Cancer evading the Immune System, covered in the New York Times

Cancer’s Trick for Dodging the Immune System

Matt Richtel, The New York Times

Cancer immunotherapy drugs, which spur the body’s own immune system to attack tumors, hold great promise but still fail many patients. New research may help explain why some cancers elude the new class of therapies, and offer some clues to a solution.

The study, published on Thursday in the journal Cell, focuses on colorectal and prostate cancer. These are among the cancers that seem largely impervious to a key mechanism of immunotherapy drugs.

The drugs block a signal that tumors send to stymie the immune system. That signal gets sent via a particular molecule that is found on the surface of some tumor cells.

The trouble is that the molecule, called PD-L1, does not appear on the surface of all tumors, and in those cases, the drugs have trouble interfering with the signal sent by the cancer.

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Long non-coding RNA triggers Cancer Resistance

Long non-coding RNA GBCDRlnc1 induces chemoresistance of gallbladder cancer cells by activating autophagy

Qiang Cai, Shouhua Wang, Longyang Jin, Mingzhe Weng, Di Zhou, Jiandong Wang, Zhaohui Tang and Zhiwei Quan

Molecular Cancer (Research Article)

Background

Gallbladder cancer is the most common biliary tract malignancy and not sensitive to chemotherapy. Autophagy is an important factor prolonging the survival of cancer cells under chemotherapeutic stress. We aimed to investigate the role of long non-coding RNAs (lncRNAs) in autophagy and chemoresistance of gallbladder cancer cells.

Methods

We established doxorubicin (Dox)-resistant gallbladder cancer cells and used microarray analysis to compare the expression profiles of lncRNAs in Dox-resistant gallbladder cancer cells and their parental cells. Knockdown or exogenous expression of lncRNA combined with in vitro and in vivo assays were performed to prove the functional significance of lncRNA. The effects of lncRNA on autophagy were assessed by stubRFP-sensGFP-LC3 and western blot. We used RNA pull-down and mass spectrometry analysis to identify the target proteins of lncRNA.

Results

The drug-resistant property of gallbladder cancer cells is related to their enhanced autophagic activity. And we found a lncRNA ENST00000425894 termed gallbladder cancer drug resistance-associated lncRNA1 (GBCDRlnc1) that serves as a critical regulator in gallbladder cancer chemoresistance. Furthermore, we discovered that GBCDRlnc1 is upregulated in gallbladder cancer tissues. Knockdown of GBCDRlnc1, via inhibiting autophagy at initial stage, enhanced the sensitivity of Dox-resistant gallbladder cancer cells to Dox in vitro and in vivo. Mechanically, we identified that GBCDRlnc1 interacts with phosphoglycerate kinase 1 and inhibits its ubiquitination in Dox-resistant gallbladder cancer cells, which leads to the down-regulation of autophagy initiator ATG5-ATG12 conjugate.

Conclusions

Our findings established that the chemoresistant driver GBCDRlnc1 might be a candidate therapeutic target for the treatment of advanced gallbladder cancer.

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Gene Regulatory Networks for Key Nutrient Responses Revealed

Scientists Develop Methods to Validate Gene Regulation Networks

A team of biologists and computer scientists has mapped out a network of interactions for how plant genes coordinate their response to nitrogen, a crucial nutrient and the main component of fertilizer.

Findings Reveal How Plants Respond to Key Nutrient in Fertilizer

A team of biologists and computer scientists has mapped out a network of interactions for how plant genes coordinate their response to nitrogen, a crucial nutrient and the main component of fertilizer. The work, published in the journal Nature Communications, offers a potential framework and more efficient methods that can be used to investigate a wide-range of vital pathways in any organism.

“The sequencing of whole genomes has transformed life sciences, leading to breakthroughs in medicine, agriculture, and basic research,” explains Matthew Brooks, an NIH-postdoctoral fellow in New York University’s Department of Biology and the paper’s lead author. “The challenge now is to determine how the genes that are encoded by an organism are regulated and work together in networks that allow plants and animals to respond to their environment.”

The scientists, working in NYU’s Center for Genomics and Systems Biology, focused on gene regulatory networks, which consist of transcription factors and the target genes that they regulate. These gene regulatory networks enable organisms to adapt to fluctuating surroundings.

Use It and Never Loose It: Embryonic Enhancers Remain Available

Cells recall the way they were

Jessica Lau, HSCRB Communications

When cells grow up, they remember their childhoods.

