Transfer RNA sequencing and application to cancer research and clinics

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Project Abstract Most effective tumor treatments target multiple cellular mechanisms. This proposal will explore a previously under-appreciated cellular mechanism in cancer biology using a newly developed high throughput sequencing technology. Transfer RNAs (tRNAs) are adaptor molecules that read the genetic code for protein biosynthesis. tRNAs are essential for gene expression, an emerging source of cancer-related biomarkers, and a treasure trove of epitranscriptomic marks from both human and disease-associated microbes. tRNAs are dysregulated in many cancers. Due to technical difficulties, tRNA biology and its implications in clinical cancer care have lagged far behind other DNA and RNA-based approaches. We recently developed a new technology called Multiplex Small RNA-seq (MSR-seq) which makes feasible for the first time clinical-scale tRNA studies. Specific Aim 1 will further expand the capability and scope of MSR-seq for clinical samples. Colorectal cancer (CRC) is the second leading cause of cancer-related death in the US. Chemotherapy regimens have not substantively changed in a decade, are unnecessary for 50% of patients, and ineffective in another 30%. Currently there is no way to categorize patients ahead of time. Recent studies provide evidence that gut bacteria can influence growth and metastasis of colorectal tumors. Interactions between tumors and commensal gut microbes provide a new lens to understand the biology of CRC and a new opportunity to identify patients at risk for cancer recurrence and patients who have no need to endure chemotherapy. Specific Aim 2 will apply MSR- seq to screen a biobank of blood, biopsy, and stool samples from CRC patients, and to study a murine model of CRC recurrence. This combination of a unique biobank with a new technology has potential to transform how CRC is treated and explores the complex host-microbe interactions in a human disease.