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Regulators of mesenchymal GBM subtype

An example of tumor oncotecture. Transcription factors involved in the activation of mesenchymal glioblastoma subtype are shown in purple. Together, they comprise a tightly knit tumor checkpoint, controlling 74% of the genes in the mesenchymal signature of high-grade glioma. CEBP (both β and δ subunits) and STAT3 regulate the other three transcription factors in the tumour checkpoint, synergistically regulating the state of mesenchymal GBM cells. (Image: Nature Reviews Cancer)

In a detailed Perspective article published in Nature Reviews Cancer, Department of Systems Biology chair Andrea Califano and research scientist Mariano Alvarez (DarwinHealth) summarize more than a decade of work to propose the existence of a universal, tumor independent “oncotecture” that consistently defines cancer at the molecular level. Their findings, they argue, indicate that identifying and targeting highly conserved, essential proteins called master regulators — instead of the widely diverse genetic and epigenetic alterations that initiate cancer and have been the focus of much cancer research — could offer an effective way to classify and treat disease.

As coverage of the paper in The Economist reports:

ONE of the most important medical insights of recent decades is that cancers are triggered by genetic mutations. Cashing that insight in clinically, to improve treatments, has, however, been hard. A recent study of 2,600 patients at the M.D. Anderson Cancer Centre in Houston, Texas, showed that genetic analysis permitted only 6.4% of those suffering to be paired with a drug aimed specifically at the mutation deemed responsible. The reason is that there are only a few common cancer-triggering mutations, and drugs to deal with them. Other triggering mutations are numerous, but rare—so rare that no treatment is known nor, given the economics of drug discovery, is one likely to be sought. 

Facts such as these have led many cancer biologists to question how useful the gene-led approach to understanding and treating cancer actually is. And some have gone further than mere questioning. One such is Andrea Califano of Columbia University, in New York. He observes that, regardless of the triggering mutation, the pattern of gene expression—and associated protein activity—that sustains a tumour is, for a given type of cancer, almost identical from patient to patient. That insight provides the starting-point for a different approach to looking for targets for drug development. In principle, it should be simpler to interfere with the small number of proteins that direct a cancer cell’s behaviour than with the myriad ways in which that cancer can be triggered in the first place. (Read full article.)

PrePPI inputs
PrePPI predicts the likelihood that two proteins A and B are capable of interacting based on their similarities to other proteins that are known to interact. This requires integrating structural data (green) as well as other kinds of information (blue), such as evidence of protein co-activity in other species as well as involvement in similar cellular functions. PrePPI now offers a searchable database of unprecedented scope, constituting a virtual interactome of all proteins in human cells. (Image courtesy of eLife.) 

The molecular machinery within every living cell includes enormous numbers of components functioning at many different levels. Features like genome sequence, gene expression, proteomic profiles, and chromatin state are all critical in this complex system, but studying a single level is often not enough to explain why cells behave the way they do. For this reason, systems biology strives to integrate different types of data, developing holistic models that more comprehensively describe networks of interactions that give rise to biological traits. 

Although the concept of an interaction network can seem abstract, at its foundation each interaction is a physical event that takes place when two proteins encounter one another, bind, and cause a change that affects a cell’s activity. In order for this to take place, however, they need to have compatible shapes and physical properties. Being able to predict the entire universe of possible pairwise protein-protein interactions could therefore be immensely valuable to systems biology, as it could both offer a framework for interpreting the feasibility of interactions proposed by other methods and potentially reveal unique features of networks that other approaches might miss. 

In a 2012 paper in Nature, scientists in the laboratory of Barry Honig first presented a landmark algorithm and database they call PrePPI (Predicting Protein-Protein Interactions). At the time, PrePPI used a novel computational strategy that deploys concepts from structural biology to predict approximately 300,000 protein-protein interactions, a dramatic increase in the number of available interactions when compared with experimentally generated resources.

