scholarly journals Merkel Cell Polyomavirus: Oncogenesis in a Stable Genome

Viruses ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 58
Author(s):  
Mona M. Ahmed ◽  
Camille H. Cushman ◽  
James A. DeCaprio
Keyword(s):  
Molecular Mechanisms ◽  
Merkel Cell Polyomavirus ◽  
Merkel Cell ◽  
T Antigens ◽  
Mutational Burden ◽  
Open Questions ◽  
Tumor Mutational Burden ◽  
Stable Genome ◽  
Tumor Genome ◽  
Proliferative Signaling

Merkel cell polyomavirus (MCV) is the causative agent for the majority of Merkel cell carcinoma (MCC) cases. Polyomavirus-associated MCC (MCCP) is characterized by the integration of MCV DNA into the tumor genome and a low tumor mutational burden. In contrast, nonviral MCC (MCCN) is characterized by a high tumor mutational burden induced by UV damage. Since the discovery of MCV, much work in the field has focused on understanding the molecular mechanisms of oncogenesis driven by the MCV tumor (T) antigens. Here, we review our current understanding of how the activities of large T (LT) and small T (ST) promote MCC oncogenesis in the absence of genomic instability. We highlight how both LT and ST inhibit tumor suppressors to evade growth suppression, an important cancer hallmark. We discuss ST interactions with cellular proteins, with an emphasis on those that contribute to sustaining proliferative signaling. Finally, we examine active areas of research into open questions in the field, including the origin of MCC and mechanisms of viral integration.

scholarly journals Large T and small T antigens of Merkel cell polyomavirus

2015 ◽  
Vol 11 ◽  
pp. 38-43 ◽  
Author(s):  
Justin A Wendzicki ◽  
Patrick S Moore ◽  
Yuan Chang
Keyword(s):  
Merkel Cell Polyomavirus ◽  
Merkel Cell ◽  
T Antigens

scholarly journals Prolonged Response to Anti–PD-1 Antibody Therapy in Chemotherapy-Refractory Cholangiocarcinoma With High Tumor Mutational Burden

2019 ◽  
Vol 17 (6) ◽  
pp. 644-648 ◽  
Author(s):  
Olumide Gbolahan ◽  
Neda Hashemi-Sadraei ◽  
Bert O’Neil
Keyword(s):  
Overall Survival ◽  
Clinical Symptoms ◽  
Checkpoint Inhibitors ◽  
Antibody Therapy ◽  
Tumor Mutation Burden ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Tumor Mutational Burden ◽  
Tumor Genome ◽  
Prolonged Response

Management of advanced intrahepatic cholangiocarcinoma (iCCA) is challenging and overall survival is poor. Progress in the development of new therapeutic options for metastatic cholangiocarcinoma (CCA) has been slow; hence, to date, there are no approved second-line agents in this setting. Although the development of immune checkpoint inhibitors has significantly improved overall survival in a variety of malignancies, there has not been a clinically important impact in CCA. This report presents a 66-year-old patient with chemotherapy-refractory iCCA who experienced a prolonged response to immunotherapy. Tumor genome profiling revealed a high tumor mutation burden of 17 mutations per megabase in the absence of microsatellite instability. He was started on immunotherapy with nivolumab and has experienced an ongoing response for 16 months without clinical symptoms and only minimal radiologic disease.

scholarly journals Molecular Mechanisms of Merkel Cell Polyomavirus Transformation and Replication

2020 ◽  
Vol 7 (1) ◽  
pp. 289-307 ◽  
Author(s):  
Wei Liu ◽  
Jianxin You
Keyword(s):  
Molecular Mechanisms ◽  
Human Tumor ◽  
Merkel Cell Polyomavirus ◽  
Merkel Cell ◽  
Virus Family ◽  
The Past ◽  
Molecular Events ◽  
Cellular Tropism ◽  
Novel Virus

