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Society for Surgery of the Alimentary Tract

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Louisa Bolm*1, Natalie Petruch1, Pascal Finetti2, Taisuke Baba1, Jorge Roldan1, Jon Michael Harrison1, Andrew L. Warshaw1, Carlos Férnandez-Del Castillo1, Andrew S. Liss1
1Department of Surgery, Massachusetts General Hospital, Boston, MA; 2Aix-Marseille Universite, Marseille, Provence-Alpes-Côte d'Azu, France

Introduction: A dense desmoplastic stroma is a defining characteristic of pancreatic ductal adenocarcinoma (PDAC). This stroma promotes tumor progression and cancer cell invasion. Patient-derived xenograft models have been used to investigate PDAC tumor biology but a systematic characterization of PDAC PDX stroma has not been performed.

Methods and Materials: To characterize stromal heterogeneity in patient-derived xenograft models (PDX), RNA sequencing of 41 low-passage PDX models grown in nu/j mice was performed. By using the species-specific expression of genes in the human cancer and mouse-derived stroma, gene expression in each compartment was defined. Consensus clustering of genes was used to identify differentially regulated genes in the stromal compartment of the PDX models and supervised analysis was performed to define stromal subtypes.

Results: Consensus clustering of identified genes disclosed a total of 1186 genes differentially regulated in the stromal compartment of the PDX models. Supervised analysis revealed four major stroma subtypes. The first stroma subtype, termed "immunogenic", is characterized by genes involved in the production of cytokines (including IL-6) and those related to positive regulation of macrophage and negative regulation of dendritic cell differentiation. Furthermore, IL-6-regulated pathways, including the MAP kinase and JAK/STAT pathways and their downstream targets, were enriched in this subtype. The second stroma subtype is enriched for genes involved in TGF-β signaling and pathways associated with epithelial-to-mesenchymal transition and has been classified as the "TGF-β/EMT-driven" subtype. The third stroma subtype was termed "invasion-driven" as members of the Rho family of small GTPases and other pathways of cancer cell invasion were enriched in this subtype. The fourth subtype is enriched in genes involved in basic cell metabolism, homeostasis, and osmotic regulation pathways and has been termed "quiescent". While the stromal subtypes were generally associated with a diversity of cancer subtypes, tumors with the invasion-driven stroma were strongly enriched for the squamous subtype of cancer. Of note, the PDX models in this study were implanted into mice with a homogeneous genetic background implicating the cancer cells in shaping these divergent stromal.

Conclusion: Four distinct stromal subtypes were identified in PDAC PDX models. The stromal diversity of PDX models provides an opportunity to investigate subtype-specific response to stroma-targeted therapies.

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