Our
Research
Research at the Rabadan Lab
Our main scientific interests lie in modeling and understanding the dynamics of biological systems through the lens of genomics. We are a very interdisciplinary team of mathematicians, physicists, engineers, biologists, and medical doctors with a common goal of solving pressing medical problems. We are currently focusing our work on:
Cancer. Genomic technologies provide an extraordinary opportunity to identify mutations that contribute to the development of tumors. We are mapping the evolution of cancers and uncovering the mechanisms of response or lack of response to multiple therapies. We work with clinicians and experimentalists all around the world.
Infectious diseases. Evolution is a dynamic process that shapes genomes. Our team at Columbia is developing algorithms to analyze genomic data, with a view to understanding the molecular biology, population genetics, phylogeny, and epidemiology of viruses. We are interested in the emergence of infectious diseases, pandemics and uncovering the mechanisms of adaptation of viruses to humans.
Electronic Health Records. Clinical databases constitute a rich and complex source of raw data. We are using the power of statistics and computers to tease out important clinical patterns in these diverse, important datasets. Combining molecular and clinical data illuminates some of the mechanisms underlying complex diseases.
In particular, we develop mathematical, statistical, and computational approaches, which cover the analysis of high throughput data right through to the altogether more abstract identification of global patterns in evolutionary processes. Learn more about the Rabadan Lab and the three main global questions that we are addressing.
Research Projects
Mutations in the RNA Splicing Factor SF3B1 Promote Tumorigenesis through MYC Stabilization
Although mutations in the gene encoding the RNA splicing factor SF3B1 are frequent in multiple cancers, their functional effects and therapeutic dependencies are poorly understood. Here, we characterize 98 tumors and 12 isogenic cell lines harboring SF3B1 hotspot mutations, identifying hundreds of cryptic 3′ splice sites common and specific to different cancer types. Regulatory network analysis revealed that the most common SF3B1 mutation activates MYC via effects conserved across human and mouse cells. SF3B1 mutations promote decay of transcripts encoding the protein phosphatase 2A (PP2A) subunit PPP2R5A, increasing MYC S62 and BCL2 S70 phosphorylation which, in turn, promotes MYC protein stability and impair apoptosis, respectively. Genetic PPP2R5A restoration or pharmacologic PP2A activation impaired SF3B1-mutant tumorigenesis, elucidating a therapeutic approach to aberrant splicing by mutant SF3B1.
Here, we identify that mutations in SF3B1, the most commonly mutated splicing factor gene across cancers, alter splicing of a specific subunit of the PP2A serine/threonine phosphatase complex to confer post-translational MYC and BCL2 activation, which is therapeutically intervenable using an FDA-approved drug.