View research highlights, news and featured publications from the Center for Cancer Research.
2020-2021 Center for Cancer Research Seminar Series
The Center for Cancer Research Seminar Series occurs weekly and provides an opportunity for the MGH research community to learn from national and international leaders in cancer research on topics such as: cancer genetics and epigenetics, signaling and molecular therapeutics, developmental and stem cell biology, genetic model organisms, DNA damage and genomic stability, immunotherapy, hematopoiesis, lymphocyte biology and miRNA regulation, among other areas. View schedule.
CCR Investigators Named Bits to Bytes Program Awardees
Congratulations to CCR faculty Raul Mostoslavsky, MD, PhD, Nabeel Bardeesy, PhD, Gad Getz, PhD, and Leif Ellisen, MD, PhD, who along with Keith Flaherty, MD have been awarded Bits to Bytes program funding from the Massachusetts Life Sciences Center (MLSC) for their project "An Integrative Platform to Understand and Exploit Cancer Metabolism."
MLSC launched Bits to Bytes in 2019 to provide grants for projects that generate and analyze large datasets to answer pressing life science questions, and to attract and train data scientists in the Commonwealth. View the press release.
Lee Zou, PhD and Raul Mostoslavsky, MD, PhD Named Scientific co-Directors
After nine years as the Scientific Director of the Mass General Cancer Center and Center for Cancer Research, Dr. Nick Dyson is stepping down from his role. Succeeding him are Lee Zou, PhD and Raul Mostoslavsky, MD, PhD, who will serve as Scientific co-Directors. Both of these highly accomplished researchers are ready to ensure that Mass General Cancer Center continues on its outstanding trajectory of discovery and innovation in cancer research. Read more.
Ultrahigh-throughput magnetic sorting of large blood volumes for epitope-agnostic isolation of circulating tumor cells
A team at Massachusetts General Hospital has devised a new ultrahigh-throughput microfluidic chip (the LPCTC-iCHIP) that improves sensitivity of CTC-based assays 100-fold as compared to the existing approaches. The team’s paper appeared recently in the May 2020 issue of Proceedings of the National Academy of Sciences.
“Drs. Mehmet Toner, Daniel Haber, and Shyamala Maheswaran applied the precision of microfluidics to rare cell sorting and helped establish the field of liquid biopsy research about ten years ago,” says Avanish Mishra, PhD, a research fellow at the Mass General Cancer Center and Harvard Medical School, who was the co-lead author on the LPCTC-iCHIP project along with Taronish Dubash, PhD. “With this novel new technology and our unique process using the leukopak, we transform CTC screening from a 10 mL blood sample to whole human blood; hoping to bring highly reliable liquid biopsies into the clinic.” View the press release.
Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma
Cancer researchers at Massachusetts General Hospital and affiliated institutions have identified changes in lung cancer-promoting genes that may allow the disease to metastasize to the brain. Their work, which points to possible therapies for preventing or treating brain metastases from lung cancer, is described in the March 2020 issue of Nature Genetics.
“It’s a terrible complication of lung cancer, because it’s associated with significant mortality, and the median survival in this patient population is on the order of months. Unfortunately, the treatment options are limited and there is no established standard of care for most patients with brain metastases from lung adenocarcinoma,” said principal investigator Priscilla K. Brastianos, MD, from the Mass General Cancer Center. View the press release.
Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis
Hormone receptor-positive breast cancer can spread throughout the body via the bloodstream as circulating tumor cells, or CTCs, which eventually reach distal (remote) body sites to form metastatic tumors. An increase in ribosomes, the protein-making machinery found in every living cell, increases their potential to form metastasis, report investigators from Massachusetts General Hospital Cancer Center and Harvard Medical School. The findings were published in a March 2020 issue of Science.
“The Haber/Maheswaran lab has been one of the pioneers in being able to isolate, analyze and now use CTCs that are derived from patient blood samples. They offer many advantages and opportunities for understanding the metastatic pathways that are involved in advanced breast cancer,” says investigator Douglas S. Micalizzi, MD, PhD, from the MGH Cancer Center. View the press release.
Tumor sequencing has traditionally focused on protein-coding genes, yet these only comprise roughly one percent of the human genome. The remainder contains important regulatory sequences that tightly control gene expression and production of proteins, making sure genes are turned on at the right time in the correct cells.
The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium, a joint effort of over 1,300 researchers from 37 countries, published a comprehensive in-depth analysis of more than 2,600 primary tumor genomes in the Feb 2020 issue of Nature. As part of this effort, CCR faculty members Gad Getz and Esther Rheinbay, together with their colleagues, studied the landscape of protein-coding and non-coding regulatory driver events in cancer. Their study presents a novel strategy to analyze recurrent driver events in whole cancer genomes, and shows that although there are clear drivers in non-coding regions, the majority of driver genetic changes alter proteins. This work also highlights that there are still challenges in finding genetic drivers of cancer and that we will need to sequence many more tumors to fully map and understand the genetic causes underlying each individual patient’s disease. View the press release.
TATR protects the genome by sensing R loops
R loops are transcription intermediates that contain DNA:RNA hybrids. In cancer cells, R loops often accumulate at aberrantly high levels, leading to genomic instability and DNA damage. In a February 2020 paper published in Molecular Cell, Matos and colleagues in the Zou laboratory reported that the ATR kinase is a key sensor of R loops and a suppressor of R loop-associated DNA damage. This paper reveals the molecular mechanisms by which human cells, especially cancer cells, use ATR to cope with R loops in their genomes, suggesting that inhibition of ATR may be an effective strategy to selectively kill cancer cells harboring high levels of R loops.
