Center for Cancer Research News

View the latest research highlights and featured publications from the Center for Cancer Research.

2020

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.

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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.

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2019

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.

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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.

 

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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.

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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.

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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.

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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

• Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish

• RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues

• The Dual PI3K/mTOR Pathway Inhibitor GDC-0084 Achieves Antitumor Activity in PIK3CA-Mutant Breast Cancer Brain Metastases

• Targeting the CBM complex causes T_reg cells to prime tumours for immune checkpoint therapy

• Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer

• TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma

• Transcriptome-wide off-target RNA editing induced by CRISPR-guided DNA base editors

• Single-cell trajectories reconstruction, exploration and mapping of omics data with STREAM

• Extranuclear DNA accumulates in aged cells and contributes to senescence and inflammation

• Engineered CRISPR-Cas12a variants with increased activities and improved targeting ranges for gene, epigenetic and base editing

• COX-2 mediates tumor-stromal prolactin signaling to initiate tumorigenesis

• A Code of Mono-phosphorylation Modulates the Function of RB

• Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity

• CRISPResso2 provides accurate and rapid genome editing sequence analysis

• IL-33/regulatory T cell axis triggers the development of a tumor-promoting immune environment in chronic inflammation

• AMPK-Mediated Lysosome Biogenesis in Lung Cancer Growth

• Alternative Lengthening of Telomeres through Two Distinct Break-Induced Replication Pathways

• KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

• Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma

• NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263

• Localized protein biotinylation at DNA damage sites identifies ZPET, a repressor of homologous recombination