CCSB in the news
The Center of Cancer Systems Biology at Steward Research & Specialty Projects Corp. / Tufts University School of Medicine, Boston, MA, USA recently held its second Annual Workshop on Cancer Systems Biology. This year's workshop focused on the topic of ‘Tumor Metronomics: Timing and Dose Level Dynamics.’ Metronomic chemotherapy is a novel concept of delivering drugs that departs from the traditional maximum tolerable dose paradigm and is instead centered around continuous low dose treatments to maintain a tumor in a non-advancing state. With a metronomic concept, the side effects on normal tissues are reduced and the often-observed selection for resistant tumor sub-populations and ultimate aggressive recurrence is avoided. This workshop addressed the problem of evaluating the metronomic concept from a quantitative, ‘systems’ perspective. We focused on tumor context — how do cell-cell interactions modify cancer dynamics, and how might we render our responses in quantitative terms that are testable, and most importantly, predictive. This workshop brought mathematicians and quantitative modelers together with biologists and clinicians to integrate interdisciplinary thinking and develop novel models of treatment response in small working groups. A number of the developed models and concepts are currently being prepared for publication. The organziers wish to thank the NCI Integrative Cancer Biology Program, Steward Research & Specialty Projects Corp., the Society for Mathematical Biology, and Springer US for supporting this workshop.
1st Annual Workshop on Cancer Systems Biology
by Heiko Enderling
The Center of Cancer Systems Biology at St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston held its first annual workshop on Cancer Systems Biology July 25-28, 2011. The workshop brought together clinicians, biologists, mathematicians, and computer scientists to discuss various aspects of tumor dormancy with emphasis on angiogenesis, the immune system, and cancer stem cells. After keynote lectures in the morning that included presentations by mathematicians Heiko Enderling, Kathleen Wilkie, and Philip Hahnfeldt, working groups were held in the afternoon, where workshop participants discussed current problems related to tumor dormancy and developed novel mathematical/computational models. Mathematicians, biologists, and clinicians in each working group engaged in interdisciplinary dialogs and model development. In the three-and-a-half day workshop, the modeling groups developed exciting new projects and laid the foundation for collaborations and joint manuscript submissions.
Monika Piotrowska, Assistant Professor from the University of Warsaw in Poland, acknowledged "the very stimulating setup for modelers to meet and talk with biologists, experimentalists, medical doctors and clinicians. The breakout sessions gave both modelers and biologists an opportunity to establish a common language necessary to talk about the same topic from different points of view. The discussion sessions helped establish new scientific contacts that," she hopes, "will lead to future successful collaborations." Gabriel Sousa, currently a postdoctoral fellow at the National Cancer Institute of Brazil, also emphasized the workshop's interactive format. "Differently from most symposiums," he says, "in which we have a very limited time for discussions, we had three intensive and very fruitful afternoons of creative discussions that were extended throughout the evening receptions."
Workshop participants were encouraged to present research posters in this interdisciplinary setup, and the opportunity to "get feedback and new ideas from both computational and experimental biologists," was appreciated by Shabnam Moobed, a PhD student from the University of California, Irvine.
The annual workshop is part of the Center's Integrative Cancer Biology Program (ICBP) funded by the National Cancer Institute, and was attended by ICBP project director Dr. Dan Gallahan. The workshop organizers wish to thank the Society for Mathematical Biology for providing travel funding to allow selected exceptional junior scientists from around the world (Taiwan, Poland, Brazil, USA) to attend this workshop. After the success of this inaugural workshop, we look forward to hosting similar interdisciplinary workshops in the years to come. Details will be posted on our website http://www.cancer-systems-biology.org/workshop.html.
NCI Cancer Bulletin, Vol. 8, No. 3, 2/8/2011
Coming Home to Roost: The Self-Seeding Hypothesis of Tumor Growth
A discussion of some of our work and an interview with Philip Hahnfeldt.
By Sharon Reynolds
...Systems biologists at the Center of Cancer Systems Biology at Tufts University School of Medicine in Boston have provided a clearer picture of how self-seeding could fuel rapid primary tumor growth.
In 2009, Dr. Philip Hahnfeldt and his colleagues published the results of computer modeling studies designed to look at the intersection of two biological phenomena found in tumors. One of these phenomena is that a small population of cancer cells may act like stem cells; they may have the ability to reproduce an infinite number of times, creating more cells like themselves with the capability for endless proliferation but also producing daughter cancer cells that eventually lose the ability to divide.