Since then, the Honig Lab has been working hard to improve PrePPI’s scope and usefulness. In a paper recently published in eLife they now report on some impressive developments. With enhancements to their algorithm and the incorporation several new types of data into its analysis, the PrePPI database now contains more than 1.35 million predictions of protein-protein interactions, covering about 85% of the entire human proteome. This makes it the largest resource of its kind. In parallel with these improvements, the investigators have also begun to apply PrePPI in new ways, using the information it contains to provide new kinds of insights into the organization and function of protein interaction networks.

Master regulators of tumor homeostasis

In this rendering, master regulators of tumor homeostasis (white) integrate upstream genetic and epigenetic events (yellow) and regulate downstream genes (purple) responsible for implementing cancer programs such as proliferation and migration. CaST aims to develop systematic methods for identifying drugs capable of disrupting master regulator activity.

The Columbia University Department of Systems Biology has been named one of four inaugural centers in the National Cancer Institute’s (NCI) new Cancer Systems Biology Consortium. This five-year grant will support the creation of the Center for Cancer Systems Therapeutics (CaST), a collaborative research center that will investigate the general principles and functional mechanisms that enable malignant tumors to grow, evade treatment, induce disease progression, and develop drug resistance. Using this knowledge, the Center aims to identify new cancer treatments that target master regulators of tumor homeostasis.

CaST will build on previous accomplishments in the Department of Systems Biology and its Center for Multiscale Analysis of Genomic and Cellular Networks (MAGNet), which developed several key systems biology methods for characterizing the complex molecular machinery underlying cancer. At the same time, however, the new center constitutes a step forward, as it aims to move beyond a static understanding of cancer biology toward a time-dependent framework that can account for the dynamic, ever-changing nature of the disease. This more nuanced understanding could eventually enable scientists to better predict how individual tumors will change over time and in response to treatment.

Factors affecting protein activity
Following gene transcription and translation, a protein can undergo a variety of modifications that affect its activity. By analyzing downstream gene expression patterns in single tumors, VIPER can account for these changes to identify proteins that are critical to cancer cell survival.

In a paper just published in Nature Genetics, the laboratory of Andrea Califano introduces what it describes as the first method capable of analyzing a single tumor biopsy to systematically identify proteins that drive cancerous activity in individual patients. Based on knowledge gained by modeling networks of molecular interactions in the cell, their computational algorithm, called VIPER (Virtual Inference of Protein activity by Enriched Regulon analysis), offers a unique new strategy for understanding how cancer cells survive and for identifying personalized cancer therapeutics.

Developed by Mariano Alvarez as a research scientist in the Califano laboratory, VIPER has become one of the cornerstones of Columbia University’s precision medicine initiative. Its effectiveness in cancer diagnosis and treatment planning is currently being tested in a series of N-of-1 clinical trials, which analyze the unique molecular characteristics of individual patients’ tumors to identify drugs and drug combinations that will be most effective for them. If successful, it could soon become an important component of cancer care at Columbia University Medical Center.

According to Dr. Califano, “VIPER makes it possible to find actionable proteins in 100% of cancer patients, independent of their genetic mutations. It also enables us to track tumors as they progress or relapse to determine the most appropriate therapeutic approach at different points in the evolution of disease. So far, this method is looking extremely promising, and we are excited about its potential benefits in finding novel therapeutic strategies to treat cancer patients.”

Andrea CalifanoAndrea Califano, the Clyde and Helen Wu Professor of Chemical Systems Biology and Chair of the Columbia University Department of Systems Biology, has been named a recipient of a National Cancer Institute Outstanding Investigator Award. The seven-year grant will support the development of systematic approaches for identifying the molecular factors that lead to cancer progression and to the emergence of drug resistance at the single-cell level. 

