GSE141684 Senescence triggers vascular remodeling and new therapeutic vulnerabilities in pancreas cancer

Contributors : Marcus Ruscetti ; John Morris IV ; Riccardo Mezzadra ; James Russell ; Josef Leibold ; Paul B Romesser ; Janelle Simon ; Amanda Kulick ; Yu-jui Ho ; Myles Fennell ; Jinyang Li ; Robert J Norgard ; John E Wilkinson ; Direna Alonso-Curbelo ; Ramya Sridharan ; Daniel A Heller ; Elisa de Stanchina ; Ben Z Stanger ; Charles J Sherr ; Scott LoweSeries Type : Expression profiling by high throughput sequencingOrganism : Mus musculusKRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, immunosuppression, and resistance to chemo- and immunotherapies. A combination of MEK and CDK4/6 inhibitors that target KRAS-directed oncogenic signaling can potently suppress PDAC proliferation through induction of RB-mediated senescence and simultaneously trigger a senescence-associated secretory phenotype (SASP) capable of remodeling the tumor-immune microenvironment. Using immunocompetent mouse models of PDAC, we find that this senescence-inducing therapy produces a pro-angiogenic SASP leading to increased vascularization that culminates in enhanced drug delivery and efficacy of cytotoxic gemcitabine chemotherapy. In addition, SASP-mediated endothelial cell activation produced by the pro-senescence therapy stimulates the accumulation of CD8+ T cells into immunologically “cold” PDAC, sensitizing tumors to PD-1 checkpoint blockade. Therefore, in PDAC, therapy-induced senescence can establish emerg...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Mus musculus Source Type: research