The second phenomenon is that tumor growth is limited by the space available for expansion. Normal, healthy cells have an amount of space between them that is not available in a tumor. Cancer cells grow tightly together in a dense mass until all available space has been occupied, at which point cell division stops. But at the edges of the tumor, where the normal tissues are less dense, cancer cells continue to multiply and push outward, expanding the tumor's size.
"This gives value to the idea that tumor growth is helped by metastatic movement," explained Dr. Hahnfeldt, "where tumor cells get away from the main mass through migration and then...the resulting space [is filled]," creating many smaller masses growing together at a faster rate. Thus, the growth of a primary tumor may be more dependent on metastatic cells populating areas adjacent to the tumor than on the outward growth and invasion of the primary tumor itself.
Their models showed an important--and counterintuitive--relationship between cell migration, cell death, and tumor growth. When the progeny of a cancer stem cell in the model did not migrate or die spontaneously, tumor growth stagnated at around 110 cells. In contrast, a combination of high death rate among the non-stem cell progeny and a high cell migration rate produced the largest tumors in the shortest amount of time, to almost 100,000 cells in just over 3 years.
..."Our model suggests that discouraging migration might provide an alternative means of cancer suppression. Importantly, the results suggest that antimitotic treatments alone, despite killing cancer cells, may actually promote tumor progression if eradication of cancer stem cells cannot be achieved," wrote Dr. Hahnfeldt and his colleagues in their 2009 paper.
...Dr. Hahnfeldt is also expanding his modeling work with a grant from NCI's Integrative Cancer Biology Program (ICBP), overseen by the Division of Cancer Biology. That research will look at how the immune system influences the way cancer cells interact with each other.
"Systems biology has focused a lot on the cancer cell itself, on the genetic changes that occur within that cell. And because cancer is a genetic disease, we're interested in the changes that occur within a normal cell that cause it to take on these cancer characteristics and become malignant," said Dr. Dan Gallahan, director of the ICBP. "But it's also true that population dynamics or cell interactions are equally important. We now know that these dynamics, along with the microenvironment and the immune system, are critical to tumor development."
The self-seeding of a tumor with its own metastatic cells, Dr. Gallahan continued, may represent a crucial step in this development.
Systems Biology and Bioinformatics: Something for Everyone
Systems biology and bioinformatics want you. These highly collaborative fields are looking for biologists, engineers, chemists, mathematicians, and computer programmers. If you can work in a diverse team, says Bernhard Palsson of the University of California, San Diego, "It's an era of unprecedented opportunity." By Chris Tachibana
Lynn Hlatky, director of the center of cancer systems biology at St. Elizabeth's Medical Center, Tufts University, agrees, saying, "For people who are changing careers, and for new investigators, there is funding, and new systems biology centers are being established worldwide."
The job opportunities aren't necessarily tied to a specific geographic location, either. Collaborators can work remotely on a common project. Wet-lab data generated at one site might be analyzed by group members cyber-networking from a distance. "It's more about getting the right people together to address the problem, no matter where they are," says Hlatky. Systems biologists just need "the ability to see the big picture and to have an open mind. Anyone can get into this game."...
... The list of specific areas within systems biology is almost comically long, and includes everything from cutting-edge computer science to traditional life sciences. Fortunately, in this field, collaboration is the name of the game. Galetti Professor of Bioengineering at the University of California, San Diego (UCSD) Bernhard Palsson says systems biology includes "an understanding of networks, biological systems and linear algebra, genomics and genetics, the biochemistry of gene products, and how everything fits into the three-dimensional architecture of the cell." Hlatky says that attacking the complex, nonlinear nature of biology requires "a team of individuals collectively versed in the traditional biological as well as the quantitative sciences, from cell and molecular biology to physics, chemistry, computer science, and mathematics."
Systems biology even needs expertise in fields that have fallen a bit out of fashion. Remember Linnaeus? "Taxonomy is a field of increasing importance, particularly combined with molecular techniques," says Stephan Schuster of the Center for Comparative Genomics and Bioinformatics at Penn State University and the Department of Biochemistry and Molecular Biology. Knowledge of physiology, "but now with quantitative and molecular tools," is valuable, says Hlatky. "We also need people who have training in population levels of thinking--developmental specialists, physicists, and ecologists."
The multidisciplinary systems biology group is like a multicellular organism, explains Hlatky, with robustness coming from specialization and a division of labor. This diversity allows the team to tackle dynamic problems with multiple variables. For example, she says, "In cancer biology, we used to think a number of oncogenes, tumor suppressors, and DNA repair genes drove the whole process, but now we are identifying thousands of genetic alterations in cancers. This means we're not going to figure it out by tracking a few or even dozens of genetic endpoints. We need computation and bioinformatics to address this part of the puzzle."...
