Salk Institute
Clodagh O'Shea
Associate Professor
Molecular and Cell Biology Laboratory
William Scandling Developmental Chair
Clodagh O'Shea

Associate Professor
Molecular and Cell Biology Laboratory
William Scandling Developmental Chair


Clodagh O'Shea, an associate professor in the Molecular and Cell Biology Laboratory, is employing the help of a small DNA virus, called adenovirus, to both understand and treat cancer. Normally, cellular replication is tightly controlled. However, both DNA viruses and tumor cells sabotage such controls to drive their respective pathological propagation, albeit with one small difference: In tumor cells the key cellular players are targeted via mutations, while in infected cells viral proteins achieve the same end. Not surprisingly, many of the cellular targets are the same. Dr. O'Shea lab is exploiting this overlap to help address three key questions:

What are the critical cellular targets and pathways that drive deregulated growth?

Human tumors acquire a myriad of mutations, which makes it difficult to pinpoint the critical therapeutic targets. In contrast, Adenovirus encodes a relatively small number of proteins that overcome all the cellular checkpoints which normally prevent aberrant replication. Hence, uncovering the cellular targets of these viral proteins is a powerful strategy with which to identify key cellular pathways that may also be deregulated in tumorigenesis. In addition, viral proteins can provide novel insights into how such targets could be modulated for cancer therapy. Dr. O'Shea's lab is currently using this paradigm to gain new insights into the p53 tumor suppressor pathway, PI-3 Kinase/mTOR signaling and RNA export/processing in tumorigenesis.

What is the human growth deregulation program and how do we uncouple it for tumor therapy?

Tumor mutations act together within integrated and complex cellular networks to elicit aberrant replication. Unfortunately, the overlapping and interconnected nature of cellular networks implies that therapies which target any single tumor mutation are likely to be ineffective. But how do we determine the correct combinations of therapeutic targets that will uncouple a pleiotropic human growth deregulation program? Just as viral proteins can be used to identify discrete tumor targets, Dr. O'Shea's lab is exploring whether viral infection can be exploited to reveal the overall program for human growth deregulation. Using a systems biology approach, they are determining the key molecular signatures that are common to both infected primary cells and tumor cells. With the help of viral mutants, RNAi and chemical genetics, this is also a powerful experimental platform in which to test and identify combination therapies that selectively abort aberrant replication, but leave normal cells unharmed.

Can we manipulate viruses as novel therapeutic agents that trigger the rapid lytic death of tumor cells but leave normal cells unharmed?

The overlap between the tumor and viral growth deregulation programs can also be exploited to develop viruses that replicate selectively in tumor cells, killing them from the inside. This approach is called oncolytic viral therapy, something that is of particular interest to Dr. O'Shea. Defective viruses that are unable to inactivate critical normal cell checkpoints selectively replicate in tumor cells in which these checkpoints are inactivated by mutations. Defining how tumor cells complement selectively the replication of defective viruses can also reveal unexpected tumor targets, such as altered tumor RNA export as the therapeutic target of ONYX-015. Oncolytic viruses offer a novel and potentially self-perpetuating cancer therapy: Each time a virus homes in on a cancer cell and successfully replicates, the virus ultimately kills the cancer cell by bursting it open to release thousands of viral progenies, which have the potential to seek out remaining tumor cells and distant micro-metastases.

"One of the burning questions in contemporary cancer research is, 'What are the critical therapeutic targets that uncouple aberrant growth and survival?' I am employing viruses to pin down key cellular processes that are dysfunctional in cancer cells and to develop novel, virus-based cancer therapies."

If a cell suffers non-repairable injury to its genetic material, or cell growth starts to go astray, the tumor suppressor protein 53 pulls the emergency brake, a built-in "auto-destruct" mechanism that eliminates abnormal cells from the body before they can cause disease, including cancer. To sidestep the cell's suicide program—a process called apoptosis—tumor cells need to inactivate p53, which turns on genes that mediate cell cycle arrest and apoptosis.

