Elucidating The Adaptive Role Of Serine Codons During Pancreatic Tumorigenesis

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.

Grant Number: 3R37CA289040-03S1
NIH Institute/Center: NIH
Principal Investigator: Robert Banh