The Pan-Cancer Atlas: “The End of the Beginning”

Yesterday, a series of 27 papers representing the most comprehensive genomic analysis of human cancers to date was published in Cell Press journals.

The collection constitutes the final outputs from the Cancer Genome Atlas (TCGA) project, a collaboration between the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) involving analysis of over 11,000 tumors representing 33 different cancers. The many research teams involved analyzed tumor DNA, mRNA, miRNA and chromatin, comparing them to matched normal cellular genomes to perform a complete molecular characterization of cancer-specific changes. The results have been presented with much hope that open access to this type of comprehensive analysis will build on recent advances in understanding tumor biology and spur further progress in developing new approaches to treatment. (See this news item for more detail).

The Pan-Cancer Atlas results are collected on a cell.com portal, where they are presented in three collections grouped by topic: Cell of Origin, Oncogenic Processes and Signaling Pathways. Each collection is accompanied by a “Flagship” paper introducing the topic and summarizing the findings. It seems fitting that these findings have been published in #HumanGenomeMonth. This comprehensive analysis of the genomic and metagenomic profiles of tumors illustrates one powerful application of the type of genomic analysis pioneered by the original Human Genome Project, and shows just how much has been made possible since the initial publication of the human genome fifteen years ago. Continue reading

Magnetic Bacteria Carry Drugs into Tumors

cancer cellAt first glance, the biology of magnetic, underwater-dwelling, oxygen-averse bacteria may seem of little relevance to our most pressing human health problems. But science is full of surprises. A paper published this week in Nature Nanotechnology presents an inspired use of these bacteria to deliver anti-cancer drugs to tumors, specifically targeting the oxygen-starved regions generated by aggressively proliferating cells. Continue reading

microRNA: The Small Molecule with a Big Story

Introduction

miR-34 precursor secondary structure. The colors indicate evolutionary conservation. Ppgardne [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

RNA molecules have become a hot topic of research. While I was taught about messenger RNA (mRNA), ribosomal RNA (rRNA) and transfer RNA (tRNA), many more varieties have come into the nomenclature after I graduated with my science degrees. Even more interesting, these RNAs do not code for a protein, but instead have a role in regulating gene expression. From long non-coding RNA (lncRNA) to short interfering RNA (siRNA), microRNA (miRNA) and small nucleolar RNA (snoRNA), these classes of RNAs affect protein translation, whether by hindering ribosomal binding, targeting mRNA for degradation or even modifying DNA (e.g., methylation). This post will cover the topic of microRNAs, explaining what they are, how researchers understand their function and role in metabolism, cancer and cardiovascular disease, and some of the challenges in miRNA research.

What are microRNAs? MicroRNAs (miRNAs) are short noncoding RNAs 19–25 nucleotides long that play a role in protein expression by regulating translation initiation and degrading mRNA. miRNAs are coded as genes in DNA and transcribed by RNA polymerase as a primary transcript (pri-miRNA) that is hundreds or thousands of nucleotides long. After processing with a double-stranded RNA-specific nuclease, a 70–100 nucleotide hairpin RNA precursor (pre-miRNA) is generated and transported from the nucleus into the cytoplasm. Once in the cytoplasm, the pre-miRNA is cleaved into an 18- to 24-nucleotide duplex by ribonuclease III (Dicer). This cleaved duplex associates with the RNA-induced silencing complex (RISC), and one strand of the miRNA duplex remains with RISC to become the mature miRNA. Continue reading

A Day in the Life: Promega France Supports Cancer Research with their Feet…and Hearts

The Promega France Courir Pour Elles team (left to right): Emeline, Florence, Emmanuel, Sylvia, Veronique and Françoise.

The Promega France Courir Pour Elles team (left to right): Emeline, Florence, Emmanuel, Sylvia, Veronique and Françoise.

In the US, Memorial Day weekend is upon us. Three luxurious days to spend doing whatever your heart desires (and/or your family needs).

Promega’s family is international, and for today’s “A Day in the Life” blog, we look at how the Branch office in France, Promega France, spends their free time in support of disease research.

I spoke with a member of the team from Lyon, France, earlier this week about a cancer fundraising event that Promega France participated in, May 21.

The event, Courir Pour Elles (Running for Her) is dedicated to raising awareness of and money to support research into cancers that affect women. Not only did this team participate, but Promega was, for the first time, a sponsor of the event (note the ankle band photo). Continue reading

Unexpected connections: Gut bacteria influence immunotherapy outcomes

Over the last few years, human microbiome studies have revealed fascinating connections between our colonizing microorganisms and ourselves—including associations between gut bacterial populations and obesity, disease susceptibility, and even mood. The relationship between us and our microbial colonists—once considered completely benign, is now being revealed as an intricate, complicated partnership with the potential to redefine who “we” are in fundamental ways.

