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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.
The Center for Cancer Research serves as the engine for discovery for the Mass General Cancer Center. We have more than 40 independent laboratories with faculty drawn from all departments of Harvard Medical School. Our faculty study everything from Cancer cell genetics and epigenetics, metabolism and microenvironments, cell signaling and DNA damage, with studies of cultured cells, all the way to patient derived samples and specimens. Learn about our investigators, look through our news and events, and our current publication highlights.
[Archive of Past Publications]
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.
Activation of ATR inhibits cyclin-dependent kinases (CDKs), but paradoxically also promotes homologous recombination (HR), a CDK-dependent process. In this December 2016 paper, researchers led by first author Remi Buisson from Lee Zou’s lab show that after the CDK-driven DNA end resection, ATR promotes HR by phosphorylating PALB2 and suppressing CDK-mediated PALB2 phosphorylation, directly coupling checkpoint-mediated CDK inhibition to HR.
Survival in quiescence requires the euchromatic deployment of Clr4/SUV39H by Argonaute-associated small RNAs. A leading cause of treatment resistance and cancer recurrence is the occurrence of a subpopulation of cancer cells which exists in a quiescent (G0) state. These cells lay dormant for several years and resist radiation and chemotherapy. In the Dec 15th issue of Molecular Cell, a group of scientists led by first author Richard Joh and senior author Mo Motamedi (pictured) use fission yeast to model quiescence. They show that as cells transition to G0, they accumulate sRNAs from several metabolic and cell cycle gene clusters. These sRNAs guide constitutive heterochromatin protein (Clr4/SUV39H) to these regions to regulate their transcription and establish the global G0 state. This work unifies previous observations about G0 and suggests the existence of a conserved Quiescent-induced Transcriptional Silencing (QuieTS) pathway in eukaryotes. Click HERE for more information.
LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. In this November 2016 paper in Nature, a group of authors led by first author Filippos Kottakis from the lab of Nabeel Bardeesy (pictured) report that a network linking metabolic and epigenetic alterations is central to oncogenic transformation by the LKB1 tumor suppressor. They found that loss of LKB1 enhances the flux of glucose into the serine biosynthetic pathway. This in turn increases the production of S-adenosyl-methionine, the methyl donor for DNA methyltransferases, leading to increased DNA methylation. LKB1-deficient tumor cells are highly sensitive to perturbations in this network, suggesting new therapeutic vulnerabilities in patients carrying inactivating LKB1 mutations. Click HERE for more information.
Genomic Instability Is Induced by Persistent Proliferation of Cells Undergoing Epithelial-to-Mesenchymal Transition. Epithelial to mesenchymal transition (EMT) is a normal developmental process that occurs in the absence of cell proliferation. In this December 2016 paper in Cell Reports, a group of authors led by first author Valentine Comaills and senior author Shyamala Maheswaran (pictured) show that cancer cells continue to proliferate while undergoing EMT. These incompatible processes result in genome instability and heritable genetic changes that increase tumorigenesis. Taken together these observations suggest that EMT might be one of the mechanisms that contributes to genomic heterogeneity and evolution of cancer cells. Click HERE for more information.
Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. In this November 2nd, 2016 letter in Nature, the group of Mario Suva (pictured) at MGH in close collaboration with Aviv Regev’s lab at the Broad Institute analyzed RNA expression profiles of 4,347 single cells from six human oligodendrogliomas. The data show that most cancer cells are differentiated towards two glial subtypes, whereas a rare population is associated with a neural stem cell signature. Importantly, expression signatures associated with proliferation are highly enriched in this rare population of stem cells. This data, as well as analyses of copy number variation and point mutations support a hierarchical model of cancer development in which cancer stem cells are primarily responsible for the growth of this tumor type. The work was led by co-first authors Itay Tirosh and Andrew Venteicher. Click HERE for more information.
SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b. In this Featured Article in the June 2nd issue of Cell, a group of authors led by Sita Kugel from Raul Mostostavsky’s laboratory, identifies SIRT6 as an important new therapeutic target in pancreatic ductal adenocarcinoma. The paper describes how the histone deacetylase SIRT6 acts as a regulator of a Lin28b/let-7 pathway critical for the growth of these tumors. Click HERE and HERE for more information.
Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors. In this April 2016 paper in Nature Genetics, Jaegil Kim, Kent Mouw (not pictured), and Paz Polak from Gad Getz's laboratory identified a unique mutational signature associated with somatic alterations in the ERCC2 core nucleotide-excision repair gene in urothelial tumors. The activity of this signature was also associated with smoking independent of ERCC2 mutation status, providing genomic evidence of tobacco-related mutagenesis in urothelial cancer. Click here for more information.
A Specialized Mechanism of Translation Mediated by FXR1a-Associated MicroRNP in Cellular Quiescence. In this March 2016 paper in Molecular Cell, Syed Bukhari and co-authors, Samuel Truesdell, Sooncheol Lee and Swapna Kollu from Shobha Vasudevan’s laboratory, reveal that microRNAs mediate a novel non-canonical translation initiation mechanism responsible for the translational upregulation of specific deadenylated mRNAs in quiescent human leukemic cells and immature frog oocytes. Because quiescence plays critical roles in early development and contributes to clinical resistance in cancers, the discovery of this mechanism has important implications for understanding developmental processes and tumor resistance.
High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects. In this January 2016 paper in Nature, Benjamin Kleinstiver, Vikram Pattanayak, Michelle Prew and others from Keith Joung’s laboratory describe a modified high-fidelity nuclease that allows CRISPR-Cas9 genome editing without detectable off-target effects. The ability to greatly reduce off-target effects will provide an alternative higher-fidelity Cas9 for genome editing experiments, and brings closer eventual therapeutic applications of the technology.
Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair. In their January 2016 paper in Cell, Nicholas Haradhvala, Paz Polak, Michael Lawrence and others from Gad Getz’s lab report that mutational asymmetries with respect to replication (leading vs. lagging strand) and transcription (transcribed vs. non-transcribed strand) are widespread in cancer. They also show that APOBEC generates mutations on the lagging strand and that an unknown process damages the non-transcribed strand in liver cancer.
Insulator dysfunction and oncogene activation in IDH mutant gliomas. In this January 2016 paper in Nature, William Flavahan and Yotam Drier from Brad Bernstein’s lab, with other MGH and Broad Institute colleagues, report that DNA hypermethylation of IDH mutant gliomas results in insulator dysfunction and inappropriate expression of PDGFRA, a potent glioma oncogene. The authors conclude that IDH mutations promote gliomagenesis by disrupting chromosomal topology and inducing oncogene expression.
Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. In this October 2015 paper in Nature Medicine, Alexandre Wagschal from Anders Näär’s lab, and co-authors from MGH and elsewhere, report that 4 microRNAs located near SNPs associated with altered blood lipid levels regulate key proteins involved in cholesterol-lipoprotein trafficking. Functional studies support that altered microRNA expression contributes to abnormal blood lipid levels and may predispose individuals to cardiometabolic disorders.
Distinct but Concerted Roles of ATR, DNA-PK, and Chk1 in Countering Replication Stress during S Phase. In this September 2015 paper in Molecular Cell, Rémi Buisson and Jessica Boisvert from the labs of Cyril Benes and Lee Zou report that cells in early S-phase undergo mitotic catastrophe when subjected to ATR inhibition (ATRi). This reflects a key role for ATR in coordinating RRM2 accumulation and origin firing. Importantly, the level of ATRi-induced ssDNA can serve as a biomarker predicting the ATRi sensitivity of cancer cells.
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