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Xuebing Wu, PhD, Wins Pershing Square Sohn Prize

The 2021 Pershing Square Sohn Prize for Young Investigators in Cancer Research has been awarded to Xuebing Wu, PhD, for his innovative approaches to cancer research. The Pershing Square Sohn Prize is an annual award that provides early career scientists the freedom to take risks and pursue bold research at a stage when traditional funding is lacking. At Columbia University Irving Medical Center, Dr. Wu shares the designation with Christine Iok In Chio, PhD, whose work focuses on the biological mechanisms that drive pancreatic ductal adenocarcinoma.

With the support from the Pershing Foundation, Dr. Wu and his lab aim to develop a technology for mutation-specific elimination of tumor cells, by integrating a highly programmable CRISPR “gene-editing” system with advanced machine learning algorithms. 

Read the full article in the HICCC Newsroom. 

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A Systems Biology Approach to Target Pancreatic Cancer

In recognition of Dr. Andrea Califano's recent Ruth Leff Siegel Award , an annual prize that honors and supports an investigator who has made outstanding contributions to our understanding of pancreatic cancer, Let's Win! Pancreatic Cancer has published the following feature article spotlighting his innovative approach to cancer research.

Dr. Andrea Califano
Dr. Andrea Califano, 2019 recipient of annual Ruth Leff Sigel Award for pancreatic cancer research. (Photo: Jörg Meyer/Columbia Magazine)

If you look at our basic biology, humans are big, cumbersome living organisms with a lot of moving parts.

For most of our lives, the cellular machinery that keeps us functioning goes off without a hitch. Starting at conception, cells have been growing and dividing, structuring themselves in a highly organized fashion. Liver cells know their job. And brain and spinal cord cells know their jobs, too.

Cancer is also a living organism. After all, it grows and evolves just like healthy cells. But cancer cells are cheats, ignoring the rules that other healthy cells play by. They mutate and divide uncontrollably, finding ways to evade our immune systems, which try to keep these invaders in check. To complicate matters, cancer cells are what scientists call heterogeneous. That means that even in the same malignant tumor there can be a variety of mutations, which is one reason why cancer treatment often fails. Drugs simply can’t target all of those mutations.

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Behind the Technique: Systems Biology with Andrea Califano

Dr. Andrea Califano sits down with BioTechniques at AACR. Video: Courtesy of BioTechniques.

At the 2019 annual meeting of the American Association for Cancer Research (AACR), Dr. Andrea Califano sat down with BioTechniques News for an overview on the field of systems biology and its impact in cancer research and in precision medicine. Dr. Califano is a pioneering researcher in the fast-growing field of systems biology whose expertise is in developing innovative, systematic approaches to identify the molecular factors that lead to cancer progression and to the emergence of drug resistance at the single-cell level. A physicist by training, Dr. Califano is the Clyde and Helen Wu Professor of Chemical and Systems Biology, founding chair of the Department of Systems Biology at Columbia University Irving Medical Center, director of the Columbia Genome Center and a program leader at the Herbert Irving Comprehensive Cancer Center.

The video interview is part of the series, Behind the Technqiue by BioTechniques News. 

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Grad Spotlight: Brian Ji, PhD

Brian Ji_2
Systems Biology Graduate Brian Ji, PhD

For Brian Ji, the big draw to systems biology stemmed from his passion for applying quantitative approaches to understanding biology. While an undergraduate at the University of Wisconsin-Madison, Ji studied nuclear engineering and credits that training for the way in which he tackles scientific questions: creatively, and as a problem solver. 

“There is no one right approach to asking a question and setting out to answer it, and that freedom is what makes science fun for me,” he says. 

Ji studied under Dr. Dennis Vitkup in the Vitkup lab and completed his thesis defense for systems biology in the fall of 2018.  Also an MD student in Columbia’s Vagelos College of Physicians and Surgeons , Ji was attracted to Columbia because of the close interplay between the Systems Biology Department and the Columbia University Irving Medical Center. “Ultimately,” he says, “the opportunity to sit at the intersection between math, biology and medicine was too good to pass up.”