Breast cancer cells

A histological slide of cancerous breast tissue. The pink "riverways" are normal connective tissue while areas stained blue are cancer cells. (Source: National Cancer Institute)

Investigators at Columbia University Medical Center and the Icahn School of Medicine at Mount Sinai have discovered a molecular signaling mechanism that drives a specific type of highly aggressive breast cancer. As reported in a paper in Genes & Development, a team led by Jose Silva and Andrea Califano determined that the gene STAT3 is a master regulator of breast tumors lacking hormone receptors but testing positive for human epidermal growth receptor 2 (HR-/HER2+). The researchers also characterized a pathway including IL-6, JAK2, STAT3, and S100A8/9 — genes already known to play important roles within the immune response — as being essential for the survival of HR-/HER2+ cancer cells. Additional tests showed that disrupting this pathway severely limits the ability of these cells to survive.

These findings are particularly exciting because the pathway the researchers identified contains multiple targets for which known FDA-approved drugs exist. The paper reports that when these drugs were tested in disease models, the cancer cells showed a dramatic response, suggesting promising strategies for the treatment of the HR-/HER2+ cancer subtype. A clinical trial is now underway to investigate the effects of these approaches in humans.

Saeed TavazoieSaeed Tavazoie, a professor in the Columbia University Department of Systems Biology, has been named a recipient of a 2015 National Institutes of Health Transformative Research Award. The grant will support research to develop state-of-the-art experimental and computational methods for comprehensively mapping and modeling all pairwise molecular interactions inside cells. 

The Transformative Research Award is a part of the NIH Common Fund’s High-Risk, High-Reward Research program, which provides critical funding to scientists it recognizes as being exceptionally creative and who propose particularly innovative approaches to solving key problems in biomedical research. The Transformative Research Award is designed to support projects that use methods and perspectives that are unconventional and untested, but show great potential to create or overturn fundamental paradigms.

DeMAND graphical abstract
By analyzing drug-induced changes in disease-specific patterns of gene expression, a new algorithm called DeMAND identifies the genes involved in implementing a drug's effects. The method could help predict undesirable off-target interactions, suggest ways of regulating a drug's activity, and identify novel therapeutic uses for FDA-approved drugs, three critical challenges in drug development.

Researchers in the Columbia University Department of Systems Biology have developed an efficient and accurate method for determining a drug’s mechanism of action — the cellular machinery through which it produces its pharmacological effect. Considering that most drugs, including widely used ones, act in ways that are not completely understood at the molecular level, this accomplishment addresses a key challenge to drug development. The new approach also holds great potential for improving drugs’ effectiveness, identifying better combination therapies, and avoiding dangerous drug-induced side effects.

According to Andrea Califano, the Clyde and Helen Wu Professor of Chemical Systems Biology and co-senior author on the study, “This new methodology makes it possible for the first time to generate a genome-wide footprint of the proteins that are responsible for implementing or modulating the activity of a drug. The accuracy of the method has been the most surprising result, with up to 80% of the identified proteins confirmed by experimental assays.”

Alex Lachmann
Alex Lachmann during his presentation to the RNA-Seq "boot camp."

In June 2015, the Columbia University Department of Systems Biology held a five-part lecture series focusing on advanced applications of RNA-Seq in biological research. The talks covered topics such as the use of RNA-Seq for studying heterogeneity among single cells, RNA-Seq experimental design, statistical approaches for analyzing RNA-Seq data, and the utilization of RNA-Seq for the prediction of molecular interaction networks. The speakers and organizers have compiled a list of lecture notes and study materials for those wishing to learn more. Click on the links below for more information.

Reposted from the Columbia University Medical Center Newsroom. Find the original article here .

Cancer bottlenecks
In an N-of-1 study, researchers at Columbia University use techniques from systems biology to analyze genomic information from an individual patient’s tumor. The goal is to identify key genes, called master regulators  (green circles), which, while not mutated, are nonetheless necessary for the survival of cancer cells. 

Columbia University Medical Center (CUMC) researchers are developing a new approach to cancer clinical trials, in which therapies are designed and tested one patient at a time. The patient’s tumor is “reverse engineered” to determine its unique genetic characteristics and to identify existing U.S. Food and Drug Administration (FDA)-approved drugs that may target them.

