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Suying Bao, PhD
Suying Bao, PhD

Suying Bao, a postdoctoral research scientist in the Chaolin Zhang lab , has been named an inaugural Precision Medicine Research fellow by Columbia’s Irving Institute of Clinical and Translational Research . The two-year fellowship aims to train postdocs to use genomics and complex clinical data to improve personalized and tailored clinical care and clinical outcomes. 

This fellowship “will provide me with more opportunities to translate my findings from basic science research into clinical application,” says Bao, “and pave my way towards an independent researcher in this field.” 

Bao’s expertise lies in RNA regulation at the interface of systems biology, ranging from the specificity of protein-RNA interaction to function of specific splice variants. RNA regulation is critical in proper cellular function; gaining deeper insights into this complex molecular mechanism will promote the development of precision medicine therapies. 

In this project, Bao is aiming to develop new approaches to identify causal noncoding regulatory variants (RVs) modulating post-transcriptional gene expression regulation, such as RNA splicing and stability.  “A majority of genetic variants associated with human diseases reside in noncoding genomic regions with regulatory roles,” notes Bao. “Thus, elucidating how these noncoding regulatory variants contribute to gene expression variation is a crucial step towards unraveling genotype-phenotype relationships and advancing precision medicine for common and complex diseases.”

To identify these RVs, she will leverage massive datasets of high-throughput profiles of gene expression and protein-RNA interactions generated from large cohorts of normal and disease human tissues and cell lines by multiple consortia, such as ENCODE, GTEx and CommonMind, and develop innovative computational methods of data mining. 

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. 

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.

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.”

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.