Ben Landry, Mike Lee and colleagues publish thier findings on the diversity in tumor–stromal cell interactions that modulate chemotherapeutic drug sensitivity in Molecular Systems Biology

June 28, 2018

Diagram of the experimental co-culture systemDue to tumor heterogeneity, most believe that effective treatments should be tailored to the features of an individual tumor or tumor subclass. It is still unclear, however, what information should be considered for optimal disease stratification, and most prior work focuses on tumor genomics. Here, we focus on the tumor microenvironment. Using a large‐scale coculture assay optimized to measure drug‐induced cell death, we identify tumor–stroma interactions that modulate drug sensitivity. Our data show that the chemo‐insensitivity typically associated with aggressive subtypes of breast cancer is not observed if these cells are grown in 2D or 3D monoculture, but is manifested when these cells are cocultured with stromal cells, such as fibroblasts. Furthermore, we find that fibroblasts influence drug responses in two distinct and divergent manners, associated with the tissue from which the fibroblasts were harvested. These divergent phenotypes occur regardless of the drug tested and result from modulation of apoptotic priming within tumor cells. Our study highlights unexpected diversity in tumor–stroma interactions, and we reveal new principles that dictate how fibroblasts alter tumor drug responses.

Job Dekker receives 2018 Edward Novitski Prize

February 9, 2018

The Genetics Society of America (GSA) has named Job Dekker, PhD, the recipient of the 2018 Edward Novitski Prize. The award honors investigators who have exhibited “an extraordinary level of creativity and intellectual ingenuity in the solution of significant problems in genetics research.”

Dr. Dekker, Howard Hughes Medical Institute Investigator, the Joseph J. Byrne Chair in Biomedical Research, professor of biochemistry & molecular pharmacology and co-director of the Program in Systems Biology at UMass Medical School, is recognized for scientific contributions that include the development of chromosome conformation capture—a technique that has revolutionized chromosome research.

Chromosome conformation capture, or 3C, allows researchers to study the interactions of chromosomes at resolutions and scales previously impossible to attain. In 3C, chromatin is treated with a crosslinking chemical that causes chromosomal regions that are near each other to be chemically linked together. By isolating these crosslinked regions of chromatin and determining their DNA sequences, geneticists can deduce which parts of the genome are in proximity to each other. Although the foundation of the technique seems simple, no one before Dekker had formulated a practical way to take advantage of it for a high-throughput molecular assay like 3C.

Study from the Dekker lab and colleagues answers 100-year-old question about how chromosomes get their distinctive X-shape

January 18, 2018

A multi-disciplinary team at UMass Medical School led by Job Dekker, PhD, has unraveled how chromosomes are packaged into their iconic X-shape during cell division. Packaging the genome inside mitotic chromosomes is critical to the faithful transmission of DNA from parent to daughter cells; these findings shed new light on the inner workings of cell division and may provide novel targets for potential cancer treatments.

“Cancer cells are experts at dividing. They do it well, and they do it very fast,” said Dr. Dekker, Howard Hughes Medical Institute Investigator, the Joseph J. Byrne Chair in Biomedical Research, professor of biochemistry & molecular pharmacology and co-director of the Program in Systems Biology at UMMS. “Many cancer therapies take advantage of this fact and attack dividing cells specifically in the hopes of eliminating the cancer. The more we understand about how this process works, the more ways we have to throw a wrench into this machine and disrupt this process.”

Job Dekker appointed inaugural Joseph J. Byne Chair in Biomedical Research

July 17, 2017

Job Dekker, Ph.D.Two newly established endowed chairs at UMass Medical School—the Joseph J. Byrne Chair in Biomedical Research and the Herman G. Berkman Chair in Diabetes Care Innovation—were approved by the UMass Board of Trustees on Monday, July 17, according to Chancellor Michael F. Collins.

Job Dekker, PhD, Howard Hughes Medical Institute Investigator, professor of biochemistry & molecular pharmacology and co-director of the Program in Systems Biology, and Michael J. Thompson, MD, clinical professor of medicine and chief of adult diabetes clinical research, were appointed to the positions, respectively.

The purpose of The Joseph J. Byrne Chair in Biomedical Research is to support the research activities of an accomplished faculty member whose work is advancing the fundamental understanding of human biological systems and offering new and innovative pathways to treat human disease. Dr. Dekker is one of the medical school’s most dynamic and cutting-edge researchers and is the inaugural holder of The Joseph J. Byrne Chair in Biomedical Research.