Rather than focusing on the usual mutated genes, only a very small number of which can be used to guide successful therapeutic strategies, the method analyzes the regulatory logic of the cell to identify genes and gene pairs that are critical for the survival of the tumor but are not critical for normal cells. FDA-approved drugs that inhibit these genes are then tested in a mouse model of the patient’s tumor and, if successful, considered as potential therapeutic agents for the patient — a journey from bedside to bench and back again that takes about six to nine months.

“We are taking a rather different approach to tailor therapy to the individual cancer patient,” said principal investigator Andrea Califano, PhD, Clyde and Helen Wu Professor of Chemical Systems Biology and chair of CUMC’s new Department of Systems Biology. “If we have learned one thing about this disease, it’s that it has tremendous heterogeneity both across patients and within individual patients. When we expect different patients with the same tumor subtype or different cells within the same tumor to respond the same way to a treatment, we make a huge simplification. Yet this is how clinical studies are currently conducted. To address this problem, we are trying to understand how tumors are regulated one at a time. Eventually, we hope to be able to treat patients not on an individual basis, but based on common vulnerabilities of the cancer cellular machinery, of which genetic mutations are only indirect evidence. Genetic alterations are clearly responsible for tumorigenesis but control points in molecular networks may be better therapeutic targets.”

Andrea Califano and Aris Floratos
Andrea Califano and Aris Floratos will lead an effort to reclassify tumors catalogued in TCGA according to their master regulators.

Andrea Califano and Aris Floratos, faculty members in the Columbia University Department of Systems Biology, have received a two-year, $624,236 subcontract to develop a new classification system of cancer subtypes. The agreement was awarded through a subcontract from Leidos Biomedical Research, Inc., which operates the Frederick National Laboratory for Cancer Research for the federal government.  

By performing an integrative analysis of genomic data from the Cancer Genome Atlas (TCGA) and proteomic data from the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (CPTAC), the researchers plan to recategorize tumors collected in TCGA based on the master regulator genes that determine their state. This is in contrast to other approaches based on expression of genes that reflect tissue lineage and proliferative processes. In addition, the team will link the genetics of each tumor sample to the specific master regulators that determine its state using a recently published novel algorithm (DIGGIT). Ultimately, the project aims to provide a more useful catalog of pan-cancer subtypes that could help to identify biomarkers and therapeutic targets for specific kinds of tumors, and ultimately provide a resource to guide the next generation of precision medicine.

“We have to reevaluate the way in which we organize tumors within subtypes, using both gene expression data and mutational data,” says Dr. Califano. “Right now the common approach is to classify tumor types based on rather generic genes that are differentially expressed between subtypes. But most of these genes play no role in actually driving the disease. We want to shift the emphasis and classify tumors based on the genes that truly regulate tumor state and survival.”

Harris Wang

Harris Wang, an assistant professor in the Columbia University Department of Systems Biology and Department of Pathology and Cell Biology, has been selected to receive a 2015 Alfred P. Sloan Foundation Research Fellowship in computational and evolutionary molecular biology. This two-year, $50,000 grant will support work that combines methods from synthetic biology and computational biology to study how horizontal gene transfer contributes to microbial evolution.

Since 1955, the Sloan Research Fellowship program has supported outstanding early-career scientists in recognition of their achievements and their potential to make important contribution to their fields. This year’s fellows included 126 investigators, with 12 awardees in the field of computational and evolutionary molecular biology. Other disciplines represented in the awards include chemistry, computer science, economics, mathematics, neuroscience, ocean sciences, and physics.

Autism Spectrum Disorders Genetic Network

Network of autism-associated genes. (Credit: Dennis Vitkup)

The following article is reposted with permission from the Columbia University Medical Center Newsroom. Find the original here.