Ji’s PhD work focused on understanding spatiotemporal dynamics of human gut microbiota. He developed several frameworks that leveraged the increasing availability of high-throughput sequencing data to better understand and precisely quantify patterns of human gut microbiota variability across time and space. His work showed that characterizing dynamics—changes in bacterial abundances in our gut—are critical to understanding how these ecosystems function and is highly connected to multiple factors such as host diet, travel and diet. 

Ji also spent part of his PhD studying limitations of cancer cell growth in different environmental conditions. He credits Columbia for exposing him to a variety of research topics. 

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Targeting Cancer and Careers: Precision Medicine

 

Andrea Califano
Andrea Califano, Dr

The migration away from “one-size-fits-all” medicine, particularly in the areas of cancer detection and treatment, holds great promise for patients and the field of precision medicine. Demand and jobs are increasing for researchers, clinicians and professionals who are at home collecting, analyzing and using more and newer forms of data, according to a recent feature reported in Science magazine which spotlights Dr. Andrea Califano , founding chair of the Department of Systems Biology . 

In the field of oncology, innovations continue to grow rapidly in precision, or targeted medicine, as clinicians seek to find better treatments for specific kinds of cancer, rather than take a blanket approach via the traditional trifecta of radiation, chemotherapy, and surgery. To do so, they must test patients, note mutations, and identify biomarkers to determine what treatments could work best with the fewest side effects.

Scientific breakthroughs, in these areas and more, have led to greater understanding of genes and their functions and have created new opportunities for precision medicine—and for those with technical, research, and clinical skills eager to work in this ever-expanding field. Special consideration will be given to those job applicants who can perform big data analysis and multidisciplinary research. However, new jobs will also emerge in previously unseen areas, such as business, translational medicine, and genetic counseling.

New and powerful tools have aided the precision medicine movement. The Human Genome Project, the first complete mapping of human genes, published its preliminary results in 2001. The project’s numerous benefits include knowing the location of the approximately 20,500 genes identified in the body and gaining a clearer understanding of how genes areorganized and operate.

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Identifying High-Risk Factors of Pancreatic Cancer

Dr. Raul Rabadan is leading a global research project as part of a new grant from the Pancreatic Cancer Collective to identify high-risk factors of pancreatic cancer. (Courtesy of Stand Up to Cancer)

A global team of researchers led by theoretical physicist Raul Rabadan, PhD, professor of systems biology at Columbia’s Vagelos School of Physicians and Surgeons, and Núria Malats, MD, PhD, head of the Genetic and Molecular Epidemiology Group of the Spanish National Cancer Research Centre (CNIO), are working to develop a comprehensive computational framework that will identify high-risk factors for pancreatic cancer.  

Armed with a new two-year, $1 million grant from the Pancreatic Cancer Collective, the team intends to attack pancreatic cancer research from multiple disciplines—genomics, mathematics and medicine—to provide an integrated, computational approach to studying genomic, environmental and immune factors that could identify populations at high risk of pancreatic cancer. The need for deeper understanding of the contributing factors to this lethal disease is pressing, as pancreatic cancer is projected to become the second leading cause of cancer-related mortality within the next decade. 

Rabadan-led Team for Pancreatic Cancer Collective
Drs. Raul Rabadan and Nuria Malats

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Dr. Cory Abate-Shen Named Chair of Pharmacology at Columbia

Cory Abate-Shen, PhD, a distinguished scientist whose multidisciplinary research has advanced our understanding of the molecular basis of cancer initiation and progression, has been named chair of the Department of Pharmacology at Columbia University Vagelos College of Physicians and Surgeons. Her appointment will be effective April 1, 2019.

Recruited to Columbia in 2007, Dr. Abate-Shen is currently the Michael and Stella Chernow Professor of Urologic Sciences and professor of pathology & cell biology, medicine, and systems biology. She has served as the leader of the prostate program, associate director, and twice as interim director of the Herbert Irving Comprehensive Cancer Center (HICCC) at Columbia University Irving Medical Center and NewYork-Presbyterian.

