scholarly journals Oncogenic role of a developmentally regulated NTRK2 splice variant

2022 ◽  
Author(s):  
Siobhan S Pattwell ◽  
Sonali Arora ◽  
Nicholas Nuechterlein ◽  
Michael Zager ◽  
Keith R Loeb ◽  
...  
Keyword(s):  
Splice Variant ◽  
Affinity Purification ◽  
Neurotrophin Receptor ◽  
Oncogenic Signaling ◽  
Developmentally Regulated ◽  
Multiple Tumor ◽  
Wide Range ◽  
Tumor Types ◽  
Affinity Purification Mass Spectrometry ◽  
Oncogenic Signaling Pathways

Temporally-regulated alternative splicing choices are vital for proper development yet the wrong splice choice may be detrimental. Here we highlight a novel role for the neurotrophin receptor splice variant TrkB.T1 in neurodevelopment, embryogenesis, transformation, and oncogenesis across multiple tumor types in both humans and mice. TrkB.T1 is the predominant NTRK2 isoform across embryonic organogenesis and forced over-expression of this embryonic pattern causes multiple solid and nonsolid tumors in mice in the context of tumor suppressor loss. TrkB.T1 also emerges the predominant NTRK isoform expressed in a wide range of adult and pediatric tumors, including those harboring TRK fusions. Affinity purification-mass spectrometry (AP-MS) proteomic analysis reveals TrkB.T1 has distinct interactors with known developmental and oncogenic signaling pathways such as Wnt, TGF-β, Hedgehog, and Ras. From alterations in splicing factors to changes in gene expression, the discovery of isoform specific oncogenes with embryonic ancestry has the potential to shape the way we think about developmental systems and oncology.

TMOD-30. NTRK2 SPLICE VARIANT, TRKB.T1, LINKS NEUROBIOLOGY, EMBRYONIC DEVELOPMENT, AND ONCOGENESIS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi222-vi222
Author(s):  
Siobhan Pattwell ◽  
Sonali Arora ◽  
Nicholas Nuechterlein ◽  
Michael Zager ◽  
Keith Loeb ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Splice Variant ◽  
Transcript Level ◽  
Neurotrophin Receptor ◽  
Unique Role ◽  
Multiple Tumor ◽  
Oncology Research ◽  
Level Data ◽  
Wide Range ◽  
Tumor Types

Abstract Temporally regulated alternative splicing choices are vital for proper development yet the wrong splice choice may be detrimental. Here we highlight a novel role for the neurotrophin receptor splice variant TrkB.T1 in neurodevelopment, embryogenesis, transformation, and oncogenesis across multiple tumor types in both humans and mice. TrkB.T1 is the predominant NTRK2 isoform across embryonic organogenesis and is highly expressed in a wide range of adult and pediatric tumors. Further, forced expression of TrkB.T1 causes multiple solid and non-solid tumors in mice in the context of tumor suppressor loss. These results highlight a unique role for the neurotrophin receptor splicing in development and oncogenesis and underscore the need for considering alternative splicing and transcript level data in neuroscience, developmental biology, and oncology research.

scholarly journals Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Ruijuan Du ◽  
Chuntian Huang ◽  
Kangdong Liu ◽  
Xiang Li ◽  
Zigang Dong
Keyword(s):  
Cancer Therapy ◽  
Molecular Mechanisms ◽  
Aurora Kinase ◽  
Interacting Proteins ◽  
Multiple Tumor ◽  
Oncogenic Pathways ◽  
Wide Range ◽  
The Family ◽  
Tumor Types ◽  
Cancer Tissues

AbstractAurora kinase A (AURKA) belongs to the family of serine/threonine kinases, whose activation is necessary for cell division processes via regulation of mitosis. AURKA shows significantly higher expression in cancer tissues than in normal control tissues for multiple tumor types according to the TCGA database. Activation of AURKA has been demonstrated to play an important role in a wide range of cancers, and numerous AURKA substrates have been identified. AURKA-mediated phosphorylation can regulate the functions of AURKA substrates, some of which are mitosis regulators, tumor suppressors or oncogenes. In addition, enrichment of AURKA-interacting proteins with KEGG pathway and GO analysis have demonstrated that these proteins are involved in classic oncogenic pathways. All of this evidence favors the idea of AURKA as a target for cancer therapy, and some small molecules targeting AURKA have been discovered. These AURKA inhibitors (AKIs) have been tested in preclinical studies, and some of them have been subjected to clinical trials as monotherapies or in combination with classic chemotherapy or other targeted therapies.

