Synapse - Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer

Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer Journal Article

Authors:	Ruscetti, M.; Morris, J. P. 4th; Mezzadra, R.; Russell, J.; Leibold, J.; Romesser, P. B.; Simon, J.; Kulick, A.; Ho, Y. J.; Fennell, M.; Li, J.; Norgard, R. J.; Wilkinson, J. E.; Alonso-Curbelo, D.; Sridharan, R.; Heller, D. A.; de Stanchina, E.; Stanger, B. Z.; Sherr, C. J.; Lowe, S. W.
Article Title:	Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer
Abstract:	KRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, immunosuppression, and resistance to chemo- and immunotherapies. We show that a combination of MEK and CDK4/6 inhibitors that target KRAS-directed oncogenic signaling can suppress PDAC proliferation through induction of retinoblastoma (RB) protein-mediated senescence. In preclinical mouse models of PDAC, this senescence-inducing therapy produces a senescence-associated secretory phenotype (SASP) that includes pro-angiogenic factors that promote tumor vascularization, which in turn enhances drug delivery and efficacy of cytotoxic gemcitabine chemotherapy. In addition, SASP-mediated endothelial cell activation stimulates the accumulation of CD8+ T cells into otherwise immunologically “cold” tumors, sensitizing tumors to PD-1 checkpoint blockade. Therefore, in PDAC models, therapy-induced senescence can establish emergent susceptibilities to otherwise ineffective chemo- and immunotherapies through SASP-dependent effects on the tumor vasculature and immune system. © 2020 In mouse models of KRAS mutant pancreatic ductal adenocarcinoma, tumor cell senescence following MEK and CDK4/6 inhibition promotes vascular remodeling through induction of a pro-angiogenic senescence-associated secretory phenotype, leading to enhanced drug delivery and T cell infiltration that sensitizes these tumors to chemotherapy and immune checkpoint blockade. © 2020
Keywords:	vasculotropin; controlled study; human cell; overall survival; nonhuman; gemcitabine; t cells; cd8+ t lymphocyte; mouse; animal tissue; gelatinase b; vascular cell adhesion molecule 1; animal experiment; animal model; tumor regression; alpha smooth muscle actin; fibroblast growth factor 2; immunotherapy; gamma interferon; pancreas adenocarcinoma; targeted therapy; pancreatic cancer; senescence; lymphocytic infiltration; hermes antigen; tumor vascularization; retinoblastoma protein; mitogen activated protein kinase kinase; intercellular adhesion molecule 1; t lymphocyte activation; cyclin dependent kinase 4; tumor necrosis factor; gelatinase a; stromelysin; matrilysin; cyclin dependent kinase 6; padgem protein; tumor microenvironment; antiproliferative activity; platelet derived growth factor b; cd69 antigen; vascular remodeling; platelet derived growth factor a; trametinib; chemotherapy resistance; senescence-associated secretory phenotype; stromelysin 2; human; female; priority journal; article; palbociclib; vascular biology; endothelial cell activation; pancreatic ductal carcinoma cell line; vascular endothelial cell
Journal Title:	Cell
Volume:	181
Issue:	2
ISSN:	0092-8674
Publisher:	Cell Press
Date Published:	2020-04-16
Start Page:	424
End Page:	441.e21
Language:	English
DOI:	10.1016/j.cell.2020.03.008
PUBMED:	32234521
PROVIDER:	scopus
PMCID:	PMC7278897
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85083049781&doi=10.1016%2fj.cell.2020.03.008&partnerID=40&md5=b39a58f6abfe59d85e31172c90ee277d
Notes:	Erratum issued, see DOI: [10.1016/j.cell.2021.07.028] -- Source: Scopus