An internationally recognized leader in genitourinary malignancies, Dr. Abate-Shen is particularly interested in advancing our understanding of the mechanisms and modeling of prostate and bladder tumors. An innovator in the generation of novel mouse models for these cancers, her work has led to the discovery of new biomarkers for early detection, as well as key advances in cancer prevention and treatment.

In the fall of 2018, Dr. Abate-Shen was elected a fellow of the American Association for the Advancement of Science (AAAS). She is an American Cancer Society Professor, the first faculty member at Columbia University Vagelos College of Physicians and Surgeons to have received this honor. Previously, she served as a member of the National Cancer Institute’s Board of Scientific Counselors, and she currently is a member of the board of directors of the American Association of Cancer Research. 

Dr. Abate-Shen will succeed Robert S. Kass, PhD, the Hosack Professor of Pharmacology, Alumni Professor of Pharmacology, and chair of pharmacology since 1995.

Visit the CUIMC Newsroom for the full announcement. 

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Why Some Brain Tumors Respond to Immunotherapy

Columbia researchers have learned why some glioblastomas—the most common type of brain cancer—respond to immunotherapy. The findings, reported by the CUIMC Newsroom, could help identify patients who are most likely to benefit from treatment with immunotherapy drugs and lead to the development of more broadly effective treatments.

The study, led by Raul Rabadan, PhD, professor of systems biology and biomedical informatics at Columbia University Vagelos College of Physicians and Surgeons and the Herbert Irving Comprehensive Cancer Center, was published online in the journal Nature Medicine. 

Fewer than 1 in 10 patients with glioblastoma­ respond to immunotherapy, which has shown remarkable success in the past few years in treating a variety of aggressive cancers. But there has been no way to know in advance which glioblastoma patients will respond. Like many other cancers, glioblastomas are able to prevent the immune system from attacking cancer cells. Cancers sometimes put the brakes on the immune system by acting on a protein called PD-1. Immunotherapy drugs called PD-1 inhibitors are designed to release those brakes, unleashing the immune system. Given the success of PD-1 inhibitors in other cancers, doctors were hopeful that the immunotherapy drugs would help patients with glioblastoma. 

To understand why only a few of these tumors respond to the immunotherapy drugs, Dr. Rabadan’s team took a comprehensive look at the tumor microenvironment—which includes the tumor itself and all of the cells that support it—in 66 glioblastoma patients before and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Of these, 17 had a response to the drugs of six months or longer.

Nonresponsive tumors had more mutations in a gene called PTEN, which led to higher levels of macrophages, immune cells that usually help the body fight bacteria and other invaders. But in glioblastoma, the macrophages release a number of growth factors that promote the survival and spread of cancer cells.

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Prostate Cancer Grant Spotlights Columbia’s Aim to Deliver Precision Cancer Medicine

 

PCF Challenge Award PIs
Principal investigators on the PCF Challenge Award grant, from left to right: Andrea Califano, Michael Shen and Charles Drake.

Columbia University Irving Medical Center experts in prostate cancer will lead a new team research project that tests a novel approach for personalized cancer treatment. 

The two-year project, funded by a $1 million Challenge Award from the Prostate Cancer Foundation (PCF) , combines cutting-edge techniques that include computational methods for targeted drug therapy, single-cell RNA sequencing and novel cancer immunotherapy. The combined approaches are behind a proof-of-concept clinical trial for patients with lethal metastatic prostate cancer.  

PCF Challenge Awards fund projects that bring together experts from a number of related fields to form a team focused on the creation of innovative, effective therapies for advanced prostate cancer. As part of Columbia’s grant, the new clinical trial will take place at the James J. Peters VA Medical Center (also known as the Bronx VA), a partner of Columbia University Irving Medical Center (CUIMC) and New York-Presbyterian .

PCF is recognized as the leading philanthropic organization for prostate cancer research. For the team at Columbia’s Herbert Irving Comprehensive Cancer Center (HICCC ), receiving a Challenge Award from the foundation was more than just an exciting achievement. It underscores CUIMC’s continued commitment to strengthen and expand its expertise in prostate cancer research and care through investments in faculty recruitment, enhanced emphases on bolstering basic science research and clinical trials centered on the disease and direct engagement with PCF. 

