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- DECONSTRUCTING PANCREATIC DUCTAL ADENOCARCINOMAS
DECONSTRUCTING PANCREATIC DUCTAL ADENOCARCINOMAS
Centre de recherche - Paris
Amphithéâtre Constant-Burg - 12 rue Lhomond, Paris 5e
12 rue Lhomond, Paris 5ème
Description
Pancreatic ductal adenocarcinomas (PDACs) are characterised by extensive non-malignant stroma in which the most abundant cells are cancer-associated fibroblasts (CAFs). CAFs represent promising therapeutic targets. They are comprised of distinct subtypes with seemingly diverse roles in disease progression and therapy response. However, most insights into PDAC biology and CAF heterogeneity are based on KPC (KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx1-Cre) mouse models that recapitulate the progression of the human disease but not its genetic complexity. We hypothesised that modelling PDACs with additional commonly occurring mutations will expand our understanding of CAF heterogeneity towards improving patient stratification, treatment strategies, and survival of this disease.
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To explore this, we developed new isogenic PDAC models with different Kras mutations and deletion of Smad4, which is lost or mutated in ~30% of PDAC cases. Smad4 was deleted by CRISPR/Cas9 in PDAC organoids. Isogenic organoid lines were used to establish co-cultures with pancreatic stellate cells (PSCs), precursors of CAFs, or orthotopic transplantation mouse models. These models were then analysed by RNA-sequencing or single-cell RNA-sequencing, multiplexed immunofluorescence, and flow cytometry. Our studies show that Smad4 deletion in PDAC malignant cells leads to a more fibro-inflammatory and neutrophil-rich stroma. Furthermore, JAK/STAT signalling was identified as a potential therapeutic vulnerability of Smad4-deleted PDACs.
Our research demonstrates how a single genetic event in PDAC malignant cells profoundly shapes the stroma and can indicate candidate targetable interdependencies of malignant cell-fibroblast crosstalk. Ongoing work focused at modelling additional mutations will further deconstruct PDACs and guide tailored therapies for distinct groups of patients.
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Organisateurs
Raphaël Rodrigez
Institut Curie
Orateurs
GIULIA BIFFI
Invité(es) par
Raphaël Rodriguez
Institut Curie