A new study has found that adult cells keep a record of which genes were activated during their early development. Even more surprisingly, the memory is retrievable: Under certain lab conditions, cells can play the story of their development in reverse, switching on genes that were active before. The study, by researchers at the Dana-Farber Cancer Institute (DFCI), Brigham and Women’s Hospital, Harvard Medical School, and the Harvard Stem Cell Institute, was published in Molecular Cell.

“We discovered that adult cells maintain a catalog of all of the genes used early in development — a record when organs and tissues are formed within the embryo,” said senior author Ramesh Shivdasani, professor of medicine at Harvard Medical School and DFCI, and faculty member of the Harvard Stem Cell Institute.

“Beyond the sheer existence of this archive, we were surprised to find that it doesn’t remain permanently locked away but can be accessed by cells under certain conditions,” he said. “This discovery has potentially profound implications for how we think about cells’ capabilities, and for the future treatment of degenerative and other diseases.”

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"Elite" stem cells help dominate the reprogramming niche

Not all stem cells are created equal

Researchers have discovered a population of cells – dubbed to be “elite” – that play a key role in the process of transforming differentiated cells into stem cells. The finding has important implications for regenerative medicine.

Stem cells have the ability to transform into specialized cells – from lung to brain. Stem cells are common in embryos, but within the last 15 years, a technique called cell reprogramming has enabled scientists to turn mature cells back into so-called pluripotent stem cells, with the power to develop into any cell type.

While reprogramming is well understood, less is known about the intricacies of how individual reprogramming cells behave in a population setting. Researchers found a group of cells that appear to have a competitive advantage in reprogramming. The research is published in Science.

The team used cells extracted from mouse skin, known as mouse embryonic fibroblasts (MEFs). They used DNA-barcoding technologies to give each MEF a unique tag, track individual cells during reprogramming and associate them with their parent population. They also used computational modelling to help understand the complex data generated and to make predictions that were tested in the lab.

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Selective Serotonin reuptake of by Chromatin

Mood-Altering Messenger Goes Nuclear

Francis Collins, NIH Director's Blog

Serotonin is best known for its role as a chemical messenger in the brain, helping to regulate mood, appetite, sleep, and many other functions. It exerts these influences by binding to its receptor on the surface of neural cells. But startling new work suggests the impact of serotonin does not end there: the molecule also can enter a cell’s nucleus and directly switch on genes.

While much more study is needed, this is a potentially groundbreaking discovery. Not only could it have implications for managing depression and other mood disorders, it may also open new avenues for treating substance abuse and neurodegenerative diseases.

To understand how serotonin contributes to switching genes on and off, a lesson on epigenetics is helpful. Keep in mind that the DNA instruction book of all cells is essentially the same, yet the chapters of the book are read in very different ways by cells in different parts of the body. Epigenetics refers to chemical marks on DNA itself or on the protein “spools” called histones that package DNA. These marks influence the activity of genes in a particular cell without changing the underlying DNA sequence, switching them on and off or acting as “volume knobs” to turn the activity of particular genes up or down.

The marks include various chemical groups—including acetyl, phosphate, or methyl—which are added at precise locations to those spool-like proteins called histones. The addition of such groups alters the accessibility of the DNA for copying into messenger RNA and producing needed proteins.

In the study reported in Nature, researchers led by Ian Maze and postdoctoral researcher Lorna Farrelly, Icahn School of Medicine at Mount Sinai, New York, followed a hunch that serotonin molecules might also get added to histones [1]. There had been hints that it might be possible. For instance, earlier evidence suggested that inside cells, serotonin could enter the nucleus. There also was evidence that serotonin could attach to proteins outside the nucleus in a process called serotonylation.

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Birds illustrate how genomics can make things harder, even if it makes things better

What’s in a Name? How Genome Mapping Can Make It Harder to Tell Species Apart

Rebecca Heisman, Living Bird

If you had opened a copy of the Sibley Guide to Birds when it was first published in the year 2000 and flipped to the section on wood-warblers, you would have found 13 pages devoted to members of a single genus: Dendroica, Latin for tree-dweller. Dendroica’s inhabitants included 21 colorful species—such as Magnolia, Blackburnian, and Cerulean Warblers—dear to the hearts of many birders.

Open a copy of the second edition of the Sibley Guide today, and Dendroica is nowhere to be found.