scholarly journals Affinity purification mass spectrometry analysis of PD-1 uncovers SAP as a new checkpoint inhibitor

2017 ◽  
Vol 115 (3) ◽  
pp. E468-E477 ◽  
Author(s):  
Michael Peled ◽  
Anna S. Tocheva ◽  
Sabina Sandigursky ◽  
Shruti Nayak ◽  
Elliot A. Philips ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
T Cells ◽  
Affinity Purification ◽  
Tyrosine Phosphatase ◽  
Significant Proportion ◽  
Lymphoproliferative Disease ◽  
T Cell Subsets ◽  
Mass Spectrometry Analysis ◽  
Multiple Tumor ◽  
Affinity Purification Mass Spectrometry

Programmed cell death-1 (PD-1) is an essential inhibitory receptor in T cells. Antibodies targeting PD-1 elicit durable clinical responses in patients with multiple tumor indications. Nevertheless, a significant proportion of patients do not respond to anti–PD-1 treatment, and a better understanding of the signaling pathways downstream of PD-1 could provide biomarkers for those whose tumors respond and new therapeutic approaches for those whose tumors do not. We used affinity purification mass spectrometry to uncover multiple proteins associated with PD-1. Among these proteins, signaling lymphocytic activation molecule-associated protein (SAP) was functionally and mechanistically analyzed for its contribution to PD-1 inhibitory responses. Silencing of SAP augmented and overexpression blocked PD-1 function. T cells from patients with X-linked lymphoproliferative disease (XLP), who lack functional SAP, were hyperresponsive to PD-1 signaling, confirming its inhibitory role downstream of PD-1. Strikingly, signaling downstream of PD-1 in purified T cell subsets did not correlate with PD-1 surface expression but was inversely correlated with intracellular SAP levels. Mechanistically, SAP opposed PD-1 function by acting as a molecular shield of key tyrosine residues that are targets for the tyrosine phosphatase SHP2, which mediates PD-1 inhibitory properties. Our results identify SAP as an inhibitor of PD-1 function and SHP2 as a potential therapeutic target in patients with XLP.

scholarly journals 2 Quantitation of CD137 and Nectin-4 expression across multiple tumor types to support indication selection for BT7480, a Bicycle tumor-targeted immune cell agonist™ (Bicycle TICA™)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A2-A2
Author(s):  
Heather Cohen ◽  
Carly Campbell ◽  
Kristen Hurov ◽  
Johanna Lahdenranta ◽  
Tara Gelb ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Unmet Need ◽  
Human Tumor ◽  
Immunofluorescence Assay ◽  
Breast Cancers ◽  
Multiple Tumor ◽  
Wide Range ◽  
Tumor Types