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Advancing the Use of Single-Cell Technology for Novel Brain Cancer Treatment

Peter Sims, PhD
Peter Sims, PhD

The Mark Foundation for Cancer Research has awarded Peter Sims , PhD, an Emerging Leader Award and will support his work to advance a novel use of single-cell RNA sequencing to develop brain cancer treatments. Dr. Sims, assistant professor of systems biology at Columbia University Irving Medical Center, is one of just eight recipients of the inaugural grant, given to promising early career scientists for projects aimed at substantially unmet needs in cancer risk prediction, prevention, detection and treatment. 

Dr. Sims is an early contributor to the emerging field of large-scale single-cell RNA sequencing, which has made it possible to analyze tens of thousands of cells while simultaneously obtaining imaging and genomic data from each individual cell. He will be using this approach to improve patient-derived models of glioblastoma multiforme (GBM), an aggressive form of cancer that invades the brain, making complete resection difficult. In other words, making it extremely difficult in surgery to remove all cancerous cells from the brain. To date, drug therapies for this type of aggressive brain cancer have had limited success, partly because of the heterogeneity of these tumors. Furthermore,  current patient-derived models for researching glioblastoma do not fully recapitulate the cellular diversity of tumor cells that are present in the tumor, so it is extremely challenging to classify those cells in order to match them with the drug therapies that work. 

Indeed, there is a critical need to better characterize and understand GBM. Dr. Sims has collaborated with several brain tumor experts in the Herbert Irving Comprehensive Cancer Center , including Drs. Peter Canoll, Jeffrey Bruce, Antonio Iavarone and Anna Lasorella to advance single-cell genomic approaches to characterizing this disease. Approaching this problem at the single cell level could result in development of novel treatments that  prioritize and identify the specific drug therapies that may actually work on diminishing these tumor cells. The ultimate goal is to attain better predictions of therapeutic efficacy. 

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Innovative Engine: Medical Research

Researchers at the Vagelos College of Physician & Surgeons are rewriting the course of scientific investigation, intent on speeding up the process of discovery that will help patients with cancer, Alzheimer’s disease, diabetes, and other intractable diagnoses.

In cancer, Andrea Califano, Dr, the Clyde and Helen Wu Professor of Chemical and Systems Biology and chair of the Department of Systems Biology, decided to turn cancer treatment theory on its head. The first wave of research in pursuit of personalized oncology focused on clues embedded within individual tumors. Decode the nucleic acids gone awry within the DNA of a particular patient’s cancer, or so the thinking goes, to identify treatments tailored to target that specific mutation.

It’s a fine theory, says Dr. Califano in the article, but investigators still have a lot of work to do before the vast majority of cancers yield to that approach. “Only maybe 25 percent of patients have a mutation that could be defined as actionable,” he says.

For more than a decade, Dr. Califano has championed what might be considered an end run around cancer mutations, focusing instead on identifying and blocking the networks of normal proteins—known as master regulators—hijacked by deranged DNA to spur tumor formation and sustain tumor growth. Prevent the signals those proteins send on behalf of a cancerous mutation, and the cancer itself screeches to a halt.

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Dr. Cory Abate-Shen Elected an AAAS Fellow

 

Cory Abate-Shen
Cory Abate-Shen, PhD

Cory Abate-Shen , PhD, who is known for her leading work in the development of innovative mouse models for translational research in prostate and bladder cancers, has been elected a fellow of the American Association for the Advancement of Science (AAAS) . The AAAS is honoring Dr. Abate-Shen for her work in mouse models to better understand how basic cellular mechanisms are co-opted in cancer and for her contributions to the field of cancer biology. 

She joins a class of 416 new fellows, including two additional Columbia University faculty members, Drs. Richard Axel and Upmanu Lall, who also were elected today to the prestigious group. 