There hasn’t been a mass extinction in the intervening years. The wood-warbler species are all still there, but filed under a different genus name, Setophaga. Instead, there has been a major shift in how ornithologists sort and classify bird species, and the genus name Dendroica was a casualty.

Decisions about how North American bird species are classified and what is and is not considered a species are made every summer by a special committee of the American Ornithological Society. An AOS committee bases its judgments on the best available science. But the science is rapidly expanding. Like many other branches of biology, ornithologists are trying to make sense of a flood of new information flowing from the latest advances in genome mapping. Today, avian geneticists can dive deep into genomes to unveil the molecular differences underlying variation between birds.

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Nat-Geo addresses the idea of a gene

The Gene: Science's Most Powerful—and Dangerous—Idea

SIMON WORRALL, National Geographic

The gene is “one of the most powerful and dangerous ideas in the history of science,” argues Siddhartha Mukherjee in The Gene: An Intimate History . Since its discovery by Gregor Mendel, an obscure Moravian monk, the gene has been both a force for good and ill. In the 1930s, the Nazis exploited the pseudoscience of eugenics as a prelude to the Holocaust. Today, gene therapy holds out the hope of eradicating hereditary conditions like Huntington’s disease and even psychological disturbances, such as schizophrenia. [See how the DNA revolution is giving us unprecedented power.]

National Geographic caught up with the author as he was driving across the Williamsburg Bridge in New York City. Mukherjee, a professor of medicine at Columbia University who also wrote the Pulitzer Prize-winning The Emperor of All Maladies about cancer, explained why the book has deep personal roots, how the United States eagerly adopted the pseudoscience of eugenics, and why allowing individuals to make decisions about altering the genetic makeup of their children may be a dangerous thing to do.

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CliffNotes genome another Synthetic Lifeform

First computer-generated genome could lead to custom synthetic lifeforms

Scientists at ETH Zurich have created the first fully computer-generated genome of a living organism. The brand new genome, named Caulobacter ethensis-2.0, was built by essentially cleaning up and simplifying the natural code of a bacterium called Caulobacter crescentus. For now it exists as one large DNA molecule and not a living organism itself, but the team says this is a huge step towards creating completely synthetic life and medicinal DNA molecules.

Over a decade ago, a team led by geneticist Craig Venter created the first "synthetic" bacterium, which was basically a digital copy of the Mycoplasma mycoides genome. That was then implanted into recipient cells and found to be a viable version of the real creature, even being able to self-replicate.

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Gene-Edited Anolis Lizards

UGA scientists create world’s first gene-edited lizards

A group of University of Georgia researchers led by geneticist Douglas Menke has become the first in the world to successfully produce a genetically modified reptile—specifically, four albino lizards—using the CRISPR-Cas9 gene-editing tool. The team’s results, which appeared online March 31, have been submitted for peer review.

“Reptiles are very understudied in terms of their reproductive biology and embryonic development,” said Menke, associate professor in the department of genetics. “There are no good methods to manipulate embryos like we can easily do with mammals, fish or amphibians. To our knowledge, no other lab in the world has produced a genetically altered reptile.”

Gene manipulation using CRISPR typically involves injecting gene-editing solutions into an animal’s newly fertilized egg or single-cell embryo, causing a mutation in the DNA that is reproduced in all subsequent cells. However female reptiles can store sperm in their oviducts for long periods, making it difficult to pinpoint the exact moment of fertilization. Also, the physiology of their fertilized eggs, which have pliable shells with no air space inside, presents challenges for manipulating embryos without damaging them.

Working with the species Anolis sagrei, commonly called the brown anole, Menke’s team overcame these challenges by microinjecting CRISPR proteins into multiple immature eggs, or oocytes, still located in the lizards’ ovaries. Targeting the tyrosinase gene, they successfully injected 146 oocytes from 21 lizards, then waited for the oocytes to be fertilized naturally. Within a few weeks, they realized their goal: four offspring displaying the telltale trait of albinism, which results when tyrosinase is inactivated.

