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Center for Cancer Research
View the latest research highlights and featured publications from the Center for Cancer Research.
The unique strengths of the Center for Cancer Research (CCR) are the exceptional quality of its faculty and the ways in which the CCR's basic scientists collaborate with Mass General’s leading oncologists, surgeons, radiologists, pathologists, and other health care professionals to advance the frontiers of cancer medicine.
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.
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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.
(Lab picture from left to right: Evmorphia Konstantakou, Danos Christodoulou, Katia Dinkelborg and Othon Iliopoulos. Insert: Arimichi Okazaki, the lead author of the paper.)
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.
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