Classification based on efficiency of mRNA translation reveals a metabolically-dependent subtype of pancreatic cancer.

Abstract Molecular profiling of Pancreatic Ductal Adenocarcinoma (PDA), based on transcriptomic analyses, identifies two main prognostic subtypes (basal-like and classical), but does not allow personalized first-line treatment. To date, tumors have not been profiled based on protein synthesis rates, yet the step of mRNA translation is highly dysregulated in both PDA cancer cells and their microenvironment. We aim at assessing whether quantification of mRNA translation could provide a distinct perspective on PDA and identify novel tumor subtypes. Using a collection of twenty-seven pancreatic Patient-Derived Xenografts (PDX), we performed transcriptome-wide analysis of translated mRNA (translatome). Unsupervised bioinformatics analysis allowed PDA tumors classification according to mRNA translation rate. PDX-derived cancer cells as well as common PDA cell lines were used to functionally characterize newly identified subtype. Independent component analysis revealed a new tumor subtype harboring a low protein synthesis rate, but associated with a robust translation of mRNAs encoding effectors of the integrated stress response (ISR), including the transcription factor ATF4. Functional characterization of the “ISR-activated” human cancer cells revealed a high resistance to drugs, low autophagic capacities, and importantly, metabolic impairments in the serine synthesis and transsulfuration pathways. Therefore, the drug-resistant cancer cell phenotype showing auxotrophy to both serine and cysteine may be amenable to targeted therapy. Overall, our study highlights profiling of mRNA translation in cancer as an underexplored avenue for identification of previously unrecognized subtypes together with potential treatments. Citation Format: Sauyeun Shin, Remy Nicolle, Mehdi Liauzun, Jacobo Solorzano, Alexia Brunel, Christine Jean, Remi Samain, Jerôme Raffenne, Cindy Neuzillet, Carine Joffre, Stephane Rocci, Juan Iovanna, Nelson Dusetti, Ola Larsson, Stephane Pyronnet, Corinne Bousquet, Yvan Martineau. Classification based on efficiency of mRNA translation reveals a metabolically-dependent subtype of pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-088.