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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 deregulated in both PDA cancer cells and their microenvironment. Using a collection of twenty-seven pancreatic Patient-Derived Xenografts (PDX), we performed genome-wide analysis of translated mRNA (translatome). Unsupervised bioinformatics 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. Overall, our study highlights the strength of translatomic profiling on PDA, which here revealed an unforeseen drug-resistant cancer cell phenotype, whose auxotrophy to both serine and cysteine may be amenable to targeted therapy.

While a number of mouse models have been made to recapituate FAP, they fall short of truly mimicking the hallmarks of the human disorder. In lineage tracing studies (Powell et al., Cell, March 2012), we found that Leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1), a pan-ErbB inhibitor, marks a population of stem cells at the base of small intestinal and colonic crypts. In our current study, we combined our Lrig1-CreERT2/+ mice with Apcflox/+ mice and eliminated one copy of Apc with tamoxifen injection. Over a period of 50-100 days, the mice developmultiple distal colonic tumors as monitored by colonoscopy, as well as by novel non-invasive imaging (tumor formation measured by TSPO ligand binding monitored via PET). These mice also exhibit periampullary and duodenal tumors, as well as gastric lesions, thus mimicking additional features of FAP. Of interest, Lrig1-CreERT2/ +;Apcflox/+ mice also have CHRPE-like lesions in their retinal pigment epithelium. Finally, when induced Lrig1-CreERT2/+;Apcflox/flox mice were treated (i.p.) with a novel Wnt inhibitor, VU-WS113, cytosolic β-catenin was markedly reduced and TSPO uptake was also dramatically decreased, providing in vivo evidence that VU-WS113 may be an effective therapy for Wnt-driven tumors. We are in the process of comparing the transcriptional profiles of Lrig1-CreERT2/+;Apcflox/+ colonic tumors and human FAP tumors to understand their similarities and differences at a molecular level. In summary, in addition to recapitulating a number of features of human FAP the most important of which is distal, colonic tumors our results suggest this model represents a tractable system to test the efficacy of innovative therapeutic interventions whose efficacy can be monitored over time by colonoscopy and non-invasive imaging modalities.