Viral infection underlies a significant share of the global cancer burden. Merkel cell polyomavirus (MCPyV) is the newest member of the human oncogenic virus family. Its discovery over a decade ago marked the beginning of an exciting era in human tumor virology. Since then, significant evidence has emerged to support the etiologic role of MCPyV in Merkel cell carcinoma (MCC), an extremely lethal form of skin cancer. MCPyV infection is widespread in the general population. MCC diagnoses have tripled over the past 20 years, but effective treatments are currently lacking. In this review, we highlight recent discoveries that have shaped our understanding of MCPyV oncogenic mechanism and host cellular tropism, as well as the molecular events occurring in the viral infectious life cycle. These insights will guide future efforts in developing novel virus-targeted therapeutic strategies for treating the devastating human cancers associated with this new tumorigenic virus.

scholarly journals Merkel Cell Polyomavirus T Antigens Induce Merkel Cell-Like Differentiation in GLI1-Expressing Epithelial Cells

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1989
Author(s):  
Thibault Kervarrec ◽  
Mahtab Samimi ◽  
Sonja Hesbacher ◽  
Patricia Berthon ◽  
Marion Wobser ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Epithelial Cells ◽  
Human Keratinocytes ◽  
Merkel Cell Polyomavirus ◽  
Bhlh Transcription Factor ◽  
Merkel Cell ◽  
T Antigens ◽  
Differentiation Potential ◽  
Transcription Factor 1

Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by the Merkel cell polyomavirus (MCPyV). It is still under discussion, in which cells viral integration and MCC development occurs. Recently, we demonstrated that a virus-positive MCC derived from a trichoblastoma, an epithelial neoplasia bearing Merkel cell (MC) differentiation potential. Accordingly, we hypothesized that MC progenitors may represent an origin of MCPyV-positive MCC. To sustain this hypothesis, phenotypic comparison of trichoblastomas and physiologic human MC progenitors was conducted revealing GLI family zinc finger 1 (GLI1), Keratin 17 (KRT 17), and SRY-box transcription factor 9 (SOX9) expressions in both subsets. Furthermore, GLI1 expression in keratinocytes induced transcription of the MC marker SOX2 supporting a role of GLI1 in human MC differentiation. To assess a possible contribution of the MCPyV T antigens (TA) to the development of an MC-like phenotype, human keratinocytes were transduced with TA. While this led only to induction of KRT8, an early MC marker, combined GLI1 and TA expression gave rise to a more advanced MC phenotype with SOX2, KRT8, and KRT20 expression. Finally, we demonstrated MCPyV-large T antigens’ capacity to inhibit the degradation of the MC master regulator Atonal bHLH transcription factor 1 (ATOH1). In conclusion, our report suggests that MCPyV TA contribute to the acquisition of an MC-like phenotype in epithelial cells.

scholarly journals Merkel Cell Polyomavirus Small T Antigen Mediates Microtubule Destabilization To Promote Cell Motility and Migration

2014 ◽  
Vol 89 (1) ◽  
pp. 35-47 ◽  
Author(s):  
Laura M. Knight ◽  
Gabriele Stakaityte ◽  
Jennifer, J. Wood ◽  
Hussein Abdul-Sada ◽  
David A. Griffiths ◽  
...  
Keyword(s):  
Skin Cancer ◽  
Cell Motility ◽  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Tumor Antigen ◽  
Molecular Mechanisms ◽  
T Antigen ◽  
Merkel Cell Polyomavirus ◽  
Merkel Cell ◽  
Potential Link

ABSTRACTMerkel cell carcinoma (MCC) is an aggressive skin cancer of neuroendocrine origin with a high propensity for recurrence and metastasis. Merkel cell polyomavirus (MCPyV) causes the majority of MCC cases due to the expression of the MCPyV small and large tumor antigens (ST and LT, respectively). Although a number of molecular mechanisms have been attributed to MCPyV tumor antigen-mediated cellular transformation or replication, to date, no studies have investigated any potential link between MCPyV T antigen expression and the highly metastatic nature of MCC. Here we use a quantitative proteomic approach to show that MCPyV ST promotes differential expression of cellular proteins implicated in microtubule-associated cytoskeletal organization and dynamics. Intriguingly, we demonstrate that MCPyV ST expression promotes microtubule destabilization, leading to a motile and migratory phenotype. We further highlight the essential role of the microtubule-associated protein stathmin in MCPyV ST-mediated microtubule destabilization and cell motility and implicate the cellular phosphatase catalytic subunit protein phosphatase 4C (PP4C) in the regulation of this process. These findings suggest a possible molecular mechanism for the highly metastatic phenotype associated with MCC.IMPORTANCEMerkel cell polyomavirus (MCPyV) causes the majority of cases of Merkel cell carcinoma (MCC), an aggressive skin cancer with a high metastatic potential. However, the molecular mechanisms leading to virally induced cancer development have yet to be fully elucidated. In particular, no studies have investigated any potential link between the virus and the highly metastatic nature of MCC. We demonstrate that the MCPyV small tumor antigen (ST) promotes the destabilization of the host cell microtubule network, which leads to a more motile and migratory cell phenotype. We further show that MCPyV ST induces this process by regulating the phosphorylation status of the cellular microtubule-associated protein stathmin by its known association with the cellular phosphatase catalytic subunit PP4C. These findings highlight stathmin as a possible biomarker of MCC and as a target for novel antitumoral therapies.