People with autism have a wide range of symptoms, with no two people sharing the exact type and severity of behaviors. Now a large-scale analysis of hundreds of patients and nearly 1000 genes has started to uncover how diversity among traits can be traced to differences in patients’ genetic mutations. The study, conducted by researchers at Columbia University Medical Center, was published Dec. 22 in the journal Nature Neuroscience.

Autism researchers have identified hundreds of genes that, when mutated, likely increase the risk of developing autism spectrum disorder (ASD). Much of the variability among people with ASD is thought to stem from the diversity of underlying genetic changes, including the specific genes mutated and the severity of the mutation.

“If we can understand how different mutations lead to different features of ASD, we may be able to use patients’ genetic profiles to develop accurate diagnostic and prognostic tools and perhaps personalize treatment,” said senior author Dennis Vitkup, PhD, associate professor of systems biology and biomedical informatics at Columbia University’s College of Physicians & Surgeons.

DIGGIT identifies mutations upstream of master regulators.

A new algorithm called DIGGIT identifies mutations that lie upstream of crucial bottlenecks within regulatory networks. These bottlenecks, called master regulators, integrate these mutations and become essential functional drivers of diseases such as cancer.

Although genome-wide association studies have made it possible to identify mutations that are linked to diseases such as cancer, determining which mutations actually drive disease and the mechanics of how they do so has been an ongoing challenge. In a paper just published in Cell, researchers in the lab of Andrea Califano describe a new computational approach that may help address this problem.

Differential decay rates in MDA-LM2 vs. MDA cells

The presence of the structural RNA stability element (sSRE) family of mRNA elements distinguishes transcript stability in metastatic MDA-LM2 breast cancer cell lines from that seen in its parental MDA cell line. Each bin contains differential decay rate measurements for roughly 350 transcripts. From left (more stable in MDA) to right (more stable in MDA-LM2), sRSE-carrying transcripts were enriched among those destabilized in MDA-LM2 cells. The TEISER algorithm collectively depicts sSREs as a generic stem-loop with blue and red circles marking nucleotides with low and high GC content, respectively. Also included are mutual information (MI) values and their associated z-scores. 

Gene expression analysis has become a widely used method for identifying interactions between genes within regulatory networks. If fluctuations in the expression levels of two genes consistently shift in parallel over time, the logic goes, it is reasonable to hypothesize that they are regulated by the same factors. However, such analyses have typically focused on steady-state gene expression, and have not accounted for modifications that messenger RNAs (mRNAs) can undergo during the time between their transcription from DNA and their translation into proteins. Researchers now understand that certain stem loop structures in mRNAs make it possible for proteins to bind to them, often causing RNA degradation and subsequently modulating protein synthesis. From the perspective of systems biology, this can have implications for the activity of entire regulatory networks, and recent studies have even suggested that aberrations in mRNA stability can play a role in disease initiation and progression.

In a new paper published in the journal Nature, Department of Systems Biology Professor Saeed Tavazoie and collaborators at the Rockefeller University describe a new computational and experimental approach for identifying post-transcriptional modifications and investigating their effects in biological systems. In a study of metastatic breast cancer, they determined that when the protein TARBP2 binds to a specific structural element in mRNA transcripts, it increases the likelihood that cancer cells will become invasive and spread. Interestingly, they also found that TARBP2 causes metastasis by binding transcripts of two genes — amyloid precursor protein (APP) and zinc finger protein 395 (ZNF395) — that have previously been implicated in Alzheimer’s disease and Huntington’s disease, respectively. Although the nature of this intersection between the regulatory networks underlying cancer and neurodegenerative diseases is unclear, the finding raises a tantalizing question about whether these very different disorders might be linked at some basic biological level.

Comparing human and mouse prostate cancer networks

Computational synergy analysis depicting FOXM1 and CENPF regulons from the human (left) and mouse (right) interactomes showing shared and nonshared targets. Red corresponds to overexpressed targets and blue to underexpressed targets.

