Elucidating The Adaptive Role Of Serine Codons During Pancreatic Tumorigenesis

Abstract public domain (NIH RePORTER)

Pancreatic ductal adenocarincomas (PDAC) is an aggressive disease with poor prognosis and is characterized by a unique microenvironment that is severely depleted of amino acids (AAs). Dietary AA interventions, such as serine/glycine (Ser/Gly)-free diet, can reduce PDAC tumor burden. However, PDAC cells can regulate various pathways to adapt, grow and survive in response to AA starvation, including transcription, mRNA translation, elongation, and the mRNA translation efficiencies (mTE) of codons. By regulating the mTE of codons, PDAC cells allow selective mRNA translation that are required for the adaptation to nutrient poor microenvironments of a tumor. Therefore, we propose that targeting the pathways that regulate the mTE of codons can provide novel therapeutic avenues to improve the outcome of patients with PDAC and other cancers I previously found that Ser-deprivation decreases the mTE of two out of the six Ser codons, TCC and TCT (TC[C/T]), to selectively suppress and promote the synthesis of TC[C/T]-rich and -poor genes, respectively. Interestingly, TC[C/T]-poor genes are significantly enriched in adaptive pathways required for survival, such as cell cycle, transcription, and secreted factors. Whereas suppression of TC[C/T]-rich proteins can promote immune escape. By blocking the mTE differences in Ser-deprived conditions, we would be able to prevent the activation of multiple adaptive pathways that are required for survival upon Ser-limitation in PDAC tumors. However, the mechanism(s) that regulate the mTE of Ser codons in response to Ser-limitation are not known. My research focus is to decipher the regulation, effects, and role of human Ser codons on mRNA translation during PDAC tumorigenesis, and to harness these findings to identify novel therapeutic strategies in the treatment of PDAC and other cancers. Using a whole genome CRISPR screen, we have already identified ELAC2, a 3' pre-tRNA processing enzyme, as a key mTE regulator of Ser-codons in PDAC cells starved of Ser. Here, we will elucidate the upstream signaling cascade(s) that sense Ser-starvation to alter the mTE of Ser codons, determine the downstream mechanism(s) that control mTE differences, and to assess the importance of mTE regulation of Ser codons during PDAC tumorigenesis. By elucidating the upstream signaling cascades, downstream mechanisms, and functions in detail, we will gain a comprehensive understanding of the role of human Ser codons on mRNA translation in response to the nutrient environment during PDAC tumorigenesis. We will identify multiple therapeutic strategies to block mTE differences that allow the activation of Ser codon-driven adaptive pathways during PDAC tumorigenesis. This work also will reveal mechanistic insight into the pathogenesis of other human genetic diseases, such as intellectual disabilities associated with ELAC2 and TPRKB mutations. A comprehensive understanding of the roles of Ser codons on mRNA translation in response to the nutrient environment can establish a new paradigm “tumor nutrient-codon preferences” as an Achilles' heel during the tumorigenesis of PDAC and other cancers.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Although pancreatic ductal adenocarcinoma (PDAC) can alter the mRNA translation efficiency (mTE) of codons in response to severe nutrient-depleted environments to selectively synthesize proteins required for adaptation and tumorigenesis, we still do not understand the pathways that regulate this process in human cancers. This proposal aims to decipher the signaling cascades and mechanisms that regulate the mRNA translation efficiencies of Ser codons upon Ser-starvation, and to target these pathways during PDAC tumorigenesis. The findings from this work will have a profound impact on our fundamental understanding of the pathways and mechanisms that regulate the mTE of Ser codons, identify a therapeutic vulnerability in the adaptation to Ser-starvation in PDAC, and can greatly shift our perception of the effects of codon regulatory pathways in human health and disease.