Two papers published back-to-back in the November 27 issue of Science add further to this growing body of knowledge—reporting a new and unexpected connection between gut bacterial species and the effectiveness of cancer immunotherapies in mice. The work suggests one reason why such treatments are effective in some circumstances, but not others. Both papers report that the presence of specific bacterial populations may be required for the efficacy of certain treatments, and raise the intriguing question “Could the composition of bacteria in the gut be manipulated to enhance the effectiveness of cancer treatments?” Continue reading

Designer Bacteria Detect Cancer

Every day scientists apply creative ideas to solve real-world problems. Every so often a paper comes up that highlights the creativity and elegance of this process in a powerful way. The paper “Programmable probiotics for detection of cancer in urine”, published May 27 in Science Translational Medicine, provides one great example of the application of scientific creativity to develop potential new ways for early detection of cancer.

The paper describes use of an engineered strain of E.coli to detect liver tumors in mice. The authors (Danino et al) developed a potential diagnostic assay that uses a simple oral delivery method and provides a readout from urine, all of which is made possible by some seriously complex and elegant science. Continue reading

Targeting MYC: The Need to Study Protein:Protein Interactions in Cells

Crystal Structure of MYC MAX Heterodimer bound to DNA ImageSource=RCSB PDB; StructureID=1nkp; DOI=http://dx.doi.org/10.2210/pdb1nkp/pdb;

Crystal Structure of MYC MAX Heterodimer bound to DNA ImageSource=RCSB PDB; StructureID=1nkp; DOI=http://dx.doi.org/10.2210/pdb1nkp/pdb;

In 1982, picked up because of its homology to chicken virus genes that could transform cells, MYC became one of the first human genes identified that could drive cellular transformation (1,2). Since that time countless laboratories have prodded and poked the human MYC gene, the MYC protein, their homologs in other animal models, and their transforming viral counterparts.

MYC is a transcription factor and forms heterodimers with a required protein partner, MAX, before binding to the E box sequences of DNA regulatory regions (3). MYC regulates gene expression of many targets through interactions with a host of proteins, often referred to as the MYC Interactome (2).  In fact, MYC is estimated to bind 10–15% of the genome, and it regulates the expression of genes that  are transcribed by by each of the three RNA polymerases (2).

MYC plays a central role in regulating cell growth, proliferation, apoptosis, differentiation and transformation, acting as a central integrator of cellular signals. MYC is tightly regulated at multiple levels from gene expression to protein stability. Dysregulation (usually upregulation) of the amount and stability of Myc protein is observed in many human cancers. Even in cancers in which MYC is not directly involved in transforming cells, its normal expression is often required to support the extracellular matrix and/or vascularization necessary for tumor growth and formation (4).

Because MYC is such a central player cancer pathology, it is an attractive target for cancer therapeutics  (2) . Continue reading

Basic Biology Matters

crop image2Every scientific paper is the story of a journey from an initial hypothesis to a final conclusion. It may take months or years and consists of many steps taken carefully one at a time. The experiments are repeated, the controls verified, the negative and positive results analyzed until the story finally makes sense. Sometimes the end of the story confirms the hypothesis, sometimes it is a surprise. A paper published last week in Cell describes a study where a team of researchers investigating one problem in basic biology (how one component of a signaling complex works), found an unexpected and potentially significant application in a different field (cancer research).

The paper, published in the June 6 issue of Cell, describes a previously unknown interaction between two cellular proteins—the transcription factor HIF1A and the cyclin-dependent kinase CDK8—in the regulation of genes associated with cellular survival under low-oxygen conditions. An accompanying press release describes how the discovery of a role for CDK8 in this process may have implications for cancer research, as CDK8 may be a potential target for drugs to combat “hypoxic” tumors. Continue reading

Dark Matter, Rosetta Stones and Hordes of Beasties

Key regulatory roles are being identified for non-coding DNA sequences, once considered "junk".

The more you know, the more you find out about how much you still don’t know. So goes the old saying. A recent New York Times article nicely illustrated the practical outworking of this phenomenon in the context of cancer research. The article highlighted several recent papers and reviews showing how much progress has been made over the last ten years, and illustrating how the focus has changed to incorporate not only research on protein-coding sequences, but also the “dark matter” of noncoding RNAs and the potential contributions of genes from the millions of bacteria that colonize the human body.

In 2000, a review describing six key traits of cancer cells was published in the journal Cell, it is one of the most cited papers from that journal. In March of this year, the same authors published an update entitled Hallmarks of Cancer: The Next Generation describing current knowledge of the mechanisms underlying the same six traits, and adding two new ones. Continue reading

An Epigenetic Mountain for Ovarian Cancer Research

Fluorescent Stained ovarian carcinoma cells. Note the visible nuclei vimentin, also known as fibroblast intermediate filament, it is the major intermediate filament found in non-muscle cells and is present in over 40% of ovarian cancer cases. Mag: unknown.

It’s tempting to look at a field like cancer research and conclude that all of the big breakthroughs have been made; that what remains are the tiny discoveries that come from throwing the contents of the Sigma chemical catalog at cells and looking for effects, screening for even the most minute “hit” that might show some promise against a tumor. Indeed the “mountains”, single genes that are found to be disrupted in a majority of occurrences of a given cancer type, are becoming rarer and rarer finds. However, in a recent study of ovarian clear cell carcinoma (OCCC), Jones and colleagues report a discovery of such a mountain. Continue reading