter injury within the primary injury site after ICH rather than on white matter (WM) injury in the brain and spinal cord. This focus partly accounts for the diminished therapeutic discovery. Recent evidence suggests that chondroitin sulphate proteoglycans (CSPG), which can bind to the neural transmembrane protein tyrosine phosphatase-sigma (PTPσ), may facilitate axonal regrowth and remyelination by ameliorating neuroinflammation. METHODS: A clinically relevant ICH model was established using adult C57BL/6 mice. The mice were then treated systemically with intracellular sigma peptide (ISP), which specifically targets PTPσ. Sensorimotor function was assessed by various behavioral tests and electrophysiological assessment. Western blot was used to verify the expression levels of Iba-1 and different inflammatory cytokines. The morphology of white matter tracts of brain and spinal cord was evaluated by immunofluorescence staining and transmission electron microscopy (TEM). Adeno-associated virus (AAV) 2/9 injection was used to assess the ipsilateral axonal compensation after injury. Parallel in vitro studies on the effects of CSPG interference on oligodendrocyte-DRG neuron co-culture explored the molecular mechanism through which ISP treatment promoted myelination capability. RESULTS: ISP, by targeting PTPσ, improved WM integrity and sensorimotor recovery via immunomodulation. In addition, ISP administration significantly decreased WM injury in the peri-hematomal region as well as cervical spinal cord, enhanced axonal myelination and facilitated neurological restoration, including electrophysiologically assessed sensorimotor functions. Parallel in vitro studies showed that inhibition of PTPσ by ISP fosters myelination by modulating the Erk/CREB signaling pathway. CONCLUSIONS: Our findings revealed for the first time that manipulation of PTPσ signaling by ISP can promote prolonged neurological recovery by restoration of the integrity of neural circuits in the CNS through modulation of Erk/CREB signaling pathway.

High expression of protein tyrosine phosphatase receptor S (PTPRS) is an independent prognostic marker for cholangiocarcinoma.

Cholangiocarcinoma (CCA) is an aggressive tumor of the bile duct with a high rate of mortality. Lymph node metastasis is an important factor facilitating the progression of CCA. A reliable biomarker for diagnosis, progression status, or prognosis of CCA is still lacking. To identify a novel and reliable biomarker for diagnosis/prognosis of CCA, liquid chromatography-mass spectrometry and tandem mass spectrometry (LC-MS/MS) in combination with bioinformatics analysis were applied for the representative serum samples of patients with CCA. The proteome results showed that protein tyrosine phosphatase receptor S (PTPRS) had the highest potential candidate. Then, a dot blot assay was used to measure the level of serum PTPRS in patients with CCA (n = 80), benign biliary disease patients (BBD; n = 39), and healthy controls (HC; n = 55). PTPRS level of CCA sera (14.38 ± 9.42 ng/ml) was significantly higher than that of BBD (10.7 ± 5.05 ng/ml) or HC (6 ± 3.73 ng/ml) (P < 0.0001). PTPRS was associated with serum albumin (P = 0.028), lymph node metastasis (P = 0.038), and the survival time of patients (P = 0.011). Using a log-rank test, higher serum PTPRS level was significantly (P = 0.031) correlated with a longer overall survival time of patients with CCA, and PTPRS was an independent prognostic marker for CCA superior to carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA) or alkaline phosphatase (ALP). High expression of PTPRS could be a good independent prognostic marker for CCA.