المؤلفون: Amira Zaher, Kranti A. Mapuskar, Michael S. Petronek, Munir R. Tanas, Alexandra L. Isaacson, Rebecca D. Dodd, Mohammed Milhem, Muhammad Furqan, Douglas R. Spitz, Benjamin J. Miller, Robert A. Beardsley, Bryan G. Allen

المصدر: Antioxidants, Vol 13, Iss 5, p 587 (2024)

مصطلحات موضوعية: soft tissue sarcoma, radiation therapy, wound healing, superoxide dismutase mimetic, avasopasem manganese, Therapeutics. Pharmacology, RM1-950

الوصف: Soft tissue sarcomas (STSs) are mesenchymal malignant lesions that develop in soft tissues. Despite current treatments, including radiation therapy (RT) and surgery, STSs can be associated with poor patient outcomes and metastatic recurrences. Neoadjuvant radiation therapy (nRT), while effective, is often accompanied by severe postoperative wound healing complications due to damage to the surrounding normal tissues. Thus, there is a need to develop therapeutic approaches to reduce nRT toxicities. Avasopasem manganese (AVA) is a selective superoxide dismutase mimetic that protects against IR-induced oral mucositis and lung fibrosis. We tested the efficacy of AVA in enhancing RT in STSs and in promoting wound healing. Using colony formation assays and alkaline comet assays, we report that AVA selectively enhanced the STS (liposarcoma, fibrosarcoma, leiomyosarcoma, and MPNST) cellular response to radiation compared to normal dermal fibroblasts (NDFs). AVA is believed to selectively enhance radiation therapy by targeting differential hydrogen peroxide clearance in tumor cells compared to non-malignant cells. STS cells demonstrated increased catalase protein levels and activity compared to normal fibroblasts. Additionally, NDFs showed significantly higher levels of GPx1 activity compared to STSs. The depletion of glutathione using buthionine sulfoximine (BSO) sensitized the NDF cells to AVA, suggesting that GPx1 may, in part, facilitate the selective toxicity of AVA. Finally, AVA significantly accelerated wound closure in a murine model of wound healing post RT. Our data suggest that AVA may be a promising combination strategy for nRT therapy in STSs.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2076-3921/13/5/587Test; https://doaj.org/toc/2076-3921Test

الوصول الحر: https://doaj.org/article/b0197ae339824cb0bd61d1901b655ed0Test

المؤلفون: Melissa A. Marchal, Devon L. Moose, Afshin Varzavand, Nicole E. Jordan, Destiney Taylor, Munir R. Tanas, James A. Brown, Michael D. Henry, Christopher S. Stipp

المصدر: Frontiers in Oncology, Vol 13 (2023)

مصطلحات موضوعية: ABL1, ABL2, prostate cancer, metastasis, cell motility, AKT, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: IntroductionAbl family kinases function as proto-oncogenes in various leukemias, and pro-tumor functions have been discovered for Abl kinases in many solid tumors as well. However, a growing body of evidence indicates that Abl kinases can function to suppress tumor cell proliferation and motility and tumor growth in vivo in some settings.MethodsTo investigate the role of Abl kinases in tumor progression, we used RNAi to generate Abl-deficient cells in a model of androgen receptor-indifferent, metastatic prostate cancer. The effect of Abl kinase depletion on tumor progression and metastasis was studied in an in vivo orthotopic model, and tumor cell motility, 3D growth, and signaling was studied in vitro.ResultsReduced Abl family kinase expression resulted in a highly aggressive, metastatic phenotype in vivo that was associated with AKT pathway activation, increased growth on 3D collagen matrix, and enhanced cell motility in vitro. Inhibiting AKT pathway signaling abolished the increased 3D growth of Abl-deficient cells, while treatment with the Abl kinase inhibitor, imatinib, promoted 3D growth of multiple additional tumor cell types. Moreover, Abl kinase inhibition also promoted soft-agar colony formation by pre-malignant fibroblasts.ConclusionsCollectively, our data reveal that Abl family kinases can function to suppress malignant cell phenotypes in vitro, and tumor progression and metastasis in vivo.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fonc.2023.1241056/fullTest; https://doaj.org/toc/2234-943XTest