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New Genome Assembler Makes Progress on Fundamental Problem

Assembly of long, error-prone reads using repeat graphs

Mikhail Kolmogorov, Jeffrey Yuan, Yu Lin & Pavel A. Pevzner

Nature Biotechnology (Research Article)

Abstract—Accurate genome assembly is hampered by repetitive regions. Although long single molecule sequencing reads are better able to resolve genomic repeats than short-read data, most long-read assembly algorithms do not provide the repeat characterization necessary for producing optimal assemblies. Here, we present Flye, a long-read assembly algorithm that generates arbitrary paths in an unknown repeat graph, called disjointigs, and constructs an accurate repeat graph from these error-riddled disjointigs. We benchmark Flye against five state-of-the-art assemblers and show that it generates better or comparable assemblies, while being an order of magnitude faster. Flye nearly doubled the contiguity of the human genome assembly (as measured by the NGA50 assembly quality metric) compared with existing assemblers

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Small transposable elements can have big effects on genome size

Genome Size Evolution: Small Transposons with Large Consequences

Alexander Suh

Current Biology (Dispatch)

"Transposable elements (TEs) heavily influence genome size variation between organisms. A new study on larvacean tunicates now shows that even non-autonomous TEs — small TEs that parasitize the enzymatic machinery of large, autonomous TEs — can have a large impact on genome size.”

Highlights

•Genome size varies up to 12× in larvaceans, chordates with a distinctive anatomy

•Small and large species have the smallest and largest genomes, respectively

•Transposable elements have driven multiple independent genome expansions

•Genomes mainly increased through accumulations of non-autonomous elements (SINEs)

Summary—In eukaryotes, genome size correlates little with the number of coding genes or the level of organismal complexity (C-value paradox). The underlying causes of variations in genome size, whether adaptive or neutral, remain unclear, although several biological traits often covary with it . Rapid increases in genome size occur mainly through whole-genome duplications or bursts in the activity of transposable elements (TEs). The very small and compact genome of Oikopleura dioica, a tunicate of the larvacean class, lacks elements of most ancient families of animal retrotransposons . Here, we sequenced the genomes of six other larvaceans, all of which are larger than that of Oikopleura (up to 12 times) and which increase in size with greater body length. Although no evidence was found for whole-genome duplications within the group of species, the global amount of TEs strongly correlated with genome size. Compared to other metazoans, however, the TE diversity was reduced in all species, as observed previously in O. dioica, suggesting a common ancestor with a compacted genome. Strikingly, non-autonomous elements, particularly short interspersed nuclear elements (SINEs), massively contributed to genome size variation through species-specific independent amplifications, ranging from 3% in the smallest genome up to 49% in the largest. Variations in SINE abundance explain as much as 83% of interspecific genome size variation. These data support an indirect influence of autonomous TEs on genome size via their ability to mobilize non-autonomous element

READ HERE… for a summary and here for the original article.

Classic sex chromosome evolution

Sex chromosome evolution of Wallace's birds-of-paradise

Qi Zhou

Ecology & Evolution

“Two groups of birds, Darwin’s finches and Birds-of-Paradise are historically and respectively associated with the discoverers of the rules of natural selection:Charles Darwin and Alfred Wallace. These two groups of species are also among the best demonstration of natural selection and sexual selection. We reconstructed the history of sex chromosome evolution of bird-of-paradise, and also other songbirds in this work.”

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Tasmanian devils adapting to transmissible cancers

Tasmanian devils 'adapting to coexist with cancer'

There's fresh hope for the survival of endangered Tasmanian devils after large numbers were killed off by facial tumours.

The world's largest carnivorous marsupials have been battling Devil Facial Tumour Disease (DFTD) for over 20 years.

But researchers have found the animals' immune system to be modifying to combat the assault.

And according to an international team of scientists from Australia, UK, US and France, the future for the devils is now looking brighter.

"In the past, we were managing devil populations to avoid extinction. Now, we are progressively moving to an adaptive management strategy, enhancing those selective adaptations for the evolution of devil/DFTD coexistence," explains Dr Rodrigo Hamede, from the University of Tasmania.

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Snake venom genomics provides important insights

New insights into chromosome evolution, venom regulation in snakes

How do snake genomes direct the production of deadly venom toxins and other key extreme features of snakes?

Snake genomes encode the secrets to their unique and often extreme adaptations, but genome resources for snakes and other reptiles have lagged behind their mammal and bird counterparts.

In a new paper, a team of biologists led by Todd Castoe, associate professor of biology at The University of Texas at Arlington, addressed these questions by generating and analyzing the first most complete chromosome-level genome for a snake – the prairie rattlesnake (Crotalus viridis). Their work, “The origins and evolution of chromosomes, dosage compensation, and mechanisms underlying venom regulation in snakes,” is published in the April issue of Genome Research, the scientific journal published by Cold Spring Harbor Laboratory.

