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Our research was highlighted among the top 10 Notable advances of 2015 by Nature Medicine.
Immuno-oncology: Going viral
DNA methyltransferase inhibitors such as 5-azacitidine have shown efficacy in some hematological cancers, but it is still unclear how they slow tumor progression. New data from two groups point to the immune response as a key mediator of the beneficial effects of 5-azacitidine in a variety of tumor types (Cell 162, 961–973, 2015; Cell 162, 974–986, 2015). Scientists exposed human colorectal and ovarian cancer cell lines to 5-azacitidine, and they found that the drug activated an inflammatory response that is dependent on MDA5, a host defense protein responsible for detecting viral double-stranded RNA (dsRNA). The drug also boosted the expression of endogenous retroviruses.
Knockdown of MDA5 or of its downstream signaling components within either tumor cell lines or primary tumor samples abolished the ability of 5-azacitidine to suppress tumor cell growth and self-renewal in vitro. RNA-seq data from tumor samples from people with melanoma, who had been treated with a therapy known as anti-CTLA4 immune checkpoint blockade, revealed a strong correlation between the abundance of viral defense transcripts and the duration of clinical response, suggesting the relevance of patient response to immunotherapy.

Article cited: Roulois D, Loo Yau H, Singhania R, Wang Y, Danesh A, Shen SY, Han H, Liang G, Jones PA, Pugh TJ, O'Brien C, De Carvalho DD. (2015). DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts. Cell, 2015 27;162(5):961-73. doi:10.1016/j.cell.2015.07.056.

Our 2015 Cell paper was recommended by Faculty of 1000 Post-publication peer review of the biomedical literature:
Below is the recomendation made by Professor Moriya Tsuji , from The Rockefeller University to F1000 Pharmacology & Drug Discovery section:

"In this work, de Carvalho and collaborators have demonstrated a novel mechanism by which a DNA-demethylating agent (5-AZA-CdR) exerts anti-tumor effects. By means of bioinformatics and epigenetic tools, the authors demonstrate that low-dose 5-AZA-CdR in vitro treatment is able to target colorectal cancer-initiating cells (CICs) by inducing the activation of endogenous retroviruses and the innate immune RNA sensors MDA5/MAVS as well as the signaling molecule IRF7. Interestingly, the interferon type III pathway, but not type I, seems to play a role in the anti-tumor effect of low-dose 5-AZA-CdR. Finally, the authors show that 5-AZA-CdR treatment induces an increase in dsRNAs by induction of endogenous retrovirus. This work provides new insight into the treatment of cancer-initiating cells and advocates the better scrutiny of pathways associated with the activation of endogenous retroviruses in order to utilize internal weapons against cancer."

Our 2015 Cell paper was recommended by Faculty of 1000 Post-publication peer review of the biomedical literature:
Below is the recomendation made by Professor Emma Whitelaw , from La Trobe University (Australia) to F1000 Genomics & Genetics section:

"The idea that abnormalities in DNA methylation, called epimutations, can initiate cancers is under debate and the fact that DNA methylation inhibitors, such as 5-aza-2-deoxycytidine (5-AZA-CdR), are clinically effective, has been used to support this hypothesis. 5-AZA-CdR is a cytidine analog that traps DNA methyltransferases, resulting in global DNA demethylation. The action of 5-AZA-CdR, in the context of cancer, has been attributed to promoter demethylation and gene reactivation of aberrantly methylated tumour suppressor genes.

However, the study by Roulois and colleagues suggests otherwise. They show that 5-AZA-CdR targets colorectal cancer-initiating cells (CICs) by "tricking" them into behaving like virus-infected cells. This involves the production of double stranded RNAs (dsRNAs) from endogenous retroviral elements, followed by the activation of the dsRNA recognition pathway. These results change our understanding of the role of DNA-demethylating agents and suggest that monitoring dsRNA levels might be a useful predictor of patient response."

Our research was named one of the top clinical cancer advances for 2012:
The American Society of Clinical Oncology (ASCO) annual report, now in its eighth year, is an independent review of clinical cancer research advances that have the greatest potential to improve patients' survival and quality of life. Compiled and edited under the guidance of 21 renowned experts in specific fields of cancer research, the report describes, in lay language, the most significant advances of the year, offering the public a window into the achievements, trends and challenges in oncology.

Article cited: De Carvalho, D.D., Sharma, S., Soo You, J. Su, S., Taberlay, P.C., Kelly, T.K., Yang, X. Liang, G., & Jones, P.A. (2012). DNA methylation screening identifies driver epigenetic events of cancer cell survival Cancer Cell, 21(5), 1-13. Published online May 14, 2012; doi:10.1016/j.ccr.2012.03.045.

