View an archive of research highlights and featured publications from the Center for Cancer Research.
Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq.
In this April 2018 paper published in Science, a group of researchers from the MGH and the Broad Institute used single-cell RNA-seq to define the cellular context of diffuse midline gliomas with histone H3 lysine27-to-methionine (H3K27M) mutations. These uniformly fatal malignancies arise primarily in the midline of the central nervous system of young children, suggesting a particular cell type present at this location and developmental stage is susceptible to transformation by H3K27M. By sequencing the RNA from 3321 single cells from 6 tumors, the authors found that H3K27M tumors largely consist of cells that resemble oligodendrocyte precursor cells (OPC) and drive the growth of the tumor, whereas more differentiated cells were in the minority and lacked proliferative potential. The authors suggest that targeting the OPC marker PDGFRA or triggering cells to differentiate might allow therapeutic intervention in these as yet incurable malignancies. For more information, click here.
This work was led by first authors Mariella Filbin (pictured), Itay Tirosh and Volker Hovestadt (pictured). It was made possible by a close collaboration between the laboratory of Mario Suva’s (pictured), Brad Bernstein and Aviv Regev.
A mitosis-specific and R loop-driven ATR pathway promotes faithful chromosome segregation.
ATR is a master kinase that regulates the DNA damage response, and it is particularly important during DNA replication to keep the genome stable. Although loss of ATR loss was known to cause problems in mitosis, these effects were thought to be indirect. In a January 2018 paper published in Science, Lilian Kabeche and colleagues in Lee Zou’s lab (pictured) report their discovery of a surprising function of ATR in mitosis. In early mitosis ATR is localized to and activated at centromeres. The activation of ATR at centromeres requires R loops, a transcription intermediate containing DNA:RNA hybrids and single-stranded DNA. Active ATR at centromeres promotes accurate segregation of whole chromosomes by stimulating the Aurora B kinase, ensuring that microtubules are attached to chromosomes properly. This study uncovers the first R loop-driven signaling cascade on chromosomes, and a new ATR pathway that specifically operates in mitosis, revealing an unexpected dimension of cell cycle regulation.
TOX regulates growth, DNA repair, and genomic instability in T-cell Acute Lymphoblastic Leukemia.
In this October 2017 paper in Cancer Discovery, a research team led by David Langenau that included Marina Theodorou (pictured) identified thymocyte selection-associated high mobility box protein (TOX) protein as a major oncogenic driver responsible for transforming normal T cells into aggressive leukemia. TOX is also required for leukemia cell growth and thus represents a new, previously unexplored therapeutic target in this disease. Importantly, the authors found that TOX is expressed in 95% of human T cell acute lymphoblastic leukemia suggesting TOX is a major oncogenic driver in a vast majority of patients with this disease. Using a wide array of functional analyses, TOX was found to bind directly to Ku70/80 and to suppress recruitment of this complex to DNA breaks, thus inhibiting non-homologous end joining repair, which is known to cause genomic instability. Collectively, this work has uncovered important roles for TOX in regulating elevating genomic instability during leukemia initiation and sustaining leukemic cell proliferation following transformation.
A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer.
Breast cancer cells with defects in two genes involved in homologous recombination, BRCA1 and BRCA2, have a specific pattern of mutations in their genomes. This pattern, known as Signature 3, is also found in some patients without mutations in BRCA1/2. In the August 21st issue of Nature Genetics, an international team led by Paz Polak and Jaegil Kim from the Mass General Cancer Center and Broad Institute group of Gad Getz (pictured) found that Signature 3 is also associated with epigenetic silencing of BRCA1 and RAD51C, and with mutations in PALB2 but not in other DNA repair genes. Epigenetic silencing was the most common alteration in African-American patients with Signature 3 whereas protein altering BRCA1/2 mutations were most common among whites. These findings help to explain a puzzling observation in breast cancer genetics and could inform future treatment decisions.
Recurrent and functional regulatory mutations in breast cancer.
Previous genomic analyses of many tumors have discovered hundreds of cancer genes with mutations in protein-coding regions. By contrast, we do not yet know much about cancer-causing mutations in non-coding regions that regulate important genes. In this June 28 article in Nature, a team of researchers from the MGH Center for Cancer Research and the Broad Institute including first and second authors Esther Rheinbay and Prasanna Parasuraman, co-investigator Andre Bernards and senior author Gad Getz (pictured) describe deep sequencing of 360 primary breast cancers and computational methods to identify significantly mutated promoters. This highly collaborative effort involving several MGH and Broad Institute laboratories found clear signals in the promoters of three genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbors a mutational hotspot in its promoter leading to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that affect protein binding to their promoters and alter expression levels. This study shows that promoter regions harbor recurrent mutations in cancer with functional consequences and that these hotspot mutations occur at similar frequencies as hotspots in coding regions. The authors also find that we have not exhausted these regulatory mutations yet and are likely to find more by analyzing additional patient tumors in the future. These results emphasize that precision cancer therapy should take account of all types of mutations that affect gene function, be they coding or non-coding. Click here for more information.
Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers.
In this March 2017 paper in the Journal of Clinical Investigation a group of authors led by Arimichi Okazaki from the lab of Othon Iliopoulos followed up on their previous observations that elevated HIF expression upon loss of the VHL tumor suppressor makes cancer cells dependent on glutamine for synthesis of nucleotides, fatty acids and the detoxification of reactive oxygen species (Metallo CM et al., Nature 2011; 481:380-4 and Gameiro PA et al., Cell Metabolism 2013; 17:372-385). These findings are the basis of an ongoing Phase1/2 clinical trial of the glutaminase 1 (GLS1) inhibitor CB-839 in patients with renal and triple negative breast cancer. In the current paper the authors used metabolic flux analysis and classic tumor biology assays to uncover the mechanism responsible for CB-839-mediated growth suppression of VHL deficient renal cancer cells. Both methodologies highlighted the importance of glutamine for pyrimidine synthesis and DNA replication. Importantly, the fact that cells subjected to GLS1 inhibition showed pronounced DNA replication stress and increased DNA damage suggested that therapeutic synergism might be achieved by combining GLS1 inhibition with inhibition of DNA repair. Indeed, combined inhibition of GLS1 and the DNA repair enzyme PARP caused enhanced DNA replication stress and growth arrest of VHL deficient renal cancer cells. The authors conclude that patients with renal and other HIF-expressing cancers might benefit from treatment with this novel combination of GLS1 and PARP inhibitors and that targeting cancer cell metabolism may lead to novel approaches to treat specific cancers.
Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq.
In this March 31 2017 article in Science, a group of investigators from Massachusetts General Hospital and the Broad Institute reports the largest effort to-date in charting brain tumors with single-cell genomic technologies. Analysis of two brain tumor subtypes (IDH-mutant oligodendroglioma and IDH-mutant astrocytoma) has revealed unexpected similarities and differences between these two entities. The authors first compared existing datasets from The Cancer Genome Atlas analyzing 165 bulk RNA-sequencing samples of IDH-mutant oligodendroglioma and IDH-mutant astrocytoma and identified hundreds of genes that are differentially expressed between these two tumor types. As bulk RNA data combines together influences of cancer cell genetics, cancer cell lineages and the tumor micro-environment (TME), the authors generated 14,226 single-cell RNA-seq profiles from 16 patient samples and were able to dissect these differences more precisely. They find that these two entities share similar developmental hierarchies of cancer cells and are both driven by subpopulations of cancer cells with neural stem cell-like programs; they observe that for both tumors, cancer cell differentiation is negatively-correlated with proliferation. While these tumors share similar developmental programs, they differ by genetics and by the composition of the TME. These studies suggest that differentiation therapies could halt tumor growth in IDH-mutant gliomas. The work was led by the team of Mario Suvà (depicted) at MGH and Aviv Regev at the Broad Institute and at MIT. First authors are Andrew Venteicher and Itay Tirosh (depicted). Christine Hebert (depicted), a technician is Suvà’s lab provided tremendous contribution to the work. Click HERE for more information.
ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor resistant BRCA-deficient cancer cells.
PARP inhibition selectively kills BRCA1/2-deficient cells, but the efficacy of this therapeutic approach is limited by the onset of drug resistance. In this February 2017 paper in Genes & Development, a group of authors led by Stephanie Yazinski from Lee Zou’s lab (pictured) analyzed how BRCA1 deficient cells develop resistance to PARP inhibition. The paper shows that PARP inhibitor resistance involves the ATR-dependent bypassing of two BRCA1 functions, namely Rad51 loading required for homologous recombination and replication fork protection after fork stalling. Thus, ATR inhibition may overcome PARP inhibitor resistance and offer a therapeutic approach in BRCA-deficient breast and ovarian cancers. Click HERE for more information.
Functions of Replication Protein A as a Sensor of R Loops and a Regulator of RNaseH1.
In this February 2017 paper in Molecular Cell, co-first authors Hai Dang Nguyen and Tribhuwan Yadav from Lee Zou’s lab (pictured) report a novel function for Replication Protein A (RPA) as a sensor of R loops, a RNA:DNA hybrid transcription intermediate that is a major source of genomic instability. Moreover, RPA interacts and stimulates the activity of RNaseH1, which plays an important role in R loop suppression. Thus, in addition to its well known roles in sensing DNA damage and replication stress, this paper extends the functions of the versatile RPA protein to the suppression of genome instability. Click HERE for more information.