الوصول الحر: https://doaj.org/article/3f74f3b22e7d4202910ff27fb642931dTest

المؤلفون: Qierra R. Brockman, Amanda Scherer, Gavin R. McGivney, Wade R. Gutierrez, Andrew P. Voigt, Alexandra L. Isaacson, Emily A. Laverty, Grace Roughton, Vickie Knepper-Adrian, Benjamin Darbro, Munir R. Tanas, Christopher S. Stipp, Rebecca D. Dodd

المصدر: JCI Insight, Vol 7, Iss 20 (2022)

مصطلحات موضوعية: Oncology, Medicine

الوصف: The histone methyltransferase PRC2 plays a complex role in cancer. Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with frequent loss-of-function mutations in PRC2 that are associated with poor outcome. Here, we identify a critical role for PRC2 loss in driving MPNST metastasis. PRC2-dependent metastatic phenotypes included increased collagen-dependent invasion, upregulation of matrix-remodeling enzymes, and elevated lung metastasis in orthotopic mouse models. Furthermore, clinical sample analysis determined that PRC2 loss correlated with metastatic disease, increased fibrosis, and decreased survival in patients with MPNSTs. These results may have broad implications for PRC2 function across multiple cancers and provide a strong rationale for investigating potential therapies targeting ECM-remodeling enzymes and tumor fibrosis to improve outcomes in patients with MPNSTs.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2379-3708Test

الوصول الحر: https://doaj.org/article/72aae0cfd35e4271a50d462f47391a87Test

المؤلفون: Nicole C. Morrow, Munir R. Tanas, Nasreen A. Syed, Anand Rajan KD

المصدر: American Journal of Ophthalmology Case Reports, Vol 20, Iss , Pp 100955- (2020)

مصطلحات موضوعية: Myofibroma, Myofibromatosis, PDGFRB mutation, Myopericytoma, Ophthalmology, RE1-994

الوصف: Purpose: Myofibromas are benign soft tissue tumors commonly encountered in infancy and childhood. Developing usually within the first two years of life, they can be multicentric and involve deep visceral organs. Observations: We present the rare occurrence of a solitary orbital myofibroma in an adult patient. The clinical, histopathologic and immunohistochemical findings of the tumor are documented. Conclusions: A comprehensive review of pediatric and adult orbital and periocular involvement by myofibroma is presented. Its characteristic pathologic and molecular findings are reviewed. Importance: Myofibromas are uncommon but important tumors that can occur in the head and neck region, including the orbit. Seen more often in children, they can rarely be encountered in adult patients. Diagnosis is possible with a panel of immunostains and molecular analysis can be further confirmatory.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S245199362030270XTest; https://doaj.org/toc/2451-9936Test

الوصول الحر: https://doaj.org/article/f2782450891743d3a7d6a5492e768ba6Test

المؤلفون: Brian P. Rubin, Munir R. Tanas

المصدر: Rare Tumors, Vol 1, Iss 2, Pp e26-e26 (2009)

مصطلحات موضوعية: Malignant peripheral nerve sheath tumor (MPNST), malignant melanoma, melanocytic differentiation, rhabdomyoblastic differentiation, malignant neuroectodermal tumor, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Malignant melanoma can metastasize widely and vary significantly in its histological appearance; it rarely presents as a deep-seated mass without an obvious primary site elsewhere. Malignant peripheral nerve sheath tumor (MPNST) is a high-grade sarcoma characterized by conventional and epithelioid subtypes. MPNST can demonstrate heterologous differentiation, usually in the form of osteosarcomatous, chondrosarcomatous, or rhabdo-myosarcomatous differentiation. MPNST does not harbor true melanocytic differentiation, although epithelioid MPNST typically is diffusely S-100 protein positive and superficially can resemble malignant melanoma. An unusual intra-abdominal mass was recently encountered with features of both melanoma and conventional or epithelioid MPNST containing a fascicular spindle cell component, an epithelioid component with melanocytic differentiation, as well as a rhabdomyosarcomatous component. The terminology “malignant neuroectodermal tumor with melanocytic and rhabdomyoblastic differentiation” is proposed to describe this neoplasm, reflecting the unusual concomittant lines of differentiation as well as offering a possible rationale for nosologically challenging aspects of this neoplasm.

