Merkel cell polyomavirus: Viral Cause , Cellular Effect

Viruses cause 10-15% of human cancers worldwide. Studies of these viruses have been central to our current understanding of the molecular biology of carcinogenesis. A long history of tumor virus analyses has revealed unexpected connections between tumor suppressors, innate immunity and signaling pathways that control both viral infection and neoplasia.

Merkel cell polyomavirus (MCV) is the most recent addition to this set of 7 known human tumor viruses. Discovered in 2008 by Dr. Yuan Chang and Patrick Moore’s laboratory it was found integrated in the Merkel cell carcinoma genome. Merkel cell carcinoma (MCC) is an uncommon, lethal, primary skin cancer frequently having a poor prognosis. MCC derives from mechanoreceptor Merkel cells, located in the basal layer of the epidermis and form an integral part of the sensory system of the skin. Like other skin cancers prolonged UV exposure, advanced age and loss of immune competence are risk factors for MCC.

Although other polyomaviruses have been associated with disease, MCV is the first polyomavirus convincingly linked to human cancer as a causative agent. Serological and molecular evidence indicate that in a vast majority of the human population MCV is a harmless, asymptomatic and life-long infection. However, MCV initiates an aggressive cancer if it integrated into the (susceptible) host genome and acquires a precise set of viral mutations that result in replication incompetence. In tumors, MCV expresses 2 oncoproteins: the small and Large T antigens. These proteins drive tumorigenesis by targeting various tumor suppressors and regulating transcription.

MCV discovery has changed the perception of an intractable cancer by revealing novel viral targets and leading to new opportunities for its early diagnosis and targeted treatments. Besides, MCV positive MCC offers a unique new model for studying human cancer, whereby a virus’s ability to modify/alter a cell can be used to understand the slow process of transformation leading to cancer. We are using MCV as a tool to address several, still unanswered questions of malignant transformation especially, dedifferentiation.

Using tumor viruses for this study provides a unique break-up of the process into two perspectives, a viral and cellular one. We are specifically asking why only MCV, out of 14 human polyomaviruses discovered so far, can cause cancer and why this cancer only occurs in Merkel cells (although the virus infects other cells as well). In other words, why does only this virus in combination with this specific tumor tissue lead to cancer.

For more details on MCV biology : http://tumorvirology.pitt.edu/?page_id=217.

Publications       

RESEARCH ARTICLES

Arora R*#, Gupta K*, Vijaykumar A, Krishna S. DETECTing Merkel Cell Polyomavirus in Merkel Tumors.Frontiers in Molecular Biosciences.2020.Feb 4; 7:10. doi: 10.3389/fmolb.2020.00010. *Authors contributed equally to the work.# -Corresponding author

Arora R #, Rekhi B #, Chandrani P, Krishna S, Dutt A. Merkel cell polyomavirus is implicated in a subset of Merkel cell carcinomas, in the Indian subcontinent. Microbial Pathogenesis.2019 Dec; 137:103778. doi: 10.1016/j.micpath.2019.103778.# -Corresponding author

Rodrigues C, Pattabiraman C, Vijaykumar A, Arora R, Narayana SM, Kumar RV, Notani D, Varga-Weisz P, Krishna S. A SUV39H1-low chromatin state characterises and promotes migratory properties of cervical cancer cells. Exp Cell Research.2019.May 15; 378(2):206-216. doi: 10.1016/j.yexcr.2019.02.010.