Clinical application of tumor evolution analysis

Translating insights into tumor evolution to clinical practice: promises and challenges

Matthew W. Fittall and Peter Van Loo

Genome Medicine (Review Article)

Abstract—Accelerating technological advances have allowed the widespread genomic profiling of tumors. As yet, however, the vast catalogues of mutations that have been identified have made only a modest impact on clinical medicine. Massively parallel sequencing has informed our understanding of the genetic evolution and heterogeneity of cancers, allowing us to place these mutational catalogues into a meaningful context. Here, we review the methods used to measure tumor evolution and heterogeneity, and the potential and challenges for translating the insights gained to achieve clinical impact for cancer therapy, monitoring, early detection, risk stratification, and prevention. We discuss how tumor evolution can guide cancer therapy by targeting clonal and subclonal mutations both individually and in combination…

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CRISPR cut slows aging

Recently Developed Gene Therapy Assists To Slow Down Aging Process

Aging is a key risk factor for numerous debilitating conditions. It includes cancer, heart disease, and Alzheimer’s disease. This situation triggers the anti-aging treatments all the more critical. Recently, the researchers at Salk Institute proclaimed that they have developed a novel gene therapy to assist decelerate this aging process.

The findings of this research can be accessed in the journal Nature Medicine. The study highlights a new CRISPR/Cas9 genome-editing therapy. It holds an ability to curb the accelerated aging observed in mice suffering from Hutchinson-Gilford progeria syndrome. This is an uncommon genetic disorder that is found to be afflicting humans as well. The latest treatment offers key insight into the molecular pathways engaged in accelerated aging. It also highlights how to minimize toxic proteins using gene therapy. Juan Carlos Izpisua Belmonte, Professor, Gene Expression Laboratory, Salk, is the senior author of this study. He proclaimed that aging is a complicated process in which cells begin losing their functionality.

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Or read the original article HERE …

RNA-based method for killing cancer cells

Scientists may have found a way to kill cancer cells without chemotherapy

• Researchers at Northwestern have discovered a genetic "kill code" that might enable the destruction of cancer cells.

• This novel new therapy "downstream" of chemo might destroy cancer cells without affecting the body's immune system.

• While no animal trials have been conducted, this potential therapy could signal the demise of chemotherapy.

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Cockroaches thrive with extra-large genomes

American cockroaches thrive in cities, thanks to their incredibly long genomes

“Few insects have a reputation for grossing people out as thoroughly as the American cockroach. The so-called water bugs, which thrive indoors on fermenting and rotting foods, are rich sources of disease-causing bacteria. Now, researchers have sequenced their genome for the first time—and have uncovered some of the secrets to their uncanny ability to survive in our urban jungles.

Compared with other insects, the genome of the American cockroach (Periplaneta americana) is the second largest sequenced to date after the locust. Like the locust, much of the cockroach genome, some 60%, is made of repetitive elements—sequences of DNA that occur over and over. And compared with three other species in its family—the German cockroach and two termite species—it is actually more closely related to the termites.“

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6mer seed toxicity in tumor suppressive microRNAs

6mer seed toxicity in tumor suppressive microRNAs

Quan Q. Gao, William E. Putzbach, Andrea E. Murmann, Siquan Chen, Aishe A. Sarshad, Johannes M. Peter, Elizabeth T. Bartom, Markus Hafner, & Marcus E. Peter

Nature Communications (Research Article)

Abstract—Many small-interfering (si)RNAs are toxic to cancer cells through a 6mer seed sequence (positions 2–7 of the guide strand). Here we performed an siRNA screen with all 4096 6mer seeds revealing a preference for guanine in positions 1 and 2 and a high overall G or C content in the seed of the most toxic siRNAs for four tested human and mouse cell lines. Toxicity of these siRNAs stems from targeting survival genes with C-rich 3′UTRs. The master tumor suppressor miRNA miR-34a-5p is toxic through such a G-rich 6mer seed and is upregulated in cells subjected to genotoxic stress. An analysis of all mature miRNAs suggests that during evolution most miRNAs evolved to avoid guanine at the 5′ end of the 6mer seed sequence of the guide strand. In contrast, for certain tumor-suppressive miRNAs the guide strand contains a G-rich toxic 6mer seed, presumably to eliminate cancer cells.

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