وصف الملف: electronic resource

العلاقة: http://www.pagepress.org/journals/index.php/rt/article/view/1100Test; https://doaj.org/toc/2036-3603Test; https://doaj.org/toc/2036-3613Test

الوصول الحر: https://doaj.org/article/3e55fa37af6c489f94ca6d2c702512cfTest

المؤلفون: Nicole Merritt, Keith Garcia, Dushyandi Rajendran, Zhen-Yuan Lin, Xiaomeng Zhang, Katrina A Mitchell, Nicholas Borcherding, Colleen Fullenkamp, Michael S Chimenti, Anne-Claude Gingras, Kieran F Harvey, Munir R Tanas

المصدر: eLife, Vol 10 (2021)

مصطلحات موضوعية: hippo pathway, sarcomas, chimeric transcription factors, fusion proteins, epigenetics, ATAC complex, Medicine, Science, Biology (General), QH301-705.5

الوصف: Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma that metastasizes early in its clinical course and lacks an effective medical therapy. The TAZ-CAMTA1 and YAP-TFE3 fusion proteins are chimeric transcription factors and initiating oncogenic drivers of EHE. A combined proteomic/genetic screen in human cell lines identified YEATS2 and ZZZ3, components of the Ada2a-containing histone acetyltransferase (ATAC) complex, as key interactors of both fusion proteins despite the dissimilarity of the C terminal fusion partners CAMTA1 and TFE3. Integrative next-generation sequencing approaches in human and murine cell lines showed that the fusion proteins drive a unique transcriptome by simultaneously hyperactivating a TEAD-based transcriptional program and modulating the chromatin environment via interaction with the ATAC complex. Interaction of the ATAC complex with both fusion proteins indicates that it is a key oncogenic driver and unifying enzymatic therapeutic target for this sarcoma. This study presents an approach to mechanistically dissect how chimeric transcription factors drive the formation of human cancers.

العلاقة: https://elifesciences.org/articles/62857Test; https://doaj.org/toc/2050-084XTest; e62857; https://doaj.org/article/f5236ab6208a49dc9d2f318dd8878eeeTest

الإتاحة: https://doi.org/10.7554/eLife.62857Test
https://doaj.org/article/f5236ab6208a49dc9d2f318dd8878eeeTest

المؤلفون: Jordan L Kohlmeyer, David J Gordon, Munir R Tanas, Varun Monga, Rebecca D Dodd, Dawn E Quelle

المصدر: International Journal of Molecular Sciences; Volume 21; Issue 8; Pages: 3018

مصطلحات موضوعية: cyclin-dependent kinase, sarcoma, cell cycle, therapeutics, retinoblastoma protein, CDK inhibitors

جغرافية الموضوع: agris

الوصف: Sarcomas represent one of the most challenging tumor types to treat due to their diverse nature and our incomplete understanding of their underlying biology. Recent work suggests cyclin-dependent kinase (CDK) pathway activation is a powerful driver of sarcomagenesis. CDK proteins participate in numerous cellular processes required for normal cell function, but their dysregulation is a hallmark of many pathologies including cancer. The contributions and significance of aberrant CDK activity to sarcoma development, however, is only partly understood. Here, we describe what is known about CDK-related alterations in the most common subtypes of sarcoma and highlight areas that warrant further investigation. As disruptions in CDK pathways appear in most, if not all, subtypes of sarcoma, we discuss the history and value of pharmacologically targeting CDKs to combat these tumors. The goals of this review are to (1) assess the prevalence and importance of CDK pathway alterations in sarcomas, (2) highlight the gap in knowledge for certain CDKs in these tumors, and (3) provide insight into studies focused on CDK inhibition for sarcoma treatment. Overall, growing evidence demonstrates a crucial role for activated CDKs in sarcoma development and as important targets for sarcoma therapy.

