ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR317/028/SRR31771928/SRR31771928_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR317/027/SRR31771927/SRR31771927_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR317/026/SRR31771926/SRR31771926_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR317/028/SRR31771928/SRR31771928_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR317/024/SRR31771924/SRR31771924_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR317/025/SRR31771925/SRR31771925_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR317/022/SRR31771922/SRR31771922_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR317/027/SRR31771927/SRR31771927_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR317/024/SRR31771924/SRR31771924_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR317/023/SRR31771923/SRR31771923_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR317/029/SRR31771929/SRR31771929_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR317/029/SRR31771929/SRR31771929_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR317/023/SRR31771923/SRR31771923_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR317/022/SRR31771922/SRR31771922_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR317/026/SRR31771926/SRR31771926_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR317/025/SRR31771925/SRR31771925_1.fastq.gzprimaryOK200Genomicsroswell park comprehensive cancer centerhttps://www.ebi.ac.uk/ena/browser/view/PRJNA1200227The incidence of pancreatic ductal adenocarcinoma (PDAC) is on the rise, and host factors like obesity increase risk by 60% and mortality by two-fold however, the mechanisms that drive obesity-associated tumorigenesis are poorly understood. Here, we showed that obesity-mediated pancreatic steatosis was associated with a higher level of neo-innervation in PDAC. Neo-innervation mostly comprised sympathetic neurons that released catecholamines, which ligated the adrenergic receptor on both tumor and immune cells, subsequently activating a downstream signaling cascade that led to a pro-tumorigenic type 2 immune microenvironment accelerating tumorigenesis. Further, we identified NgCAM-related cell adhesion molecule (NrCAM) and nerve growth factor (NGF) as major mediators secreted by adipocytes that drove neurogenesis. Targeting neuro-adrenergic signaling by nerve ablation or pharmacologic approaches abolished obesity-related tumor progression. Overall, this study advances our understanding of the fundamental biology underpinning obesity-mediated neo-innervation and its causal link to exacerbating PDAC development, providing new avenues for therapeutic intervention.ENAfalseObesity-mediated intratumoral innervation increases pancreatic cancer tumorigenesis2025-05-092025-05-09PRJNA1200227