Dr. Abate-Shen, the Michael and Stella Chernow Professor of Urologic Sciences at Columbia University Irving Medical Center (CUIMC) , holds joint appointments in the Departments of Systems Biology , Medicine and Pathology & Cell Biology , and is a member and former interim director of the Herbert Irving Comprehensive Cancer Center (HICCC) . An internationally recognized leader in genitourinary malignancies, Dr. Abate-Shen is particularly interested in advancing our understanding of the mechanisms and modeling of prostate and bladder tumors. An innovator in the generation of novel mouse models for these cancers, her work has led to the discovery of new biomarkers for early detection, as well as key advances in cancer prevention and treatment. Dr. Abate-Shen has been the recipient of numerous awards, including a Sinsheimer Scholar Award, an NSF Young Investigator Award, a Bladder Cancer Advocacy Network Innovator Award and the Women in Cell Biology Junior Award from the American Society for Cell Biology. Currently, she is an American Cancer Society Research Professor, the first to be awarded at CUIMC. 

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Columbia Team Awarded New Prostate Cancer Grant for Innovative Precision Cancer Research

A research team from Columbia University Irving Medical Center has received a 2018 PCF Challenge Award from the Prostate Cancer Foundation (PCF) to advance prostate cancer research. The interdisciplinary team at Columbia includes leading experts in systems biology, cancer research and medicine from Columbia’s Department of Systems Biology and the Herbert Irving Comprehensive Cancer Center (HICCC). 

Announced today, PCF is awarding more than $5.5 million in funding to a total of six teams to conduct research with the highest potential for accelerating new and improved treatments for advanced prostate cancer. PCF is one of the largest non-governmental organizations dedicated solely to funding prostate cancer research, and its annual Challenge Awards are highly coveted in the scientific and medical fields. 

In the United States, prostate cancer is the most common non-skin cancer, and 1 out of every 9 men in the U.S. will be diagnosed with the disease in his lifetime. To date, treatment of the most aggressive forms of prostate cancer represents a clinical challenge. After treatment failure with anti-androgen drugs, which are part of the standard of care for advanced metastatic prostate cancer, only few current therapeutic options remain and the impact on patient survival is limited. Indeed, the field needs major innovative, out-of-the-box approaches to new therapies to combat advanced prostate cancer. 

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Spotlighting Interdisciplinary Research and Young Investigators

 

DSB Retreat
Members of the Dennis Vitkup Lab, from l to r: Konstatine Tchourine, German Plata and Jon Chang (Credit: Sandra Squarcia); Photo Gallery of the retreat.

Innovative research projects were highlighted at the Department of Systems Biology’s annual retreat, held October 5, at Wave Hill Public Garden and Cultural Center in Riverdale, NY. The retreat, attended by 160 faculty, staff, post-doctoral scientists, students and guests, also provided an opportunity for young investigators to showcase their work during a poster competition. 

Andrea Califano , Dr., chair of the department, opened the day’s sessions with welcome remarks, as the retreat also served as a site visit by the National Cancer Institute for the Columbia University Center for Cancer Systems Therapeutics (CaST) . CaST, co-directors Drs. Califano and Barry Honig , vice-chair of the department, was established in 2016 as one of the key centers in the NCI’s Cancer Systems Biology Consortium (CSBC). The initiative behind CSBC is heavily grounded on innovation—bringing together interdisciplinary teams of clinical and basic cancer researchers with physical scientists, engineers, mathematicians and computer scientists who collaborate to tackle major questions in cancer biology from a novel out-of-the-box point of view. 

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Dr. Andrea Califano Elected to the National Academy of Medicine

 

Andrea Califano
Andrea Califano, Dr.

Andrea Califano , Dr., a pioneer in the field of systems biology and founding chair of the Department of Systems Biology at Columbia University Irving Medical Center (CUIMC), has been elected to the National Academy of Medicine (NAM) . Membership in the NAM is considered one of the highest honors in the fields of health and medicine and recognizes individuals who have demonstrated outstanding professional achievements and commitment to service.  

