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, 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.

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. 

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. 

Drs. Raul Rabadan and Nuria Malats

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.

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. 

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. 

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. 

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.

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.