Our 2012 Cancer Cell paper was recommended by Faculty of 1000 Post-publication peer review of the biomedical literature:
Below is the recomendation made by Professor Frank Rosenbauer, from the Medical Faculty Münster to F1000 Genomics & Genetics section:

"Modern genome-wide techniques provide great opportunities to describe cancer methylomes, but identification of critical tumor-initiating epigenetic events still remains a challenging task. This is a pioneer study to discover key methylation changes essential for cancer cell survival.

Cancer is characterized by global genome hypomethylation and regional hypermethylation of the CpG islands in the promoters of tumor suppressor genes. The authors hypothesized that the tumorigenic process might activate death-promoting genes which should be epigenetically silenced to prevent cancer cell elimination. The hypothesis was tested by the clustering of DNA methylation profiles from the colorectal cell line HCT116 and its daughter clones with a genetic disruption of major de novo and maintenance DNA methyltransferases (double knockout, DKO, cell lines). By further comparison of 566 CpG sites resistant to demethylation in DKO cells, with tumor and normal colon methylomes, a set of cancer-specific hypermethylated promoters was identified. Neither chromatin structure, nor gene architecture of these loci could explain their predisposition to DNA methylation, suggesting that these regions might become methylated to promote cancer cell survival. Gene expression analysis showed that the majority of hypermethylated promoters were associated with down-regulated genes in cancer cells. The same genes were found silent by methylation in lung adenocarcinoma, confirming their cancer-related nature. Interestingly, none of the candidate genes were reported as a classical tumor suppressor before. The authors provided a mechanistic explanation for one of them, IRAK3, an indirect inhibitor of anti-apoptotic SURVIVIN gene.

The discovered genes represent potentially good targets for future therapies because of the cancer specificity and epigenetic regulation. Novel targeted treatments should be developed since cancer-specific promoter hypermethylation is resistant to conventional demethylating drugs (5-Aza-2’-deoxycytidine), as reported in the study".

Epigenetics: Dissecting driving DNA methylations
Darren J. Burgess, from Nature Reviews Cancer, has just published a Research Highlight about our 2012 Cancer Cell paper. He highlighted the potential of our method to pinpoint various putative driver gene methylations on which cancer cells may particularly rely and in identify promising candidates for therapeutic re-activation in cancer treatment.

DNA Methylation Addiction Keeps Cancer Cells Alive
Epigenie, has just posted a Research Highlight about our Epigenetic Addiction concept.

Our PNAS paper was recommended by Faculty of 1000 Post-publication peer review of the biomedical literature:
Below is the recomendation made by Professor Stephan Beck, from University College London to F1000 Immunology section:

"Although not a method paper, this article describes an ingenious method (termed NOMe-seq) for simultaneously determining nucleosome occupancy and CpG (cytosine-phosphate-guanine) methylation on the same DNA strand at single-base resolution in a single assay.

The simple but ingenious innovation consists of the addition of a single in vitro enzymatic treatment step of chromatin with a GpC (guanine- phosphate-cytosine) DNA methyltransferase (e.g. M.CviPI) that methylates only nucleosome-free GpCs. Following standard DNA extraction, bisulfite conversion and sequencing, the readout of the methylation status of GpCs then provides a digital footprint of nucleosome occupancy (unmethylated GpCs are occupied and methylated GpCs are nucleosome-free) and that of CpGs a profile of DNA methylation. There is one small limitation though: in the context of non-CpG methylation, endogenous GpC methylation cannot be distinguished from in vitro methylated GpCs by M.CviPI".

Surprising mechanism for the inheritance of DNA methylation patterns found
Our PLoS Genetics paper describing the DNMT3a/3b self-regulatory inheritance mechanism was highlighted by Epigenomics, where the critical role of this mechanism in preserving gene-expression patterns and cellular identity was highlighted.

HOT PAPERS IN BIOLOGY & BIOCHEMISTRY
ISI Web of knowledge, has just released its Essential Science Indicators and named our 2010 Nature Biotechnology review as a hot paper in Biology and Biochemistry.

5-mC Stabilizes High-Maintenance Methyltransferases
Epigenie, has just posted a Research Highlight about our PLoS Genetics paper.

Cura para o câncer está dentro de nós (Portuguese)
The Brazilian popular science Magazine 'Revista Conhecer', has just published an article about the potential of our research in the battle against cancer.

Our research was featured at 'Correio Braziliense' (Portuguese)
The Brazilian major Newspaper 'Correio Brasiliense', has just published a full page article about our research.

Our research was featured at 'Estado de Minas' (Portuguese)
The Brazilian major Newspaper 'Estado de Minas', has just published a full page article about our research.