Prior to 2003, there was almost no multiple myeloma (MM) research ongoing at UW-Madison. However, the Trillium Fund was established that year by several generous patients to support myeloma research at the UW Carbone Cancer Center. In 2004, Dr. Natalie Callander was recruited to the UW-Madison and the Multiple Myeloma Working Group was established. Now, the MM working group is vibrant with physician scientists, pathologists, and basic scientists working together to improve our understanding of the disease and to develop new treatment approaches. Members receive multi-investigator grants from National Cancer Institute and other agencies to support research activities. Since the formation of the MM working group, the members of the group have held many seminar presentations for patients, their family members and friends over the years with topics ranging from basic discoveries to clinical trials to new therapeutic options.
On November 9 this year, the MM working group held “UWCCC Multiple Myeloma Update” seminars for over 200 patient participants with topics including clinical trials update (Dr. Callander), mind-body influences on myeloma (Dr. Constanzo), immunotherapy (Dr. Hall), predicting drug responses (Dr. Miyamoto), anti-myeloma immunity (Dr. Asimakopoulos), minimal residual disease (Dr. Leith), synstatin drugs (Dr. Rapraeger), microbiome influence (Dr. D’Angelo), and novel cell therapies (Dr. Hematti). This morning seminar session was followed by lunch and tours of the bone marrow transplantation clinic (Dr. Hematti) and WIMR labs (Drs. Asimakopoulos and Miyamoto). Many of the participants took the opportunity to take these tours and asked questions regarding basic and clinical research and how their myeloma biopsies and samples are utilized to learn the biology of the disease and to develop new therapeutics. Overall, this public event was highly successful and the MM group is looking forward to continuing to host future events to inform the patients on ongoing multiple myeloma research at UW-Madison and to provide up-to-date information on MM therapy.
-Dr. Shigeki Miyamoto
Feature image on home page: McArdle facuty member Shigeki Miyamoto presents at November 9th's event.
Dr. Xu and her lab group. From left to right: Kristine Donahue, lead author Fabao Liu, author Yidan Wang, Justine Coburn, Carlos Coriano, senior author Wei Xu, Steve Chan, Eui-Jun Kim, and Dominic Dharam. Contributing scientists not pictured: Fengfei Ma, Yuyuan Wang, Ling Hao, Hao Zeng, Chenxi Jia, Peng Liu, Irene M. Ong, Baobin Li, Guojun Chen, Jiaoyang Jiang, Shaoqin Gong, and Lingjun Li.
As cells with a propensity for cancer break down food for energy, they reach a fork in the road: They can either continue energy production as healthy cells, or shift to the energy production profile of cancer cells. In a new study published on Oct. 23, 2017 in the journal Nature Cell Biology, University of Wisconsin–Madison researchers map out the molecular events that direct cells’ energy metabolism down the cancerous path.
The findings could lead to ways to interrupt the process.
“Cancer cells often change their nutrient utilization and energy production, so many efforts are being made to develop drug inhibitors of cancer cell metabolism to starve them,” says senior author Wei Xu, the Marian A. Messerschmidt Professor in Cancer Research at the UW Carbone Cancer Center and McArdle Laboratory for Cancer Research. “We have found that inhibiting a chemical modification of a cancer-associated metabolism protein is enough to inhibit the aggressive nature of cancer cells.”
Cancer biologists have identified nearly a dozen “hallmarks of cancer,” or large-scale changes that send a precancerous cell over the tipping point to become a cancerous one. One hallmark of cancer is the loss of properly regulated energy metabolism, a process referred to as the “Warburg effect” after the Nobel laureate, Otto Warburg, who identified it.
Other hallmarks of cancer include continuous activation of growth pathways, the inability to respond to signals that put the brakes on cell growth, and a gain of invasion and spread to distant organs.
“My lab studies a protein, CARM1, which is associated with worse outcomes in breast cancer patients, though it has also been found expressed in many other cancer types,” Xu says. “CARM1 chemically modifies its target proteins to alter their function, and in doing so directly leads to the activation of several hallmarks of cancer.”
