Preexisting senescent fibroblasts in the aged bladder create a tumor-permissive niche through CXCL12 secretion.

Aging is a major risk factor for cancer, but the precise mechanism by which aging promotes carcinogenesis remains largely unknown. Here, using genetically modified mouse models, we show that p16high senescent (p16h-sn) fibroblasts accumulate with age, constitute inflammatory cancer-associated fibroblasts (CAFs) and promote tumor growth in bladder cancer models. Single-cell RNA sequencing of fibroblasts from aged mice revealed higher expression of the C-X-C motif chemokine 12 gene (Cxcl12) in p16h-sn fibroblasts than in p16low fibroblasts. Elimination of p16h-sn cells or inhibition of CXCL12 signaling notebly suppressed bladder tumor growth in vivo. We identified high expression levels of SMOC2, GUCY1A1 (GUCY1A3), CXCL12, CRISPLD2, GAS1 and LUM as a signature of p16h-sn CAFs in humans and mice, which was associated with age and poor prognosis in patients with advanced and nonadvanced bladder cancer. Here we show that p16h-sn fibroblasts in the aged bladder create a cancer-permissive niche and promote tumor growth by secreting CXCL12.