Two genes work together to drive the most lethal forms of prostate cancer, according to new research by investigators in the Columbia University Department of Systems Biology.  These findings could lead to a diagnostic test for identifying those tumors likely to become aggressive and to the development of novel combination therapy for the disease.

The two genes—FOXM1 and CENPF—had been previously implicated in cancer, but none of the prior studies suggested that they might work synergistically to cause the most aggressive form of prostate cancer. The study was published today in the online issue of Cancer Cell.

M. Tuberculosis Culture

M. tuberculosis bacterial colonies. Photo credit: CDC/Dr. George Kubica [Public domain], via Wikimedia Commons

Dennis Vitkup, an associate professor in the Columbia University Department of Systems Biology and Department of Biomedical Informatics, has  been awarded an R01 grant from the National Institute of General Medical Sciences (NIGMS) to develop a computational pipeline for predicting bacterial metabolic networks. Building on a framework called GLOBUS that was previously developed in his lab, the project will produce probabilistic annotations of metabolic networks for all of the major bacterial species that cause disease in humans. It will both offer a method that can be used to study metabolism in any species of bacteria and produce valuable information that will aid researchers who are looking for therapies against many of the world’s most deadly pathogens.

Saeed Tavazoie

One of the defining features of systems biology has been its integration of computational and experimental methods for probing networks of molecular interactions. The research of Saeed Tavazoie, a professor in the Columbia University Department of Systems Biology, has been emblematic of this approach. After undergraduate studies in physics, he became fascinated by the processes that govern gene expression, particularly in understanding how gene expression is regulated by information encoded in the genome. Since then, his multidisciplinary approach to research has generated important insights into the principles that orchestrate genome regulation, as well as a number of novel algorithms and technologies for exploring this complex landscape.

In this conversation, Dr. Tavazoie discusses his research in the areas of gene transcription, post-transcriptional regulation, and molecular evolution, as well as some innovative technologies and experimental methods his lab has developed.

A panel at the Helix Center, titled "Synthetic and Systems Biology: Reinventing the Code of Life included Columbia University professors Saeed Tavazoie and Andrea Califano, as well as Michael Hecht (Professor of Chemistry, Princeton University), Mark Fishman (President, Novartis Institutes for BioMedical Research), Christopher Mason (Assistant Professor of Physiology and Biophysics, Institute for Computational Biology, Weill Cornell Medical College), and Michael Waldholz (Medical Science Writer and Media Consultant).

Advances in genomics and the development of new technologies over the past decade have given biologists the ability to engineer DNA to perform specific functions. This emerging science, called synthetic biology, holds great potential for a number of applications, and experiments have already been done to reprogram algae to produce biofuels, design bacteria that can sense and consume toxic substances, and use living cells to manufacture compounds that can be used as drugs.

Synthetic biology has emerged in parallel with systems biology, but in many ways the two sciences are closely intertwined. As systems biology improves our mechanistic understanding of how biology functions at the molecular level, synthetic biology is taking this knowledge to push biology in new directions, from synthesizing molecules using biology all the way to synthesizing new forms of biological life.

In a public roundtable discussion at the Helix Center in New York City, Columbia University Department of Systems Biology professors Saeed Tavazoie  and Andrea Califano  joined a panel of experts in discussing the intersection of systems and synthetic biology, and the role that these two disciplines will play in the development of the biological and biomedical sciences in the coming years.

Reversing glucocorticoid resistance

A representative example of tumor load analysis using bioluminescence imaging in mice following xenograft with T-ALL. Treatment with either MK2206 or dexamethasone showed limited efficacy, while combination treatment saw near complete elimination of tumor cells.

In a paper published in Cancer Cell, a team of researchers led by Adolfo Ferrando and Andrea Califano at Columbia University has identified the protein kinase AKT as a target for reversing resistance to glucocorticoid therapy in patients with acute lymphoblastic leukemia (ALL).  

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