BackgroundBicycles are fully synthetic constrained peptides with antibody-like affinities that target selectively, readily penetrate tumor tissue, have relatively short half-lives, and can be chemically linked together to generate multifunctional molecules. BT7480 is a Bicycle TICA™ that binds both CD137 on immune cells and Nectin-4 on cancer cells to deliver a potent anti-tumor immune signal in Nectin-4 expressing tumors. Nectin-4 has been reported to be highly expressed in a wide range of human solid tumors, however the expression of CD137, abundance and localization of CD137+ immune cells in Nectin-4+ tumors are unknowns. A translational and informatics pipeline was established to interrogate the human tumor microenvironment to identify patient populations most likely to benefit from BT7480, which is being developed as a potential first-in-class molecule for the treatment of high unmet need cancers associated with Nectin-4 expression.MethodsTCGA RNAseq data for Nectin-4 and CD137 were analyzed from ~10,000 samples across 36 human cancers. Using a proprietary Nectin-4 mAb and MultiOmyx™ technology, a 19-plexed immunofluorescence assay was developed to simultaneously quantify the presence of Nectin-4+ and CD137+ cells, identify immune cell subsets and their spatial topography in 43 human tumor FFPE samples from HNSCC, lung, bladder, and breast cancers. Each FFPE slide was presented to a pathologist for tissue annotation and selection of regions of interest for image analysis. Proprietary deep learning-based workflows were applied to identify stroma and tumor regions, individual cells and perform cell classification for phenotypes of interest.ResultsRNA expression analysis indicated co-expression of Nectin-4 and CD137 in several tumor types with >50% tumors within NSCLC, HNSCC, breast, esophageal, and ovarian cancers expressing high levels of both targets. Spatial proteomic studies in HNSCC, lung, breast and bladder cancer samples demonstrated that Nectin-4 and CD137 co-expression at the protein level (>1% positive cells) was detected in 74% samples tested. CD137+ cells in Nectin-4+ tumors were identified as CD4+ T cells (37.6%), CD8+ T cells (16.8%) and CD68+ macrophages (5.9%). A subset of CD137+ cells (32.7%) were found to be deeply tumor penetrant and within close proximity of Nectin-4+ tumor cells across all indications tested.ConclusionsResults from this study support prioritization of indications for BT7480 clinical development and the utility of the MultiOmyx™ assay to monitor Nectin-4 and CD137 expression and to demonstrate proof-of-mechanism for the BT7480 FIH clinical trial expected to start in 2H-2021.

scholarly journals Molecular characterization of a marine turtle tumor epizootic, profiling external, internal and postsurgical regrowth tumors

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Kelsey Yetsko ◽  
Jessica A. Farrell ◽  
Nicholas B. Blackburn ◽  
Liam Whitmore ◽  
Maximilian R. Stammnitz ◽  
...  
Keyword(s):  
Predictive Biomarkers ◽  
Sea Turtle ◽  
Tumor Formation ◽  
Marine Turtle ◽  
Oncogenic Signaling ◽  
Kidney Tumors ◽  
Poor Outcomes ◽  
Tumor Types ◽  
Oncogenic Signaling Pathways

AbstractSea turtle populations are under threat from an epizootic tumor disease (animal epidemic) known as fibropapillomatosis. Fibropapillomatosis continues to spread geographically, with prevalence of the disease also growing at many longer-affected sites globally. However, we do not yet understand the precise environmental, mutational and viral events driving fibropapillomatosis tumor formation and progression.Here we perform transcriptomic and immunohistochemical profiling of five fibropapillomatosis tumor types: external new, established and postsurgical regrowth tumors, and internal lung and kidney tumors. We reveal that internal tumors are molecularly distinct from the more common external tumors. However, they have a small number of conserved potentially therapeutically targetable molecular vulnerabilities in common, such as the MAPK, Wnt, TGFβ and TNF oncogenic signaling pathways. These conserved oncogenic drivers recapitulate remarkably well the core pan-cancer drivers responsible for human cancers. Fibropapillomatosis has been considered benign, but metastatic-related transcriptional signatures are strongly activated in kidney and established external tumors. Tumors in turtles with poor outcomes (died/euthanized) have genes associated with apoptosis and immune function suppressed, with these genes providing putative predictive biomarkers.Together, these results offer an improved understanding of fibropapillomatosis tumorigenesis and provide insights into the origins, inter-tumor relationships, and therapeutic treatment for this wildlife epizootic.

scholarly journals β-Hexachlorocyclohexane Drives Carcinogenesis in the Human Normal Bronchial Epithelium Cell Line BEAS-2B

2021 ◽  
Vol 22 (11) ◽  
pp. 5834
Author(s):  
Elisabetta Rubini ◽  
Marco Minacori ◽  
Giuliano Paglia ◽  
Fabio Altieri ◽  
Silvia Chichiarelli ◽  
...  
Keyword(s):  
Cell Line ◽  
Environmental Pollutants ◽  
Bronchial Epithelium ◽  
Oncogenic Signaling ◽  
Carcinogenic Agent ◽  
Cell Cycle Profile ◽  
Epithelium Cell ◽  
Carcinogenic Potential ◽  
Wide Range ◽  
Oncogenic Signaling Pathways