... Medicine in the Era of Systems Biology and Bioinformatics
Another booming area is systems medicine. Clinical applications are limited today, but leaders in the field believe that radical changes are coming to health care and medical research. Hlatky of Tufts predicts that progress in analyzing physiological networks, integrating data from multiple levels, and monitoring biological changes over time will have a major impact. Future physicians, take note. "We'll pay more attention to all the parts, and recognize connections between different medical disciplines, like cancer and cardiology," she says. "Medicine will become more of what it is supposed to be, an integrated treatment of the individual." Hlatky says that stem cell biology is another area where a systems approach has strong potential, because of the complexity of the cells, and their impact on everything from neurological diseases, to chronic conditions, to regenerative medicine....
... Tufts' Hlatky adds, "We need to take the multiscale, dynamic interactions among molecules, cells, and tissues and knit them together in a quantitative construct." Thornton of the EMBL-EBI also sees integrating different levels of information as the next step, particularly in processing, storing, and interpreting imaging data. "We're developing advanced imaging tools from the cellular, to the organ, and up to the whole organism level." These methods have to be automated, and the data they generate need to be processed, integrated, and analyzed. Thorton says, "The opportunities are clearly in understanding biology at all different scales, bridging information from molecules to cells to organs to the whole organism, and being able to bring all those aspects together, basically to interpret the entire genome at all levels."...
CCSB webpage, 2/28/2010
CCSB becomes part of NCI's Integrative Cancer Biology Program (ICBP)
This past week, St. Elizabeth's Medical Center received funding from the National Cancer Institute (NCI) to become a Center for Cancer Systems Biology (CCSB). These centers are part of NCI's Integrative Cancer Biology Program (ICBP), which is the NCI's primary effort in cancer systems biology, a field that is rapidly seen as an essential component in the future of cancer research.
"These centers represent a unique multidisciplinary union of outstanding scientists and clinicians who will work to unravel the complexities of cancer through the novel application of technology and mathematical modeling. Their discoveries and models will be critical to our continued success in understanding and treating this disease," said Dan Gallahan, program director for the Integrative Cancer Biology Program.
In addition to the funding received by St. Elizabeth's Medical Center, 10 other outstanding centers nationwide will share NCI's commitment to this area of research. Selection of St. Elizabeth's Medical Center as part of NCI's Integrative Cancer Biology Program underscores and reflects St. Elizabeth's leadership within the community. These new centers and the research that evolves from them should enable scientists to gain a better understanding, and therefore better treatment and prevention, for the disease.
"This program is part of the next generation of cancer research, in that it will approach the disease from a holistic or comprehensive viewpoint in order to understand how all of the components of the disease fit together," said John E. Niederhuber, M.D., NCI Director.
This approach to cancer research is made possible by advances in technology and computational modeling. These centers will not only explore new insights in the areas of cancer systems biology, but will generate computational and mathematical models for application in the lab and the clinic. The centers, such as the one at St. Elizabeth's Medical Center, will work closely with all aspects of the research community and rely heavily on data and insight from other prominent NCI efforts.
Boston Globe 12/17/2009.
St. E's researchers win grants to study low-dose radiation and cancer
Two researchers from St. Elizabeth's Medical Center have won a total of $8.6 million over five years to study cancer risk and exposure to low-dose radiation that people encounter in everyday life.
Lynn Hlatky, director of the Center of Cancer Systems Biology at Tufts University School of Medicine, has won $7.5 million to investigate the risk of cancer from radon in people's basements, getting a CT scan, or living near a site with high background radiation. These are considered low-dose radiation exposures, as opposed to high doses from radiation therapy for cancer or from a nuclear accident, Hlatky said in an e-mail interview.
Philip Hahnfeldt, a senior investigator in the cancer center, has won a $1.05 million grant to formulate mathematical models of low-dose radiation and cancer.
Both grants were awarded by the US Department of Energy's Office of Biological and Environmental Research.
JNCI Editorial 101:1108-1109, 2009.
