Interferon-dependent SLC14A1+ cancer-associated fibroblasts promote cancer stemness via WNT5A in bladder cancer
Menée à partir du séquençage à l'échelle cellulaire de l'ARN d'échantillons tumoraux issus de patients atteints d'un cancer de la vessie, cette étude met en évidence un mécanisme par lequel une sous-population de fibroblastes CAF, surexprimant le transporteur d'urée SLC14A1 et dépendante de l'interféron, favorise le développement de cellules cancéreuses présentant des caractéristiques de cellules souches via la voie paracrine impliquant la protéine WNT5A
Cancer-associated fibroblasts (CAFs) play a role in response to cancer treatment and patient prognosis. CAFs show phenotypic and functional heterogeneity and differ widely in tumors of different tissue origin. Here, we use single-cell RNA sequencing of bladder cancer (BC) patient samples and report a CAF subpopulation characterized by overexpression of the urea transporter SLC14A1. This population is induced by interferon signaling and confers stemness to BC cells via the WNT5A paracrine pathway. Activation of cGAS-STING signaling in tumor cells drives interferon production, thereby revealing a link between cGAS-STING signaling and SLC14A1+ CAF differentiation. Furthermore, the inhibition of SLC14A1+ CAF formation via targeting of STAT1 or STING sensitizes tumor cells to chemotherapy. More important, BC patients with high proportions of intratumoral SLC14A1+ CAFs show cancer stage-independent poor outcome and a worse response rate to neoadjuvant chemotherapy or immunotherapy.
Cancer Cell 2022