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McArdle News

2017

Dr. Megan Spurgeon, a scientist in Dr. Paul Lambert’s group, is the first recipient at the University of Wisconsin of an R50 Research Specialist Award. This new funding mechanism from the National Cancer Institute seeks to "encourage the development of stable research career opportunities for exceptional scientists who want to pursue research within the context of an existing cancer research program."

The R50, a five-year award, provides the salary for its recipient, allowing the staff researcher some autonomy and alleviating financial strain on their Principal Investigator's budget. The grant also provides a travel allowance for the researcher to attend conferences and research meetings.  

Spurgeon initially came to Lambert's lab as a postdoc in 2010, and joined the McArdle staff as an Assistant Scientist in 2014. The R50 grant mechanism came to fruition during her second year as a McArdle staff scientist, and Lambert encouraged her to apply during the grant’s first round of applications.  

"I had heard that a grant for staff scientists was in the pipeline, so it was kind of serendipitous that I was a staff scientist in a position to apply by the time that the R50 funding mechanism was introduced," Spurgeon said. "I’m personally honored that my grant application was funded, but I also hope that this grant mechanism helps pave the way for other funding opportunities for staff scientists."

The R50 award was created in part to address the current climate in biomedical research, where a large number of successful postdocs are competing for a very limited number of tenure-track faculty positions. As support from scientists and core facility specialists becomes increasingly important at research institutions, the R50 seeks to help make staff scientist positions more attractive to exceptional researchers like Dr. Spurgeon.

“It is very fitting for Dr. Spurgeon to be awarded the first NIH R50 award here at the University of Wisconsin-Madison," writes Dr. Lambert. "She has contributed greatly to the University’s discussion on the future of biomedical research over the past two years, and is now participating on a campus-wide committee on how the University can provide scientists like her the career security to pursue their life ambition here on campus."

With this award, Spurgeon looks forward to continuing her research within Lambert's lab at McArdle on DNA tumor viruses, including human papillomavirus (HPV) and Merkel cell polyomavirus (MCPyV). On the heels of her recent paper publication in the journal Proceedings of the National Academy of Sciences, she is especially excited about further exploring the pathways by which HPV and the female hormone estrogen affect cell signaling between the epithelium and the microenvironment in HPV-associated cervical cancer. 

"I think this new analysis gave us insight into some potential players," Spurgeon said. "We have been chasing after this elusive signaling factor for a long time so now we at least have a sense of where to focus our efforts."

Read more about Spurgeon and the Lambert lab's recent publication here.

Every year, Sun Prairie High School seniors decide on a way they would like to give back to their community before graduation. Two beloved faculty members at Sun Prairie had recently passed away due to cancermotivating the 2017 graduating class to focus their donation on supporting cancer research at McArdle.

"Every student in our high school had known at least one of the two teachers that passed away and felt the impact that their dedication had on the school," said Justice Hadley, a class co-president and freshman at UW-Madison. "My fellow class officers and I knew that donating to research was something both teachers would have appreciated."

In choosing an institution to give to, the senior class especially valued the local connection with McArdle. 

"The class presidents researched different institutes around the country, and we all decided that we wanted to support an institute that was close to home, and whose research would be able to help our families and friends," explained class co-president Nathan Smith, now attending West Point.

The senior class was able to raise money in a variety of ways, ranging from setting aside proceeds from school events like prom to collecting individual student donations. John Barth, a social studies teacher at Sun Prairie, helped facilitate the process, but emphasized that the entire effort was driven and funded by the students.

“Often times young people get a bad reputation of either not knowing or not caring about problems,” Barth said. We as staff are proud that our kids are so giving, and really want to make their community a better place and pay it forward.”

Director Paul Lambert writes, "We are extremely honored that the students of Sun Prarie High School chose to donate to McArdle. We will use these donations to pursue new discoveries about how cancer arises, and thereby new directions for how we can prevent and treat this human malady.”

Kenny Lab ImageTeriflunomide inhibits the growth of EBV-transformed cells in a mouse model. Immune-deficient mice were injected under the skin on their flanks with cells carrying luminescent EBV.  Once a small tumor had grown, mice were treated with teriflunomide three times per week.  This image shows the amount of luminescence 13 days after treatment was started.  Purple = least luminescence; Red = highest luminescence. From Bilger et al., Oncotarget 2017 Jul 4; 8(27): 44266–44280.

Epstein-Barr virus (EBV) can cause the development of fatal lymphomas in transplant patients.  EBV can infect human cells in two different forms: latent infection, in which the virus does not kill the infected cell, but expresses cancer-causing viral proteins; and lytic infection, in which viral proteins are expressed that kill the infected cell.  Both the latent and lytic types of infection contribute to the proliferation of infected cells in immunosuppressed patients.