Aurian García-González, Marian Walhout, and colleagues publish study in Cell showing that bacteria modulate host chemotherapeutic drug responses

April 21, 2017

Marian Walhout, Ph.D., and MD/PhD student Aurian Garcia-GonzalezThe bacteria residing in your digestive tract, or your gut microbiota, may play an important role in your ability to respond to chemotherapy drugs, according to a new study by scientists at UMass Medical School. Published in Cell, the study by Marian Walhout, PhD, and colleagues shows that when a common research model, the roundworm Caenorhabditis elegans, was fed a diet of E.coli bacteria, the worms were 100 times more sensitive to the chemotherapy drug floxuridine (FUDR) than worms who were fed different bacteria. FUDR is a commonly used drug to treat colorectal cancer.

Cancer doctors have long been puzzled by how dramatically patients with the same disease can respond differently to the same treatment—even in cases where identical twins have the same diagnosis. “Two twins, genetically identical, who have colorectal cancer could potentially respond very differently to the same treatment because of their microbiome,” said Dr. Walhout, the Maroun Semaan Chair in Biomedical Research, professor of molecular medicine and co-director of the Program in Systems Biology. “If we can learn how bacteria affect the efficacy or toxicity of chemotherapies, it’s not hard to imagine developing personalized medicine built on probiotics that could improve the clinical benefits of some cancer treatments.”

Rob Brewster and colleagues publish a kinetic model of transcription that incorporates the interplay between transcription factor copy number and its binding sites in PLoS Computational Biology

April 17, 2017

Transcription Factors on PromotersGene expression is intrinsically a stochastic (noisy) process with important implications for cellular functions. Deciphering the underlying mechanisms of gene expression noise remains one of the key challenges of regulatory biology. Theoretical models of transcription often incorporate the kinetics of how transcription factors (TFs) interact with a single promoter to impact gene expression noise. However, inside single cells multiple identical gene copies as well as additional binding sites can compete for a limiting pool of TFs. Here we develop a simple kinetic model of transcription, which explicitly incorporates this interplay between TF copy number and its binding sites. We show that TF sharing enhances noise in mRNA distribution across an isogenic population of cells. Moreover, when a single gene copy shares it’s TFs with multiple competitor sites, the mRNA variance as a function of the mean remains unaltered by their presence. Hence, all the data for variance as a function of mean expression collapse onto a single master curve independent of the strength and number of competitor sites. However, this result does not hold true when the competition stems from multiple copies of the same gene. Therefore, although previous studies showed that the mean expression follows a universal master curve, our findings suggest that different scenarios of competition bear distinct signatures at the level of variance. Intriguingly, the introduction of competitor sites can transform a unimodal mRNA distribution into a multimodal distribution. These results demonstrate the impact of limited availability of TF resource on the regulation of noise in gene expression.

Marian Walhout appointed inaugural Maroun Semaan Chair in Biomedical Research

April 12, 2017

Marian Walhout, Ph.D.UMass Medical School will invest three faculty members into newly endowed chairs and three more to existing endowed chairs, according to a vote by the University of Massachusetts Board of Trustees at its April 12 meeting.

Marian Walhout, PhD, professor of molecular medicine and co-director of the Program in Systems Biology, has been appointed the inaugural recipient of The Maroun Semaan Chair in Biomedical Research. Dr. Walhout is a pioneer among those working to understand how genes are expressed on a system level, and how these complex biological networks adapt to various conditions. Her research, which combines large-scale data sets and uses computational modeling to unravel regulatory networks involved in metabolic and genetic development, has advanced the fundamental understanding of these systems and offers potentially new and innovative pathways to treat human disease.

Job Dekker receives inaugural International Award from British Biochemical Society

April 11, 2017

Job Dekker, PhDJob Dekker, PhD, has been recognized by the Biochemical Society, based in London, as the inaugural recipient of the International Award. One of 11 eminent scientists honored overall by the Biochemical Society, Dr. Dekker, Howard Hughes Medical Institute investigator, professor of biochemistry & molecular pharmacology, and co-director of the Program in Systems Biology, was recognized for his distinguished and independent interdisciplinary research that illustrates the importance of the molecular biosciences in the advancement of life sciences research. Recipients of the International Award conduct research outside of the UK and Ireland and may be of any nationality.

“I am extremely delighted to have been selected for this award,” said Dekker. “This really honors the work of my students, postdocs, collaborators and colleagues in this field that was started to uncover how cells fold their chromosomes.”