FCF Researcher Praveen Sethupathy

The Fibrolamellar Cancer Foundation (FCF) first met Dr. Praveen Sethupathy in 2014 through his collaboration with Dr. Lola Reid and her associates, who had been working since 2010 on establishing the first-ever tumor model of fibrolamellar carcinoma (FLC). Since 2014, Praveen has served as lead PI on two FCF-funded projects at the University of North Carolina Chapel Hill, and will continue that work as he transfers to Cornell University later in 2017.

 

Praveen grew up with a strong interest in the intersection of different disciplines, enjoying history, language, math and science. Praveen’s father was a computer scientist and mathematician, which challenged Praveen to think about ways in which traditionally descriptive fields, such as biology, could take advantage of the quantitative sciences. He studied both disciplines at Cornell University as an undergraduate, and then trained in gene regulation, bioinformatics, and functional genomics at the University of Pennsylvania where he received his doctorate degree. Praveen completed an interdisciplinary post-doctoral fellowship at the National Human Genome Research Institute (NHGRI) with Dr. Francis Collins, the current director of the National Institute of Health (NIH).

 

After his post-doctoral fellowship, Praveen was recruited to the Department of Genetics at UNC Chapel Hill in 2011. For the past six years, his lab has focused on gene regulation in human disease. Praveen is particularly interested in the means by which non-coding RNAs regulate gene expression and contribute to normal physiological and pathophysiological processes in the liver, pancreas, and intestine. Disease areas of focus include diabetes, lipidemia, inflammatory bowel disease, and more recently, liver cancers such as FLC.

 

Praveen’s work in FLC began in 2014 in collaboration with Lola’s group, who had established the first-ever disease model of FLC, a patient-derived xenograft (PDX).  That patient was FCF founder Tucker Davis. Praveen’s team worked to characterize this model at the molecular level using high-throughput sequencing technology.  These findings were published in Nature Communications in 2015 (Oikawa et al., 2015), in which it was established that FLC is rich in cancer stem cells, and that it resembles at the molecular level biliary tree stem cells more closely than any other lineage stage of the liver.  This is in contrast to typical hepatocellular carcinoma (HCC), which has a molecular profile resembling that of mature hepatocytes or progenitor cells committed to a hepatocyte fate.

 

Subsequent to this study, Lola and Praveen co-authored a review article in the journal Hepatology on FLC and the potential utility of the fusion gene DNAJB1-PRKACA as an FLC biomarker and candidate therapeutic target (Reid and Sethupathy, 2016).

 

Most recently, Praveen’s lab analyzed the gene expression profiles of approximately 10,000 tumors across ~30 different cancer types from The Cancer Genome Atlas (TCGA).  They identified FLC cases previously mis-annotated as HCCs, determined that the fusion gene DNAJB1-PRKACA is specific to FLC, and defined a unique RNA signature of FLC.  The signature includes LINC00473, a long, non-coding RNA (lncRNA) that has recently been implicated as a therapeutic target in non-small cell lung cancer (NSCLC).  Their analysis demonstrates that LINC00473 is significantly more highly expressed in FLC than in any other cancer type, including NSCLC.  This work was recently published in Nature’s open access journal Scientific Reports (Dinh et al., 2017).

 

Praveen’s current FLC work is focused on evaluating the role of DNAJB1-PRKACA and several of the mRNAs and lncRNAs that comprise the FLC signature mentioned above as drivers of the invasive potential of FLC using the recently established PDX model. This work is being led by Timothy Dinh, a talented MD/PhD student in Praveen’s laboratory.  Others closely involved in this study who merit recognition include Jonathan Villanueva, a post-baccalaureate student in Praveen’s lab, and Eliane Wauthier, a senior staff scientist in Lola’s group.