Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer

Cell. 2020 Apr 16;181(2):424-441.e21. doi: 10.1016/j.cell.2020.03.008. Epub 2020 Mar 31.


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.

Keywords: T cells; chemotherapy resistance; endothelial cell activation; immunotherapy; pancreatic cancer; senescence; senescence-associated secretory phenotype; targeted therapy; tumor microenvironment; vascular biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / physiology*
  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinoma, Pancreatic Ductal / microbiology
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6 / metabolism
  • Gene Expression Regulation, Neoplastic / genetics
  • Genes, ras / genetics
  • Humans
  • Immunotherapy / methods
  • MAP Kinase Signaling System / physiology
  • Mice
  • Pancreatic Neoplasms / pathology
  • Retinoblastoma Protein / immunology
  • Signal Transduction / genetics
  • Tumor Microenvironment
  • Vascular Remodeling / genetics
  • Vascular Remodeling / physiology*


  • Retinoblastoma Protein
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6