... One recent model, developed by Heiko Enderling, Ph.D., Lynn Hlatky, Ph.D., and Philip Hahnfeldt, Ph.D., of the Center of Cancer Systems Biology at Tufts University School of Medicine in Boston, aims not just to mimic tumor behavior but ultimately to predict it and assist physicians in choosing treatment options. The model, published in June in the British Journal of Cancer, suggests an explanation for recurrence of cancer after treatment with chemotherapy and radiation. The research team applied basic physical parameters of cell proliferation, migration, and death to show how physical constraints and interactions influence cell behavior. When cell proliferation is low and cell death is high, as in after treatment, tumor growth is paradoxically accelerated because space has been freed up for self-metastatic expansion.
Hlatky pointed out that the model closely mimics the well-documented phenomenon of posttreatment recurrence seen in the clinic. "A simple population-dynamical model like ours that accounts for the liberation and increased symmetric division of stem cells during cell killing, which is biased to nonstem cells, can explain many of the features of the phenomenon," she said. Hlatky argues that posttreatment recurrence may be an effect attributed to the cells acting as a population rather than to any selectable quality of individual cells themselves.
"One could infer that a new, emergent property of cancer behavior arises specifically because the cells are interacting with one another in a population," she said. "And when a property of a population affects tumor growth as a whole, it points to the need to look beyond the genes, and even individual cells, to gain a more complete picture of cancer development." ...
JNCI Editorial 100:1566-1569, 2008.
Superhighway or Blind Alley? The Cancer Genome Atlas Releases First Results
An interview with Lynn Hlatky.
... "This idea of digging deep into the genome gives you a lot of information, and it's an important tool, but it's really only one tool," said Lynn Hlatky, Ph.D., director of the Center of Cancer Systems Biology at Tufts University in Boston. "If your goal is making progress therapeutically, I think it's not the best investment to dig this deep until you have a larger overriding principle that really works for you. You need unifying principles that are predictive."
...Hlatky and her colleagues are investigating how perturbations in the cancer cell's angiogenic lifeline, a unifying requirement for cancer growth, can be exploited as a target common to most solid tumors. In a July 31, 2007, report in Proceedings of the National Academy of Sciences, lead authors Amir Abdollahi, Ph.D., and Peter Huber, Ph.D., of the German Cancer Research Center in Heidelberg, along with Hlatky and her colleagues, described how gene expression shifts when pancreatic cancer cells change from a relatively benign state to an aggressive, invasive state. The group's strategy is to find compounds that could alter the balance toward a quiescent state, thus removing the tumor's ability to spread.
"The genes are simply the players carrying out the story," said Hlatky. "The key is that these tumors really need oxygen - that's a constraint. You either have to be right on a [blood] vessel, or you have to have something that brings these vessels to you, so that was a very good place to think about targeting. Even though there could be redundancies, you know what the tumor needs to do and if you cut that off, that's checkmate to that tumor."
The trouble with TCGA, she said, is that it is stuck at the level of the gene. It's not hypothesis driven and doesn't address the complexity of the cancer in its environment.
"You could question putting this kind of investment into a single level," she said. "This level is important, but you have to have overriding principles that tell you the dynamics of the tumor and where it is going in order to stop it."...
Discovery (e-Newsletter of the St. Elizabeth's Medical Center Research Community), May 2009, Issue 1, page 1-2 [pdf]
Cancer Systems Biology Researcher awarded $180,000 to study intrinsic tumor dynamics
The American Association for Cancer Research (AACR) has awarded Dr. Heiko Enderling (Senior Research Associate, Center of Cancer Systems Biology), a three-year
$180,000 grant to study intrinsic dynamics in tumor progression.
The programs and services of the AACR, the largest scientific organization in the world, promote the development of new ideas in every aspect of cancer research to prevent and cure cancer through research, education, communication and collaboration (www.aacr.org).
“Being awarded this prestigious grant reflects the recognition of the need for interdisciplinary cancer systems biology initiatives to define future research. To be named one of the five Centennial Postdoctoral Fellows is a truly outstanding honor, especially for such an unconventional project entitled ‘Paradoxical proliferation-apoptosis-migration dynamics in tumor progression’ ” said Dr. Enderling.
The supported project combines mathematical and computational modeling techniques to simulate tumor progression in its early stages. The rigorous exploration of how intrinsic cell properties combine to advance or inhibit the disease will inevitably give insights for future treatment planning.
Under the supervision of his mentor, Dr. Philip Hahnfeldt (Senior Investigator, Center of Cancer Systems Biology), and with the generous support of this AACR Fellowship, Dr. Enderling will develop a data-driven theoretical model to seek a better understanding of the anomalous long-term tumor growth response often observed in response to treatment. This approach will be a vital augment to existing dynamical models for tumor development and should provide valuable new insights.