In the study, Xu and her colleagues found that CARM1 protein modifies a cell metabolism protein, PKM2, and changes its function. This drives the Warburg effect, activating a hallmark of cancer. Nearly a decade ago, researchers found that PKM2 was expressed at high levels in cancer cells, but how these levels translated to more aggressive cancers was not known.
So, Xu and colleagues performed a protein interaction assay in a breast cancer cell line and found that CARM1 interacts with and chemically modifies PKM2.
They also assessed whether CARM1-directed modifications of PKM2 might be responsible for leading cells down a cancerous pathway. By engineering cells to express “normal” PKM2 or a mutated form that was not modifiable, the researchers learned that PKM2 appears to be the deciding factor in picking the direction cell metabolism takes at that fork in the road. The CARM1-modified PKM2 shifted cells toward the cancer cell metabolism path while cells with PKM2 that could not be modified took the metabolic path associated with noncancerous cells.
With a clearer picture of how cancer cells shift their metabolism, the researchers next used a mouse model of breast cancer and a competitor drug that prevents CARM1 from effectively modifying PKM2 to test what would happen.
“When we block PKM2 modification by CARM1, the metabolic energy balance in cancer cells is reversed, and we see a decrease of cell growth and cell spreading potential,” Xu says. “This study, then, identifies another therapeutic target to help reverse several hallmarks of cancer.”
In addition to targeting PKM2 modification by CARM1, Xu’s lab is investigating how CARM1 recognizes all of its many target proteins, with the goal of disrupting those protein modifications from driving aggressive cancers.
Xu’s research colleagues include postdoctoral fellow and lead author Fabao Liu, and co-investigators Shaoqin Sarah Gong and Lingjun Li. Gong’s group engineered the unique nanoparticle that allowed for the delivery of the PKM2 competitor, and Li’s group identified where the PKM2 protein was modified by CARM1.
The work was supported by grants NCI R01 CA213293 and R21 CA196653, as well as the UW Carbone Cancer Center core support grant, NIH/NCIP30CA014520.
Slideshow image on home page: Inhibiting PKM2 methylation increases Ca2+ uptake and mitochondrial membrane potential, both important factors for oxidative phosphorylation. The top row images show the co-localization of mitochondrial tracker and Rhod-2 (a Ca2+ indicator) in MCF7 PMK2-KO cells. The bottom row images show Rhod-2-labelled mitochondria in parental MCF7, PKM2-KO, PKM2WT/shPKM1 and PKM2mut/shPKM1 cells. From Liu et al., Nature Cell Biology 2017 Oct 23; 19(11): 1358–1370.
This article was originally published at https://www.med.wisc.edu/news-events/new-study-shows-how-cells-can-be-led-down-non-cancer-path/51459
Expression of both HPV oncogenes E6/E7 and estrogen (E2) alter host gene expression in the cervical stroma. The Venn diagrams and pie charts in this figure show the differential expression of genes in the stroma for E6/E7, E2, and E6/E7+E2 compared to WT mice. From Spurgeon et al., PNAS. 2017 Oct 9; 114(43): E9076-E9085.
Human papillomavirus (HPV) and the hormone estrogen are both linked to the development of cervical cancers, but how they work together has remained unclear. A new study by University of Wisconsin-Madison researchers shows how the combination of two factors influences the local cervical environment and drives the progression of cancer development.
HPV is a virus that infects epithelial cells of mucous membranes such as the vagina, anus or back of the throat. Over 150 strains of HPV are known, ranging from those that cause benign warts to the high-risk strains that cause the majority of all HPV-associated cancers. However, only some high-risk infections progress to cancers, and a better understanding of what factors drive cancer formation should lead to improved therapies.
“Before I started in the Lambert lab, former lab members had discovered that not only is estrogen important in HPV-associated cervical cancers in mice, it is estrogen signaling through the non-cancerous stromal cells, also called the microenvironment, that is important,” said lead author Dr. Megan Spurgeon, an assistant scientist in Dr. Paul Lambert’s lab. “At the same time, Dr. Paul Ahlquist’s lab was looking at human cervical cancer samples and found a role for estrogen signaling through the stroma.