Organochlorine pesticides constitute the majority of the total environmental pollutants, and a wide range of compounds have been found to be carcinogenic to humans. Among all, growing interest has been focused on β-hexachlorocyclohexane (β-HCH), virtually the most hazardous and, at the same time, the most poorly investigated member of the hexachlorocyclohexane family. Considering the multifaceted biochemical activities of β-HCH, already established in our previous studies, the aim of this work is to assess whether β-HCH could also trigger cellular malignant transformation toward cancer development. For this purpose, experiments were performed on the human normal bronchial epithelium cell line BEAS-2B exposed to 10 µM β-HCH. The obtained results strongly support the carcinogenic potential of β-HCH, which is achieved through both non-genotoxic (activation of oncogenic signaling pathways and proliferative activity) and indirect genotoxic (ROS production and DNA damage) mechanisms that significantly affect cellular macroscopic characteristics and functions such as cell morphology, cell cycle profile, and apoptosis. Taking all these elements into account, the presented study provides important elements to further characterize β-HCH, which appears to be a full-fledged carcinogenic agent.

scholarly journals A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Siobhan S. Pattwell ◽  
Sonali Arora ◽  
Patrick J. Cimino ◽  
Tatsuya Ozawa ◽  
Frank Szulzewsky ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Splice Variant ◽  
Oncogenic Signaling ◽  
Oncogenic Signaling Pathways

scholarly journals The Ins and Outs of RAS Effector Complexes

2021 ◽  
Author(s):  
Christina Kiel ◽  
David Matallanas ◽  
Walter Kolch
Keyword(s):  
Computational Modeling ◽  
Large Scale ◽  
Control Cell ◽  
Ras Signaling ◽  
Oncogenic Signaling ◽  
Functional Studies ◽  
Human Cancers ◽  
Wide Range ◽  
Effector Pathways ◽  
Oncogenic Signaling Pathways

RAS oncogenes are amongst the most commonly mutated proteins in human cancers. They regulate a wide range of effector pathways that control cell proliferation, survival, differentiation, migration and metabolic status. Including aberrations in these pathways, RAS dependent signaling is altered in more than half of human cancers. Targeting mutant RAS proteins and their downstream oncogenic signaling pathways has been elusive. However, recent results comprising detailed molecular studies, large scale omics studies and computational modeling have painted a new and more comprehensive portrait of RAS signaling that helps us to understand the intricacies of RAS, how its physiological and pathophysiological functions are regulated, and how we can target them. Here, we review these efforts particularly trying to relate the detailed mechanistic studies with global functional studies. We highlight the importance of computational modeling and data integration to derive an actionable understanding of RAS signaling that will allow us to design new mechanism based therapies for RAS mutated cancers.

scholarly journals The Ins and Outs of RAS Effector Complexes

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 236
Author(s):  
Christina Kiel ◽  
David Matallanas ◽  
Walter Kolch
Keyword(s):  
Computational Modeling ◽  
Large Scale ◽  
Control Cell ◽  
Ras Signaling ◽  
Oncogenic Signaling ◽  
Functional Studies ◽  
Human Cancers ◽  
Wide Range ◽  
Effector Pathways ◽  
Oncogenic Signaling Pathways

RAS oncogenes are among the most commonly mutated proteins in human cancers. They regulate a wide range of effector pathways that control cell proliferation, survival, differentiation, migration and metabolic status. Including aberrations in these pathways, RAS-dependent signaling is altered in more than half of human cancers. Targeting mutant RAS proteins and their downstream oncogenic signaling pathways has been elusive. However, recent results comprising detailed molecular studies, large scale omics studies and computational modeling have painted a new and more comprehensive portrait of RAS signaling that helps us to understand the intricacies of RAS, how its physiological and pathophysiological functions are regulated, and how we can target them. Here, we review these efforts particularly trying to relate the detailed mechanistic studies with global functional studies. We highlight the importance of computational modeling and data integration to derive an actionable understanding of RAS signaling that will allow us to design new mechanism-based therapies for RAS mutated cancers.

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