scholarly journals The Merkel Cell Polyomavirus T Antigens Function as Tumor Promoters in Murine Skin

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 222
Author(s):  
Megan E. Spurgeon ◽  
Amy Liem ◽  
Darya Buehler ◽  
Jingwei Cheng ◽  
James A. DeCaprio ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Constitutive Expression ◽  
T Antigen ◽  
Tumor Formation ◽  
Merkel Cell Polyomavirus ◽  
Tumor Promoter ◽  
Tumor Promoters ◽  
Merkel Cell ◽  
T Antigens

Merkel cell polyomavirus (MCPyV) causes the majority of human Merkel cell carcinomas (MCC), a rare but highly aggressive form of skin cancer. We recently reported that constitutive expression of MCC tumor-derived MCPyV tumor (T) antigens in the skin of transgenic mice leads to hyperplasia, increased proliferation, and spontaneous epithelial tumor development. We sought to evaluate how the MCPyV T antigens contribute to tumor formation in vivo using a classical, multi-stage model for squamous cell carcinoma development. In this model, two chemical carcinogens, DMBA and TPA, contribute to two distinct phases of carcinogenesis—initiation and promotion, respectively—that are required for tumors to develop. By treating the MCPyV transgenic mice with each chemical carcinogen, we determined how the viral oncogenes contributed to carcinogenesis. We observed that the MCPyV T antigens synergized with the tumor initiator DMBA, but not with the tumor promoter TPA, cause tumors. Therefore, the MCPyV tumor antigens function primarily as tumor promoters, similar to that seen with human papillomavirus (HPV) oncoproteins. These studies provide insight into the role of MCPyV T antigen expression in tumor formation in vivo and contribute to our understanding of how MCPyV may function as a human DNA tumor virus.

scholarly journals Merkel cell polyomavirus small tumour antigen activates the p38 MAPK pathway to enhance cellular motility

2020 ◽  
Vol 477 (14) ◽  
pp. 2721-2733
Author(s):  
Samuel J. Dobson ◽  
Anthony Anene ◽  
James R. Boyne ◽  
Jamel Mankouri ◽  
Andrew Macdonald ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Merkel Cell Polyomavirus ◽  
Cell Junctions ◽  
Tumour Antigen ◽  
Merkel Cell ◽  
Cellular Motility ◽  
Small Tumour ◽  
Mapk Signalling

Merkel cell carcinoma (MCC) is an aggressive skin cancer with high rates of recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is associated with the majority of MCC cases. MCPyV-induced tumourigenesis is largely dependent on the expression of the small tumour antigen (ST). Recent findings implicate MCPyV ST expression in the highly metastatic nature of MCC by promoting cell motility and migration, through differential expression of cellular proteins that lead to microtubule destabilisation, filopodium formation and breakdown of cell–cell junctions. However, the molecular mechanisms which dysregulate these cellular processes are yet to be fully elucidated. Here, we demonstrate that MCPyV ST expression activates p38 MAPK signalling to drive cell migration and motility. Notably, MCPyV ST-mediated p38 MAPK signalling occurs through MKK4, as opposed to the canonical MKK3/6 signalling pathway. In addition, our results indicate that an interaction between MCPyV ST and the cellular phospatase subunit PP4C is essential for its effect on p38 MAPK signalling. These results provide novel opportunities for the treatment of metastatic MCC given the intense interest in p38 MAPK inhibitors as therapeutic agents.

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