Immunity to Commensal Virome Blocks Cancer
In an October 2019 paper published in Nature, Strickley, Messerschmidt et al. investigated the role commensal human papillomaviruses (HPVs) play in the development of skin cancer. Using a novel skin colonization model, they show that adaptive immunity against papillomavirus infection is able to protect the host from developing cancer. In stark contrast to the established “hit and run hypothesis,” which postulates that skin HPVs initiate cancer and are later lost, this work elucidates the significant and previously unrecognized beneficial contributions of skin-resident HPVs. Considering the >100-fold increase in skin cancer risk among immunosuppressed patients, these findings potentiate novel therapeutic interventions to prevent the development of skin cancer in this high-risk population. Furthermore, these results establish a new field of investigation into the beneficial contributions of viruses that live in our skin and other organs. View the press release.
CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity.
Building on their research showing that an exciting new form of immunotherapy for cancer has activity in patients with glioblastoma, the most common and most deadly form of brain cancer, Mass General investigators have created a new method that could make immune therapy more effective again brain tumors and expand its use against other types of solid tumors. Their study is published in the July 2019 issue of Nature Biotechnology. View the press release.
An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma.
The researchers profiled gene expression in more than 24,000 tumor cells from 20 adult and eight pediatric glioblastoma patients and also analyzed glioblastoma models in the lab. They found four glioblastoma cellular states, which each has a unique gene expression program and together help account for the large variation in the disease. The scientists then used the single-cell data to reanalyze glioblastoma data from The Cancer Genome Atlas, and identified genetic alterations associated with each of the four states. The results, published in Cell, also show that the cells are remarkably flexible or plastic — that is, they can switch between the four states. This shape-shifting ability could help explain why these cancer cells are so difficult to kill with drugs and help inform the development of better therapies for glioblastoma. The research was led by co-first authors Cyril Neftel, Department of Pathology at Massachusetts General Hospital (MGH) and Broad Institute; Julie Laffy, Weizmann Institute of Science; Mariella Filbin, Department of Pathology at MGH, Broad Institute, and Dana-Farber Institute; Toshiro Hara, Salk Institute for Biological Studies; and co-senior authors Itay Tirosh, Weizmann Institute of Science, and Mario Suvà, Department of Pathology at MGH and Broad Institute. View the press release.
Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish.
In a June 2019 paper published in Cell, Yan, Langenau and coworkers show that they can engraft a wide array of human tumors in optically clear zebrafish. The advantages of this system for imaging mean that it is readily possible to visualize dynamic changes in single engrafted cells. The authors have used their zebrafish models to show the preclinical efficacy of a drug combination of the PARP inhibitor Olaparib and the DNA-damaging agent Temozolomide for rhabdomyosarcoma. The ability to grow patient-derived tumors in zebrafish will likely open many new avenues for personalized medicine.
Passenger hotspot mutations in cancer driven by APOBEC3A and mesoscale genomic features.
The DNA of cancer cells contains many mutations. A few of these mutations are called "driver mutations" because they were responsible for changing the behavior of the cells to make them multiply out of control and form a tumor. But the vast majority of mutations in the cell had no effect and are just "along for the ride" - these are called "passenger mutations". Telling driver mutations apart from the far more numerous passenger mutations can be very challenging. One commonly used approach is to look for exactly the same mutation occurring in many different patients' cancers. This "recurrence" approach has been very successful over the past decade at identifying cancer driver genes and mutations. However, it assumes that every recurrent mutation ("mutation hotspot") is a driver hotspot. In this 2019 paper published in Science, MGH researchers Dr. Lee Zou and Dr. Michael Lawrence took a new critical look at this assumption. Combining the power of biochemistry and bioinformatics, they and their co-authors showed that some hotspots are actually "passenger hotspots," a term that would be seen as contradictory given the current thinking of the field. These passenger hotspots result from the very specific preferences of APOBEC3A, a DNA-mutating enzyme that is often upregulated in cancer cells. They showed that APOBEC3A has a very strong preference for mutating C nucleotides exposed in a short loop at the end of a DNA "hairpin". DNA hairpins form when nearby palindromic DNA sequences in one DNA strand pair to each other instead of their complementary partner on the opposite DNA strand. This generates a perfect substrate for APOBEC3A to attack, and leads to the formation of passenger hotspots, which are recurrently mutated in many patients' cancers, despite contributing nothing to the development or fitness of the cancers. These results show that some previously nominated cancer drivers (e.g. a hotspot in the gene MB21D2) are actually passenger hotspots, and would likely not be worthwhile targets for further study. Incorporating these insights into driver discovery algorithms will improve our ability to detect the true drivers of cancer.
Transcriptome-wide off-target RNA editing induced by CRISPR-guided DNA base editors.
In a May 2019 paper published in Nature, Grünewald et al investigated the effects of cytosine base editors for RNA and DNA editing. They show that targeting of rat APOBEC1 can cause extensive transcriptome-wide deamination of RNA cytosines in human cells, inducing tens of thousands of C-to-U edits. They engineered two variants bearing mutations in rat APOBEC1 that substantially decreased the number of RNA edits (by more than 390-fold and more than 3,800-fold) in human cells. These variants also showed more precise on-target DNA editing than the wild-type protein and, for most guide RNAs tested, no substantial reduction in editing efficiency. These results, together with experiments with an adenine base editor, have important implications for the use of base editors in both research and clinical settings.
2020 Research Highlights
- Analyses of non-coding somatic drivers in 2,658 cancer whole genomes
- Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis
- ATR Protects the Genome against R Loops through a MUS81-Triggered Feedback Loop
2019 Research Highlights