Similarly, adenovirus, which causes upperrespiratory infections, needs to get p53 out of the way to multiply successfully; therefore it brings along a viral protein, E1B-55K, which binds and degrades p53 in infected cells. Without E1B-55K to inactivate p53, adenovirus should only be able to replicate in p53-deficient tumor cells, making it the perfect candidate for oncolytic cancer therapy. Oncolytic viruses offer a novel and potentially self-perpetuating cancer therapy: Each time a virus infects a cancer cell and successfully multiplies, the virus ultimately kills the cancer cell by bursting it open to release thousands of viral progeny. The next generation seeks out remaining tumor cells and distant micro-metastases but leaves normal cells unharmed.

Clinical trials found such viruses to be safe and promising. Contrary to all expectations, however, patient responses did not correlate with the p53 status of their tumors. When O'Shea followed up on this unexpected finding, she discovered that the inability of the E1B-55K–mutant virus to replicate in normal cells was not because the virus failed to degrade p53. Instead, adenovirus brings along another protein, E4-ORF3, which neutralizes the p53 checkpoint through a completely different mechanism. It prevents p53 from binding to its target genes in the genome by modifying histone proteins, the "spools" around which DNA winds. With its access denied, p53 is powerless to pull the trigger on apoptosis. O'Shea and her team are now exploiting this new viral protein as a powerful tool to both pinpoint and connect critical new targets in the cellular p53 tumor suppressor network and to develop the next generation of oncolytic viruses.

Selected Publications

Miyake-Stoner, S.J. and O'Shea, C.C. (2014) Metabolism goes viral. Cell Metab 19:549-550.

Ou, H.D., Kwiatkowski, W., Deerinck, T.J., Noske, A., Blain, K.Y., Land, H.S., Soria, C., Powers, C.J., May, A.P., Shu, X., Tsien, R.Y., Fitzpatrick, J.A.J., Long, J.A., Ellisman, M.H., Choe, S. and O'Shea, C.C. (2012) A structural basis for the assembly and functions of a viral polymer that inactivates multiple tumor suppressors. Cell 151:304-19.

Soria, C., Estermann, F., Espantman, K.E. and O'Shea, C.C. (2010). Heterochromatin silencing of p53 target genes by a small viral protein. Nature, 466, 1076-81.

Ou, H. May, A.P. and O'Shea, C. C. (2010). The critical protein interactions and structures that elicit growth deregulation in cancer and viral replication. WIREs Systems Biology and Medicine (DOI: 10.1002/wsbm.88).

Espantman, K.C. and O'Shea, C.C. (2010) aMAGEing new players enter the RING to promote ubiquitylation. Mol Cell 39:835-837

Iacovides, D., O'Shea, C.C., Oses-Prieto, J., Burlingame, A. and McCormick, F. (2007) Critical role for arginine methylation in adenovirus-infected cells. J Virol 81:13209-13217.

Ringshausen, I., O'Shea, C.C., Finch, A.J., Brown Swigart, L., and Evan, G.I. (2006). Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo. Cancer Cell 10(6), 501-514.

O'Shea, C.C. (2005). Viruses: tools for tumor target discovery and agents for lytic cancer therapies - an introduction. Oncogene 24, 7636-7639.

O'Shea, C.C. (2005). Viruses- seeking and destroying the tumor program. Oncogene 24, 7640-7655.

O'Shea, C. C., Soria, C., Bagus, B., and McCormick, F. (2005). Heat shock phenocopies E1B-55K late functions and selectively sensitizes refractory tumor cells to ONYX-015 oncolytic viral therapy. Cancer Cell 8 (1), 61-74. (Cover Article).

O'Shea, C. C., Choi, S., McCormick, F., and Stokoe, D. (2005). Adenovirus overrides cellular checkpoints for protein translation. Cell Cycle 4 (7), 883-888.

O'Shea, C. C., Klupsch, K., Choi, S., Bagus, B., Soria, C., Shen, J., McCormick, F., and Stokoe, D. (2005).Adenoviral proteins mimic nutrient/growth signals to activate the mTOR pathway for viral replication. Embo Journal 24, 1211-1221.