We show that an FDA-approved drug currently used to treat multiple sclerosis, teriflunomide, not only inhibits the growth of latently EBV-infected cells, but also prevents the lytic form of EBV replication.  Furthermore, we find that a clinically relevant dose of teriflunomide inhibits the development and growth of EBV-induced lymphomas in two mouse models.  Our investigations suggest that teriflunomide (and its prodrug, leflunomide) may be useful for preventing and/or treating both latent and lytic EBV infection in patients who require immunosuppression (such as transplant recipients) and are at high risk for developing EBV-induced lymphomas.

-Andrea Bilger

 

Link to paper in Oncotarget: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=17863&pubmed-linkout=1

 

Contributing scientists shown on the home page: From left to right:  James Romero-Masters, Shannon Kenney, Jillian Bristol, Andrea Bilger, Elizabeth Barlow

Wei and Eui-JunDr. Wei Xu (left) and new Komen Fellow Dr. Eui-Jun Kim (right).

Eui-Jun Kim, a post-doctoral fellow training in the laboratory of Wei Xu (Messerschmidt Professor of Oncology), was awarded a $185,000 research fellowship from the Susan G. Komen Foundation to study triple-negative breast cancer, a devastating subtype of breast cancer for which the only current treatment option is chemotherapy.

Triple-negative refers to a breast cancer wherein the tumor cells lack expression of three key cancer markers: HER2, the estrogen receptor, and the progesterone receptor. Eui-Jun's project will study how triple-negative breast cancer cells metastasize (spread) to other tissues in the body.

Additional highlights:

http://www.med.wisc.edu/news-events/uw-carbone-center-researcher-receive...

http://www.channel3000.com/health/susan-g-komen-funds-research-on-triple...

 

Sugden KSHV Imaging Scientists Clockwise from top left: Bill Sudgen, Arthur Sugden, Ya-Fang Chiu, Mitch Hayes, and Kathryn (Norby) Fox

 

Kaposi's Sarcoma Herpesvirus (KSHV) causes tumors in people, often among those who are immunocompromised. It is related to Epstein-Barr Virus (EBV) which is a human tumor virus, too. Both viruses maintain their DNAs as plasmids in tumor cells.

We had developed a means of tracking EBV plasmids in live-cells over multiple generations by engineering them to bind a fluorescent protein.  We had thereby discovered that EBV plasmids had a defect in their synthesis and were partitioned quasi-faithfully to daughter cells (Nanbo et al. EMBO J. 2007). I suggested to Kathryn, a graduate student early in her studies, that she use the same approach to study the plasmid replication of KSHV, assuring her that it might not be "novel" because it would be just like EBV but it should be straight-forward.

Ten years later the combined efforts of five of us, Ya-Fang, Arthur, Kathryn, Mitch, and I led to this paper demonstrating how wrong I was! 

KSHV does have a defect in its DNA synthesis but clusters some of its plasmids, leading not only to these clusters being inherited as units, but also partitioning randomly. This clustering was observed in live-cell, fluorescent images in which some signals grow in intensities more than four-fold during sequential cell cycles, but also partition randomly. We found that this clustering was mediated by the sole KSKV protein required for DNA synthesis which tethers KSHV to nucleosomes on host DNA and to nucleosomes on other KSHV plasmids as depicted in the cartoon.

 

Sugden KSHV Partitioning ModelThis cartoon figure represents our model for how KSHV's encoded protein, LANA1, not only binds the TRs of KSHV1 DNA and tethers it to nucleosomes on host chromosomes but also tethers KSHV genomes to KSHV genomes by tethering to the nucleosomes on each of these KSHV plasmid DNAs.

 

The mechanisms by which these tumor viruses partition their DNAs not only are virus-specific but also offer specific targets for therapeutic intervention because another insight of these studies is that each virus provides the tumors it causes essential advantages.

-Bill Sugden, James A. Miller Professor of Oncology

 

Read the paper in the Journal of Cell Biology:

http://jcb.rupress.org/content/early/2017/07/07/jcb.201702013

Additional research highlight:

http://www.med.wisc.edu/news-events/new-method-of-viral-maintenance-in-cancer-cells-identified-in-uw-study/51122

 

Slide show image on home page. The figure with the 10 fluorescence images of cells spans 48 hours in which 63 images at each time point in sequential Z-planes were compressed to yield the pictures of live cells followed through 3 mitoses. The cells, their signals, and their intensities measured from uncompressed raw data are depicted in the cartoons above the images. The intensities of some of the signals grow at least 4-fold and remain intact during mitosis showing that these clusters of KSHV genomes are inherited as units. Source: Chiu et al., J Cell Biol. 2017 Sep 4; 216(9): 2745–2758. 

