RESUMO
Inflammatory bowel diseases (IBDs) are chronic disorders of the gastrointestinal tract with the following two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). To date, most IBD genetic associations were derived from individuals of European (EUR) ancestries. Here we report the largest IBD study of individuals of East Asian (EAS) ancestries, including 14,393 cases and 15,456 controls. We found 80 IBD loci in EAS alone and 320 when meta-analyzed with ~370,000 EUR individuals (~30,000 cases), among which 81 are new. EAS-enriched coding variants implicate many new IBD genes, including ADAP1 and GIT2. Although IBD genetic effects are generally consistent across ancestries, genetics underlying CD appears more ancestry dependent than UC, driven by allele frequency (NOD2) and effect (TNFSF15). We extended the IBD polygenic risk score (PRS) by incorporating both ancestries, greatly improving its accuracy and highlighting the importance of diversity for the equitable deployment of PRS.
Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Humanos , Colite Ulcerativa/genética , Doença de Crohn/genética , População do Leste Asiático , População Europeia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doenças Inflamatórias Intestinais/genética , Polimorfismo de Nucleotídeo Único/genética , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genéticaRESUMO
UNLABELLED: The signaling mechanisms between prostate cancer cells and infiltrating immune cells may illuminate novel therapeutic approaches. Here, utilizing a prostate adenocarcinoma model driven by loss of Pten and Smad4, we identify polymorphonuclear myeloid-derived suppressor cells (MDSC) as the major infiltrating immune cell type, and depletion of MDSCs blocks progression. Employing a novel dual reporter prostate cancer model, epithelial and stromal transcriptomic profiling identified CXCL5 as a cancer-secreted chemokine to attract CXCR2-expressing MDSCs, and, correspondingly, pharmacologic inhibition of CXCR2 impeded tumor progression. Integrated analyses identified hyperactivated Hippo-YAP signaling in driving CXCL5 upregulation in cancer cells through the YAP-TEAD complex and promoting MDSC recruitment. Clinicopathologic studies reveal upregulation and activation of YAP1 in a subset of human prostate tumors, and the YAP1 signature is enriched in primary prostate tumor samples with stronger expression of MDSC-relevant genes. Together, YAP-driven MDSC recruitment via heterotypic CXCL5-CXCR2 signaling reveals an effective therapeutic strategy for advanced prostate cancer. SIGNIFICANCE: We demonstrate a critical role of MDSCs in prostate tumor progression and discover a cancer cell nonautonomous function of the Hippo-YAP pathway in regulation of CXCL5, a ligand for CXCR2-expressing MDSCs. Pharmacologic elimination of MDSCs or blocking the heterotypic CXCL5-CXCR2 signaling circuit elicits robust antitumor responses and prolongs survival.