Spurgeon and her research colleagues wanted to know if HPV infection caused the epithelial cells to send a signal that altered the microenvironment, and if the stromal cells in turn sent a signal to the HPV-infected cells that promoted their cancerous growth. So they took a more detailed look at the Lambert lab’s mouse model of cervical cancer. In these mice, high-risk HPV genes are expressed only in cervical epithelial cells; the mice only develop cervical cancer if they are given extra estrogen.
“This model allows us to determine the contribution of HPV alone, estrogen alone, or both together,” Spurgeon said. “And then we used a really precise laser-based dissection tool that allowed us to exactly capture epithelial tissue or stromal tissue and to ask how they each respond to the different factors.”
With the epithelial and stromal tissue precisely separated, the researchers measured changes in total gene expression of the different tissue compartments in response to HPV or estrogen. They compared HPV mice to non-HPV mice, and found hundreds of gene expression differences in the stromal cells.
“The high-risk HPV genes alone were able to reprogram or change gene expression in the nearby stroma, even though HPV genes are not present in the stroma,” Spurgeon said.
Next, they asked how estrogen affected stromal gene expression with or without HPV in the epithelium. They found that estrogen alone causes some changes, as expected. But in the HPV mice treated with estrogen, they found a different set of genes expressed in the stroma than with either factor alone. It was this subset of genes that helped them identify the potential factors involved in crosstalk between the HPV-infected epithelial cells and the estrogen-receptive microenvironment.
Using human cervical cancer cells, they further investigated a class of these genes, the pro-inflammatory chemokines, which are known to move between cells. They grew cells either by themselves or in co-culture with cervical stromal cells, and measured levels of the inflammatory chemokines, and found higher levels in the co-culture.
“The hypothesis now is that those inflammatory chemokines are secreted by the stroma and are feeding back on the epithelial cells or some other cells in the microenvironment to drive cancer development,” Spurgeon said. “The next step is to use our mouse model and genetically engineer it to knock down the chemokine receptors on different cell types or inhibit the chemokine signaling with drugs to see if they are directly contributing to cancer.”
While estrogens are not linked to other HPV-associated cancers, this study highlights how HPV influences the microenvironment to contribute to other cancers.
“The fact that HPV alone was able to reprogram the nearby stroma is an important finding, and suggests that HPV could be conditioning the microenvironment to respond to other factors in other HPV-associated cancers,” Spurgeon said.
The study was published online October 9 in the journal Proceedings of the National Academy of Sciences. It was funded in part by NIH grants CA022443 and P30 CA014520.
Spurgeon is supported by an NIH R50 Research Specialist award (CA211246), a category of new support grants for exceptional scientists who are pursuing research in an existing research program but are not faculty leads themselves. She is the first recipient of such an award at UW; read more about Spurgeon and her R50 award here. Study co-authors include UW Carbone Cancer Center members Lambert, director of the McArdle Laboratory for Cancer Research; Ahlquist, investigator at the Howard Hughes Medical Institute, the Morgridge Institute for Research and McArdle; Dr. David Beebe, director of the UW Microtechnology, Medicine and Biology Lab; and Dr. Avtar Roopra, associate professor of neuroscience.
Conflict of interest statement: Beebe holds equity in Bellbrook Labs LLC, Tasso Inc., Stacks to the Future LLC, Lynx Biosciences LLC, Onexio Biosystems LLC, and Salus Discovery LLC.
Slideshow image on home page: Lead author Megan Spurgeon and principle investigator Paul Lambert.
This article was originally published at https://www.med.wisc.edu/news-events/study-shows-hpv-works-across-cellular-borders-to-drive-cervical-cancer/51428
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 cancer, motivating 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.”
The photo for this article was found on http://findorff.com/project/detail/sun-prairie-high-school/
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.
Link to paper in Oncotarget:
Dr. 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.
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.
This 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:
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 (email@example.com). 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.