syngeneic-mouse-orthotopic-allografts-to-model-pancreatic-cancer

Syngeneic Mouse Orthotopic Allografts to Model Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is a very complex disease characterized by a heterogeneous tumor microenvironment made up of a diverse stroma, ...

German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)

Technical University of Munich

Pancreatic ductal adenocarcinoma (PDAC) represents a major global health problem that causes over 200000 deaths each year worldwide. The disease is highly resistant to cytotoxic and targeted therapies and the average survival is less than 12 months. This situation prompted Alessandro Carugo and Giulio Draetta to develop a novel genetic mouse system, termed Patient-Based In Vivo Lethality to Optimize Treatment (PILOT), to perform functional RNAi-based in vivo screens to uncover and target PDAC drivers. In a forward genetic screen focused on epigenetic modifiers, a WDR5-Myc axis that regulates the DNA replication checkpoint was identified and exploited in vivo for therapeutic intervention.

In Vivo RNAi Screening for Pancreatic Cancer Drivers: PILOTing the WDR5-MYC Axis.

Molecular profiling of cancer patients and modelling of human cancer in mice revealed cell type and tissue-specific differences in tumor development and evolution. However, the context-dependent determinants of cancer remain poorly understood. A systematic characterization of the biological underpinnings of context-specificity will, therefore, be pivotal to design more effective therapies. In this review article, we focus on recent advances on molecular, cellular and microenvironmental aspects of context-dependency. We highlight new strategies to study this phenomenon in tumorigenesis and tumor evolution. Notably, we elucidate tissue and cell type-specific signaling cues as well as tumor microenvironment niches, using novel next-generation dual and triple recombinase-based mouse models of cancer.

Deciphering the universe of genetic context-dependencies using mouse models of cancer.

  mutations occur almost exclusively in pancreatic ductal adenocarcinoma. The results of a study that reveals specific differences in KRAS downstream signaling and metabolic rewiring of pancreatic cancer cells harboring   mutations promise to improve our possibilities to better stratify patients for individualized therapies..

Personalizing -Mutant Allele-Specific Therapies.

Two studies by Lodestijn et al. in Cell Stem Cell and Cell Reports reveal a lack of stem cell hierarchies in acinar cell-derived tissue renewal and host instructed clonogenic growth of pancreatic cancer, thereby elucidating determinants of pancreas regeneration and cancer.

Self-renewal equality in pancreas homeostasis, regeneration, and cancer.

KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is highly immunosuppressive and resistant to targeted and immunotherapies. Among the different PDAC subtypes, basal-like mesenchymal PDAC, which is driven by allelic imbalance, increased gene dosage and subsequent high expression levels of oncogenic KRAS, shows the most aggressive phenotype and strongest therapy resistance. In the present study, we performed a systematic high-throughput combination drug screen and identified a synergistic interaction between the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib, which targets KRAS-directed oncogenic signaling in mesenchymal PDAC. This combination treatment induces cell-cycle arrest and cell death, and initiates a context-dependent remodeling of the immunosuppressive cancer cell secretome. Using a combination of single-cell RNA-sequencing, CRISPR screens and immunophenotyping, we show that this combination therapy promotes intratumor infiltration of cytotoxic and effector T cells, which sensitizes mesenchymal PDAC to PD-L1 immune checkpoint inhibition. Overall, our results open new avenues to target this aggressive and therapy-refractory mesenchymal PDAC subtype.

Article	Year
In Vivo RNAi Screening for Pancreatic Cancer Drivers: PILOTing the WDR5-MYC Axis. Trends in cancer\| PubMed ID: 28741490	2016
Deciphering the universe of genetic context-dependencies using mouse models of cancer. Current opinion in genetics & development\| PubMed ID: 31078084	2019
Personalizing -Mutant Allele-Specific Therapies. Cancer discovery\| PubMed ID: 31919121	2020
Self-renewal equality in pancreas homeostasis, regeneration, and cancer. Cell reports\| PubMed ID: 34910913	2021
Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment. Nature cancer\| PubMed ID: 35122074	2022

Dieter Saur

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