Dr. Enderling has recently presented initial ideas and results from this project at the centennial annual meeting of the American Association for Cancer Research in Denver, CO with 17,000 attendees. In addition to listening to lectures by leading scientists in the field, Dr. Enderling had the opportunity to present and discuss his work with colleagues, and establish new contacts with interested researchers from different parts of the world.
Dr. Enderling (second from left) presenting and discussing his work with colleagues at the annual meeting of the AACR in Denver, CO, April 2009.
Discovery (e-Newsletter of the St. Elizabeth's Medical Center Research Community), May 2009, Issue 1, page 2-3 [pdf]
Natalie V. Zucker Research Grant for Women Scholars
Nava Almog, Ph.D., (Senior Research Associate, Center of Cancer Systems Biology) has been awarded a Natalie V. Zucker Research grant to attend the 14th World Congress on Advances in Oncology and the 12th International Symposium on Molecular
Medicine that will be held in Greece in October. Dr. Almog has been invited to give a lecture at the meeting on her recent research work. The annual grant award of the Natalie V. Zucker Research Center for Women Scholars is designed to
support and enhance the research careers of women basic and clinical scientists at Tufts University School of Medicine and its affiliates. The award is intended to support items or activities that will advance and benefit the awardee research career and professional stature.
Dr. Almog's research is focused on the identification of the molecular mechanisms underlying dormancy of human tumors. She has previously developed and characterized in-vivo models of human tumor dormancy. She has used these models together with a genome-wide gene expression profiling analysis to identify the molecular signature of human dormant tumors. Her team is currently searching for ‘master - regulators’ of tumor dormancy by analysis of expression of microRNA molecules. This work may advance ongoing efforts to develop dormancy-promoting therapy strategies, the discovery of early tumor biomarkers, and possible therapeutic targets for the blockage of early tumor development.
New Directions (Newsletter for Caritas St. Elizabeth's Donors), Winter 2006 [pdf]
Center of Cancer Systems Biology at CSEMC will work to develop new insights into cancer prevention and treatment
The new Center of Cancer Systems Biology (CCSB) at Caritas St. Elizabeth's Medical Center was established in 2005. The CCSB is dedicated to a broad-based approach to cancer research and will maintain a sharp focus on cancer biology and treatment optimization...
Click on image below to read full article as a PDF.
St. Elizabeth's Medical Center webpage
Lynn Hlatky, PhD, Named Founding Director
Lynn Hlatky, PhD, has been named founding director of the Center of Cancer Systems Biology at Caritas St. Elizabeth's Medical Center. Dr. Hlatky joins the medical center from the Dana-Farber Cancer Institute and the department of radiation oncology at Harvard Medical School. She brings with her a diverse and rich background in cancer research, ranging from the elucidation of fundamental molecular steps in carcinogenesis to the optimization of cancer treatment.
Dr. Hlatky graduated from the University of California-Berkeley with a doctorate in biophysics. She is recognized internationally for her research in tumor growth dynamics, tumor microenvironment, DNA damage and repair, chromosome aberrations, radiation biology and tumor angiogenesis. Her laboratory has been funded uninterruptedly by federal agencies since its inception. She has received numerous awards for her research accomplishments, including the James A. Shannon Director's Award from the NIH and the Patty Roche Chair of Research from the Brain Tumor Society.
Dr. Hlatky serves on federal, nonfederal and international scientific granting committees and has participated in Special Emphasis Panels for the review of NIH/National Cancer Institute's Program Centers. In 2003, Dr. Hlatky was designated as an Expert in Cancer Biology by the European Commission for Restructuring European Science.
An inspiring and committed teacher, she serves on the Educational Outreach Committee of the Integrated Cancer Biology Program of the National Cancer Institute and has supervised the research training of many students, fellows and visiting scientists.
Recently, Dr. Hlatky received a $10 million award from NASA to establish and direct a multi-institutional "NASA Specialized Center of Research" (NSCOR) for the study of solid-tumor carcinogenesis. This NASA Center will be based at Caritas St. Elizabeth's Medical Center under the directorship of Dr. Hlatky. The NSCOR will investigate the heightened cancer risks from space radiation faced by astronauts, but is also expected to offer valuable insights into cancer prevention and treatment in the general population.
In addition to NASA, Dr. Hlatky's group currently is supported by the NIH and the DOE.
The Hlatky group will be transferring to Caritas St. Elizabeth's Medical Center grants exceeding $12 million in funding over the next five years.
Dr. Hlatky's office is located in the Center for Biomedical Research building, and she can be reached at (617) 789-2997.