O'Shea, C. C., and Fried, M. (2005). Modulation of the ARF-p53 pathway by the small DNA tumor viruses. Cell Cycle 4 (3), 449-452.

O'Shea, C. C. (2005). DNA tumor viruses - the spies who lyse us. Current Opinion in Genetics and Development 15, 18-26.

O'Shea, C. C., Johnson, L., Bagus, B., Choi, S., Nicholas, C., Shen, A., Boyle, L., Pandey, K., Soria, C., Kunich, J., Shen, Y., Habets, G., Ginzinger, D., McCormick, F. (2004). Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell 6, 611-623.

Awards and Honors

  • W. M. Keck Medical Research Program Award, 2014-2017
  • Rose Hills Fellow, 2014-2015
  • Science/NSF International Science & Visualization Challenge, People's Choice, 2011
  • Anna Fuller Award for Cancer Research, 2011-2012
  • Kavli Frontiers Fellow, National Academy of Sciences, 2010, 2011, 2012
  • Sontag Distinguished Scientist Award, 2009-2013
  • American Cancer Society Research Scholar Award, 2009-2013
  • ACGT Young Investigator Award for Cancer Gene Therapy, 2008-2011
  • Arnold and Mabel Beckman Young Investigator Award, 2008-2011
  • William Scandling Assistant Professor, Developmental Chair, 2008-2011
  • Emerald Foundation Scholar, 2007-2009
  • UC Discovery Grant, 2003-2007
  • Leukemia Society of America Research Fellowship, 2000-2003
  • Human Frontiers in Science Program Long-Term Fellow, 1998-2000


O'Shea Lab website

Careers and Positions within the O'Shea Lab

O'Shea technologies available for licensing

News Highlights

W.M. Keck Award for Cracking the Nucleus

Two Microscopes Are Better Than One. Nature, 492, 293-7.

Spinning a E4dly Weave. Science, 338, 582.

Science Wonders get an artistic spin, Washington Post.

Separation of a Cell (2012). Science, 355, 529.

Viruses' Backup Plan. Nature, 466, 1054-55.

Collaborations and Associations

UCSD Assistant Adjunct Professor

The San Diego Center for Systems Biology (UCSD)
Currently an Investigator with SDCSB and submitted as Project I Co-Leader.

National Center for Microscopy and Imaging Research (UCSD)
Currently a Collaborator with Mark Ellisman, Ph.D. and team at the NCMIR

Funding and Awards

The Leona M. and Harry B. Helmsley Charitable Trust and the Salk Institute Helmsley Center for Genomic Medicine


The Kavli Foundation

Alliane for Cancer Gene Therapy

Sontag Foundation

The Sontag Foundation

American Cancer Society

American Society for Cell Biology ASCB TV

Produced by WebsEdge/Health
December 2014

Cold viruses point the way to new cancer therapies

October 16, 2012

Adenovirus, a type of cold virus, has developed molecular tools—proteins—that allow it to hijack a cell's molecular machinery, including large cellular machines involved in growth, replication and cancer suppression. The Salk scientists identified the construction of these molecular weapons and found that they bind together into long chains (polymers) to form a three-dimensional web inside cells that traps and overpowers cellular sentries involved in growth and cancer suppression. The findings, published October 11 in Cell, suggest a new avenue for developing cancer therapies by mimicking the strategies employed by the viruses. Read more>>

Cathedrals of Culture

Salk Institute, La Jolla, CA
Film by Robert Redford
June 5, 2014 (published)

TWiV 291: Ft. Collins abuzz with virologists

33rd annual meeting of the American Society for Virology at Colorado State
University in Ft. Collins, Colorado
Featuring Clodagh O'Shea
Hosted by Vincent Racaniello
June 5, 2014 (published)

Use the common cold virus to target and disrupt cancer cells?

August 25, 2010

A novel mechanism used by adenovirus to sidestep the cell's suicide program, could go a long way to explain how tumor suppressor genes are silenced in tumor cells and pave the way for a new type of targeted cancer therapy, report researchers at the Salk Institute for Biological Studies in the Aug. 26, 2010 issue of Nature. Read more>>

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