وصف الملف: application/pdf

العلاقة: Molecular Pathology, Diagnostics, and Therapeutics; https://dx.doi.org/10.3390/ijms21083018Test

الإتاحة: https://doi.org/10.3390/ijms21083018Test

المؤلفون: Dawn E. Quelle, Munir R. Tanas, Benjamin W. Darbro, Rebecca D. Dodd, Jill M. Weimer, K.D. Zamba, David K. Meyerholz, Mariah R. Leidinger, Jessica C. Sieren, Rajesh Khanna, Vickie Knepper-Adrian, Kendall E. Cornick, Heather J. Major, Allison Moreno Samayoa, Chandra K. Maharjan, Casey Pulliam, Courtney A. Kaemmer, Jordan L. Kohlmeyer

الوصف: RNA-Seq Gene Expression

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::920ee80e1af2be68a88f0ab59c9465b2Test
https://doi.org/10.1158/1078-0432.22475733Test

المؤلفون: Dawn E. Quelle, Munir R. Tanas, Benjamin W. Darbro, Rebecca D. Dodd, Jill M. Weimer, K.D. Zamba, David K. Meyerholz, Mariah R. Leidinger, Jessica C. Sieren, Rajesh Khanna, Vickie Knepper-Adrian, Kendall E. Cornick, Heather J. Major, Allison Moreno Samayoa, Chandra K. Maharjan, Casey Pulliam, Courtney A. Kaemmer, Jordan L. Kohlmeyer

الوصف: Purpose:Malignant peripheral nerve sheath tumors (MPNST) are deadly sarcomas that lack effective therapies. In most MPNSTs, the retinoblastoma (RB1) tumor suppressor is disabled by hyperactivation of cyclin-dependent kinases (CDK), commonly through loss of CDK-inhibitory proteins such as p27(Kip1). RABL6A is an inhibitor of RB1 whose role in MPNSTs is unknown. To gain insight into MPNST development and establish new treatment options, we investigated RABL6A-RB1 signaling and CDK inhibitor–based therapy in MPNSTs.Experimental Design:We examined patient-matched MPNSTs and precursor lesions by RNA sequencing (RNA-Seq) and IHC. Molecular and biological effects of silencing RABL6A and/or p27 in MPNST lines and normal human Schwann cells were determined. Tumor-suppressive effects of CDK inhibitors were measured in MPNST cells and orthotopic tumors.Results:RABL6A was dramatically upregulated in human MPNSTs compared with precursor lesions, which correlated inversely with p27 levels. Silencing RABL6A caused MPNST cell death and G1 arrest that coincided with p27 upregulation, CDK downregulation, and RB1 activation. The growth-suppressive effects of RABL6A loss, and its regulation of RB1, were largely rescued by p27 depletion. Importantly, reactivation of RB1 using a CDK4/6 inhibitor (palbociclib) killed MPNST cells in vitro in an RABL6A-dependent manner and suppressed MPNST growth in vivo. Low-dose combination of drugs targeting multiple RB1 kinases (CDK4/6, CDK2) had enhanced antitumorigenic activity associated with potential MPNST cell redifferentiation.Conclusions:RABL6A is a new driver of MPNST pathogenesis that acts in part through p27-RB1 inactivation. Our results suggest RB1 targeted therapy with multiple pathway drugs may effectively treat MPNSTs.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::30dd56d880240716d96cf8ae8c86d42cTest
https://doi.org/10.1158/1078-0432.c.6529155Test

المؤلفون: Dawn E. Quelle, Munir R. Tanas, Benjamin W. Darbro, Rebecca D. Dodd, Jill M. Weimer, K.D. Zamba, David K. Meyerholz, Mariah R. Leidinger, Jessica C. Sieren, Rajesh Khanna, Vickie Knepper-Adrian, Kendall E. Cornick, Heather J. Major, Allison Moreno Samayoa, Chandra K. Maharjan, Casey Pulliam, Courtney A. Kaemmer, Jordan L. Kohlmeyer

الوصف: Antibody Table

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1847e45ac5123d2616c4dc83595c77c3Test
https://doi.org/10.1158/1078-0432.22475736.v1Test