In this January 2017 paper in Cancer Cell, a group of researchers led by first author Vinod Saladi from Leif Ellisen’s lab (pictured) show that the SWI/SNF chromatin remodeling subunit gene ACTL6A is frequently amplified and highly expressed together with TP63 in head and neck squamous cell carcinoma (HNSCC). ACTL6A and p63 interact and coordinately regulate key genes to control oncogenic YAP activity and patient outcomes in HNSCC. Taken together, the findings define ACLT6A as a potent oncogene and mediator of aggressive tumor behavior in HNSCC. Click HERE for more information.
2018 Research Highlights
- Vangl2/RhoA Signaling Pathway Regulates Stem Cell Self-Renewal Programs and Growth in Rhabdomyosarcoma
- hichipper: a preprocessing pipeline for calling DNA loops from HiChIP data
- Molecular signatures of circulating melanoma cells for monitoring early response to immune checkpoint therapy
- Expressed Gene Fusions as Frequent Drivers of Poor Outcomes in Hormone Receptor-Positive Breast Cancer
- An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality
- SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors
- A mitosis-specific and R loop-driven ATR pathway promotes faithful chromosome segregation
- Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to Chromatin Signaling
- An RNA-based digital circulating tumor cell signature is predictive of drug response and early dissemination in prostate cancer
- Engineered nano-interfaces for microfluidic isolation and molecular profiling of tumor-specific extracellular vesicles
2017 Research Highlights
- Whole blood stabilization for the microfluidic isolation and molecular characterization of circulating tumor cells
- Inducible and multiplex gene regulation using CRISPR-Cpf1-based transcription factors
- Resistance to checkpoint blockade therapy through inactivation of antigen presentation
- AKT1low quiescent cancer cells promote solid tumor growth
- TOX regulates growth, DNA repair, and genomic instability in T-cell Acute Lymphoblastic Leukemia
- Detection of dysregulated protein-association networks by high-throughput proteomics predicts cancer vulnerabilities
- Analysis of somatic microsatellite indels identifies driver events in human tumors
- Dissecting hematopoietic and renal cell heterogeneity in adult zebrafish at single-cell resolution using RNA sequencing
- Cancer-Specific Retargeting of BAF Complexes by a Prion-like Domain
- A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer
- A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma
- Recurrent and functional regulatory mutations in breast cancer
- Negative regulation of EGFR signalling by the human folliculin tumour suppressor protein
- The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival
- APOBEC3A and 3B activities render cancer cells susceptible to ATR inhibition
- Prolonged Mek1/2 suppression impairs the developmental potential of embryonic stem cells
- The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma
- Microfluidic Isolation of Circulating Tumor Cell Clusters by Size and Asymmetry
- Phf8 loss confers resistance to depression-like and anxiety-like behaviors in mice
- CIRCLE-seq: a highly sensitive in vitro screen for genome-wide CRISPR-Cas9 nuclease off-targets
- Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors
- Cisplatin Analogs Confer Protection against Cyanide Poisoning
- DUSP9 Modulates DNA Hypomethylation in Female Mouse Pluripotent Stem Cells
- Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq
- Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers
- Identification of Glycopeptides as Posttranslationally Modified Neoantigens in Leukemia
- Functions of Replication Protein A as a Sensor of R Loops and a Regulator of RNaseH1
- ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells
- OTX2 Activity at Distal Regulatory Elements Shapes the Chromatin Landscape of Group 3 Medulloblastoma
- Expression of β-globin by cancer cells promotes cell survival during blood-borne dissemination
- An RNA-based signature enables high specificity detection of circulating tumor cells in hepatocellular carcinoma
- Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma
- ACTL6A Is Co-Amplified with p63 in Squamous Cell Carcinoma to Drive YAP Activation, Regenerative Proliferation, and Poor Prognosis
- Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance
- FXR1a-associated microRNP: A driver of specialized non-canonical translation in quiescent conditions
2016 Research Highlights
- HER2 expression identifies dynamic functional states within circulating breast cancer cells
- Sox2 Suppresses Gastric Tumorigenesis in Mice
- Erasure of DNA methylation, genomic imprints, and epimutations in a primordial germ-cell model derived from mouse pluripotent stem cells
- Accelerated Loss of TCR Repertoire Diversity in Common Variable Immunodeficiency
- σ1 receptor ligands control a switch between passive and active threat responses
- Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma
- Inhibition of Histone Deacetylase 6 Reveals a Potent Immunosuppressant Effect in Models of Transplantation
- Single-molecule decoding of combinatorially modified nucleosomes
- Gad Getz appointed to Blue Ribbon Panel that will help guide Vice President Biden’s National Cancer Moonshot Initiative
- A Serial shRNA Screen for Roadblocks to Reprogramming Identifies the Protein Modifier SUMO2
- An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma
- Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition
- Imaging tumour cell heterogeneity following cell transplantation into optically clear immune-deficient zebrafish