Arora R*#, Vats A*, Chimankar V. MCV Truncated Large T antigen interacts with BRD4 in tumors. Science Matters. 2019. Jan 11; 10.19185/matters.201811000004.*Authors contributed equally to the work.#- Corresponding author

Park ED, Cheng J, Berrios C, Montero J, Cortes-Cros M, Ferretti S, Arora R, Tillgren M, Gokhale P, DeCaprio JA. Dual inhibition of MDM2 and MDM4 in virus positive Merkel cell carcinoma enhances the p53 response. PNAS, 2019 Jan 15;116(3):1027-1032.doi:10.1072/pnas.1818798116. [PMID:30598450] 

Cheng J, Park DE, Berrios C, White EA, Arora R, Yoon R, Branigan T, Xiao T, Westerling T, Federation A, Zeid R, Strober B, Swanson SK, Florens L, Bradner JE, Brown M, Howley PM, Padi M, Washburn MP, DeCaprio JA. Merkel cell polyomavirus recruits MYCL to the EP400 complex to promote oncogenesis.2017. PLoS Pathog. 2017 Oct 13; 13 (10): e1006668. [PMID: 29028833]

Cheedipudi S., Puri D., Saleh A., Gala H., Rumman M., Pillai M., Sreenivas P., Arora R., Sellathurai J., Schroeder H., Mishra   R., Dhawan   J. A fine balance:  Epigenetic   control   of cellular   quiescence   by the tumor suppressor PRDM2/RIZ at a bivalent domain in Cyclin A gene.  2015.  Nucleic Acids Research. 2015.  Jul 27; 43 (13): 6236-56. [PMID: 26040698]

Dresang L.R., Guastafierro A., Arora R., Normolle D., Chang Y., Moore P.S.. Response of Merkel cell polyomavirus--positive Merkel cell carcinoma xenografts to a survivin inhibitor. PLoS One. 2013. Nov 18;8(11): e80543. [PMID 24260412]  

Arora R., Shuda, M., Guastafierro A., Feng, H., Toptan T., Tolstov Y., Normolle D., Vollmer L., Vogt A., Dömling A., Brodsky J., Chang Y., Moore P.S. Survivin is a therapeutic target in Merkel cell carcinoma.  Science Translational Medicine.2012 May 9; 4(133): 133ra56. [PMID: 22572880]  

Tolstov Y.L., Arora R., Scudiere S.C., Busam K.J., Chaudhary P.M., Chang Y., Moore P.S. Lack of evidence   for direct involvement    of Merkel   cell polyomavirus    (MCV) in chronic   lymphocytic leukemia (CLL). Blood.2010; 115(23): 4973---4974. [PMID: 20538816]  

Shuda M.*, Arora R.*, Kwun H.J.*, Feng H., Sarid R., Fernández---Figueras M.T., Tolstov Y., Gjoerup O., Mansukhani M. M., Swerdlow S. H., Chaudhary P.M .,  Kirkwood J.M .,  Nalesnik M.A.,  Kant  J.A.,  Weiss L.M., Moore P.S., Chang Y. Human  Merkel  cell polyomavirus  infection  I. MCV T antigen  expression  in Merkel ce l l carcinoma, ly m p h o i d  tissues a nd lymphoid  tumors. Int J Cancer.2009; 125(6):  1243---1249. *Authors contributed equally to the work. [PMID: 19499546]

Busam K.J., Jungbluth A.A., Rekthman N., Coit D., Pulitzer M., Bini J., Arora R., Hanson N.C., Tassello J.A., Frosina D., Moore P.S., Chang Y. Merkel cell polyomavirus expression in Merkel Cell Carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas. The American journal of surgical pathology.2009; 33(9): 1378---1385. [PMID: 19609205]

REVIEW

Arora R., Chang Y., Moore P.S. MCV and Merkel cell carcinoma:  a molecular success story. Curr Opin Virol. 2012 Aug; 2(4): 489---98 [PMID: 22710026]

BOOK CHAPTER

Arora R., Rumman M., Venugopal N., Gala H.P. and Dhawan J. Mimicking muscle stem cell quiescence in culture:methods for synchronization in reversible  arrest. Eusebio Perdiguero and Dawn Cornelison  (Eds). Muscle Stem Cells: Methods in Molecular Biology. 2017; Vol. 1556, 978-1-4939-6769-8,329459_1_En, (15)