Are you a golfer who wants to support breast cancer research? Then here is a perfect way. Enjoy the beautiful day this coming Saturday, September 16th, 2017, by participating in the Breast Cancer Golf Rally at the Foxboro Golf Club in Oregon, WI, 20 minutes from UW, and in the process raise money to support breast cancer research at McArdle Laboratory for Cancer Research and the UW Carbone Cancer Center. This fund raising event was started 16 years ago by Sonja Henriksen in honor of her mother-in-law, who died of breast cancer. Starting last year, a portion of the proceeds are donated directly to McArdle. For more information click here! Registration starts at 9 AM. Shotgun start is at 10 AM. The address for the golf club is 1020 County Road MM, Oregon, Wisconsin 53575.

If you plan to participate and are looking for a sponsor, or a golf partner, then email Kristen Adler (adler@oncology.wisc.edu). If you do not golf but would like to contribute to this fund raising event, then please email Kristen Adler at McArdle for help in doing so.

Hope to see you there!

A new study from Dr. Yongna Xing’s group at the University of Wisconsin Carbone Cancer Center (UWCCC) and the McArdle Laboratory for Cancer Research, recently published in the journal Proceedings of the National Academy of Sciences, solved the structure of the aryl hydrocarbon receptor (AHR) transcriptional complex. AHR responds to diverse chemicals and cellular metabolites that might cause different biological consequences, from toxicity responses, development, to normal functions of immune and cardiovascular systems.  AHR is inactive in cells until it interacts with one of its chemical signals, known as ligands. Then, AHR changes its shape, exposing a part of the receptor that directs it to enter the nucleus – nuclear localization signal (NLS). Once in the nucleus, where all the cell’s DNA resides, AHR partners with another protein, ARNT, and together they increase the expression of genes which correspond to the chemical signal which the AHR receptor protein “received.” In the structure, Xing and colleagues, including oncology professor Dr. Christopher Bradfield, show how AHR and ARNT interact with each other and with target DNA. Because of its higher structural flexibility, AHR is able to adopt more changes in the protein structure upon chemical activation than other transcription factors in the same family. This would allow AHR to adopt different conformations upon binding to different ligands. The structure underlies highly integrative, naturally-evolved protein machinery for versatile responses to many different environmental and chemical cues to create different biological outputs.

Bob Liu moved to be a Senior Scientist at Amunix in Mountain View California. This company is developing long-lasting protein-based therapeutics, currently with a particular interest in bispecific T-cell engager platform technologies.

On Friday, January 20, 2017, teachers and other staff from the Verona Area High School hosted the 11th Annual Night of Hope fundraiser for cancer research to benefit the McArdle Laboratory. The Night of Hope was started in 2006 as a fundraiser for a local family touched by cancer, and grew into an annual event with silent auction and children's raffle. Nancy Cahill reached out to McArdle in 2013 to get students and staff to attend the event and subsequently McArdle participants have hosted several personal tours of UW-Madison cancer laboratories to check out the cutting edge research facilities and observe McArdle researchers in action.

Since 2006, the event has raised more than $44,000 for basic cancer research. This years event brought in more than $5,000 and featured musical performances from Mike Cahill's MUD MUSIC & The Fauxtons. The McArdle Laboratory is very grateful to the Verona Area High School staff and all other contributors for their incredible support!

It is always wonderful to meet individuals in our community who try to make a difference in our fight against cancer. Sonja Henriksen is just such a person. For 16 years she has organized the BC Golf Rally at the Foxboro Golf Club in Oregon, Wisconsin to raise funds for breast cancer research. Sonja visited us recently to present a check to McArdle. She organizes this event in honor of her mother-in-law, who died of breast cancer. This past year she asked Bill Markham, who has golfed in the event for years, to help with organizing the BC Golf Rally. Bill is the husband of long-time administrator in McArdle, Mary Jo Markham. Mary Jo currently oversees grant submissions for all faculty in McArdle. Sonja and Bill met with a number of faculty including Wei Xu, Elaine Alarid and Mike Gould - all of whom do research on breast cancer - as well as Bill Sugden, Mike Hoffmann, and myself, Paul Lambert, Director of McArdle. They all thanked Sonja and Bill for their incredible efforts over the years, which have benefitted the UWCCC and McArdle. We look forward to participating in next year's event!

- Paul Lambert

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