A physicist by training, Dr. Califano has taken innovative, systematic approaches to identify the molecular factors that lead to cancer progression and to the emergence of drug resistance at the single-cell level. Directing the conversation about cancer research away from focusing solely on gene mutations, Dr. Califano examines the complex and tumor-specific molecular interaction networks that determine cancer cell behavior. Using information theoretic approaches, analysis of these networks can precisely pinpoint master regulator proteins that are mechanistically responsible for supporting tumorigenesis and for implementing tumor cell homeostasis. Dr. Califano and his lab have shown that master regulators represent critical drivers and tumor dependencies, despite the fact that they are rarely mutated or differentially expressed, thus establishing them as a bona fide new class of therapeutic targets.

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New Study Explains Why Genetic Mutations Cause Disease in Some People but Not in Others

composite image of the scientists and research figure
Tuuli Lappalainen (top photo) and Stephane Castel co-led the new study. The hypothesis of the study is illustrated here with an example in which an individual is heterozygous for both a regulatory variant and a pathogenic coding variant. The two possible haplotype configurations would result in either decreased penetrance of the coding variant, if it was on the lower-expressed haplotype, or increased penetrance of the coding variant, if it was on the higher-expressed haplotype. (Composite image courtesy of NYGC)

Researchers at the New York Genome Center (NYGC) and Columbia University's Department of Systems Biology have uncovered a molecular mechanism behind one of biology’s long-standing mysteries: why individuals carrying identical gene mutations for a disease end up having varying severity or symptoms of the disease. In this widely acknowledged but not well understood phenomenon, called variable penetrance, the severity of the effect of disease-causing variants differs among individuals who carry them. 

Reporting in the Aug. 20 issue of Nature Genetics, the researchers provide evidence for modified penetrance, in which genetic variants that regulate gene activity modify the disease risk caused by protein-coding gene variants. The study links modified penetrance to specific diseases at the genome-wide level, which has exciting implications for future prediction of the severity of serious diseases such as cancer and autism spectrum disorder.

NYGC Core Faculty Member and Systems Biology Assistant Professor Dr. Tuuli Lappalainen, PhD, led the study alongside post-doctoral research fellow Dr. Stephane Castel.

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Hyundai Awards Columbia Team $2.5M Grant to Advance Pediatric Cancer Research

Hyundai $2.5M Grant to Columbia
Julia Glade Bender, MD, (center) at the Hyundai Hope on Wheels announcement Mar. 29 during the New York International Auto Show at the Jacob Javitz Center. (Photo courtesy of HHOW)

A team of researchers at Columbia University Irving Medical Center (CUIMC) has recently been awarded a five-year $2.5 million grant from Hyundai Hope on Wheels (HHOW) to fund innovative pediatric cancer research. 

The team at Columbia is being led by principal investigator (PI), Julia Glade Bender , MD, associate professor of pediatrics at CUIMC, with co-PIs Andrea Califano , Dr, chair of Columbia’s Department of Systems Biology and Darrell Yamashiro , MD, PhD, director of pediatric hematology, oncology and stem cell transplantation, along with researchers from Memorial Sloan Kettering, University of San Francisco Children’s and Dana-Farber Cancer Center. 

The Quantum Collaboration award from HHOW is aimed at funding research focused on childhood cancers with poor prognosis. At Columbia, the team will target osteosarcoma, the most commonly diagnosed bone tumor in children and adolescents. No new treatment approaches have successfully been introduced for osteosarcoma in nearly 40 years, and patients with the disease have not benefited from recent breakthroughs like immunotherapy or DNA sequencing and require a shift in the understanding and approach to therapy. 

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Michael Shen Wins Cancer Research Innovation Award

Michael Shen, PhD
Michael Shen, PhD (Image Courtesy of the Shen Lab)

The Bladder Cancer Advocacy Network (BCAN) has awarded Professor Michael Shen, PhD, the 2018 Bladder Cancer Research Innovation Award. The honor is given to scientists whose novel, creative research has great potential to produce breakthroughs in the management of bladder cancer.  

Dr. Shen, who is professor of medicine, genetics & development, urology and systems biology at Columbia University, has used new techniques of 3D cell culture to establish “organoids” from primary bladder tumors obtained from patients. These personalized laboratory models, which the Shen lab can create in a matter of weeks, provide a new, innovative way to study the molecular mechanisms associated with drug response and drug resistance in bladder cancer patients. 

The BCAN award supports the Shen lab’s efforts in furthering their work in patient-derived bladder tumor organoids . 

“We will employ these organoid lines to examine how specific oncogenic drivers may regulate the invasiveness and metastatic ability of muscle-invasive bladder cancer (MIBC), both in cell culture and in mouse models,” says Dr. Shen. “Our goal is to use these new experimental approaches to provide molecular insights into the lethal properties of human MIBC, which will hopefully lead to improved therapeutic approaches.”

Bladder cancer is the fifth most common cancer in the United States, and the primary treatment of the disease is surgery. Overall, this new project will examine central questions of bladder cancer biology using Dr. Shen’s innovative approach involving patient-derived tumor organoids, and may provide the basis for future therapies for metastatic bladder cancer.

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New Insights on How the Reprogramming Factor LIN28 Regulates its Targets

LIN28 Selectively Modulates Subclass Let-7 miRNAs
The proposed model of selective Let-7 microRNA suppression modulated by the bipartite LIN28 binding.(Image courtesy of Zhang Lab)

A new study led by Chaolin Zhang, PhD , assistant professor of systems biology , published today as the cover story of  Molecular Cell , sheds light on a critical RNA-binding protein that is widely researched for its role in stem cell biology and its ties to cancer progression in multiple tissues.

The LIN28 RNA-binding protein, initially found in worms about 15 years ago, is specifically expressed in stem cells.  It became well known because the protein is one of the four factors that were used to “reprogram” skin cells to induced pluripotent stem cells, or iPSCs, a breakthrough that was awarded the Nobel Prize in 2012. More recently, it was determined that the LIN28 RNA-binding protein can also be reactivated in cancer to drive tumor growth and progression. Due to its critical importance in developmental and cancer biology, scientists want to understand the role LIN28 plays at the molecular level. This new study provides some understanding of how the LIN28 protein suppresses a specific family of microRNAs, called Let-7, which are selectively lost in cancer.

“Let-7 microRNAs are the major downstream targets controlled by LIN28 identified so far. While LIN28 is mostly found in stem cells, Let-7 is only detected in differentiated cells because of stem cell-specific suppression by LIN28. However, the interplay between the two is still not well understood,” says Dr. Zhang, who is also a member of Columbia University’s Center for Motor Neuron Biology and Disease . “This study contributes to our understanding of how LIN28 suppresses Let-7, as well as provides a refined model for this important, rather complex molecular pathway.”

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Matching Cancer Patients to Personalized Therapies

Califano-Cancer Bottleneck
The N of 1 trial leverages systems biology techniques to analyze genomic information from a patient’s tumor. The goal is to identify key genes, called master regulators (green circles), which, while not mutated, are necessary for cancer cell survival. Master regulators are aberrantly activated by patient-specific mutations (X symbols) in driver genes (yellow circles), which are mutated in large cancer cohorts. Passenger mutations (blue circles) that are not upstream of master regulators have no effect on the tumor. (Image: Courtesy of the Califano Lab)

A novel N of 1 clinical trial led by the Califano Lab at Columbia University Irving Medical Center is focusing on rare or untreatable malignancies that have progressed on multiple lines of therapy, with the goal of identifying and providing more effective, customized therapies for patients. The approach is grounded in a computational platform developed over the last 14 years by the Califano Lab to allow accurate identification of a novel class of proteins that represent critical tumor vulnerabilities and of the drug or drug combination that can most effectively disarm these proteins, thus killing the tumor. Platform predictions are then validated in direct tumor transplants in mice, also known as Patient-Derived Xenografts (PDX). 

“We call these proteins master regulators and have developed innovative methodologies that allow their discovery on an individual patient basis,” said Dr. Andrea Califano , Clyde and Helen Wu Professor of Chemical and Systems Biology and chair of the Department of Systems Biology at Columbia. 

N-of-1 brochure to learn more.
N-of-1 brochure to learn more.

 

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