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Single-cell resolution spatial analysis of antigen-presenting cancer-associated fibroblast niches [Xenium PDAC]

ABSTRACT: To explore the CAF niches in pancreatic ductal adenocarcinoma (PDAC), we performed Xenium assays in 3 treatment-naïve and 3 chemoradiotherapy-treated human PDAC samples. We found that after the chemoradiotherapy treatment, tissues became more desmoplastic with a larger CAF proportion. And interestingly, we found there was a reduction of cancer cell 1 in the chemoradiotherapy group while the ratio of cancer cell 2 remained similar, suggesting cancer cell 2 was the chemoradiotherapy-resistant cancer cell population. Through differential gene analysis, we found cancer 2 was marked by a high level of SPP1 expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274673 | GEO | 2025/09/15

REPOSITORIES: GEO

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by desmoplastic stroma surrounding most tumors. Activated stromal fibroblasts, namely Cancer-associated fibroblasts (CAFs), play a major role in PDAC progression. Here we analyzed if CAFs influence acinar cells and impact PDAC initiation, namely “Acinar to Ductal Metaplasia” (ADM). ADM connection with PDAC pathophysiology is indicated but not yet established. Hence, we hypothesized that CAF secretome might play a significant role in ADM in PDAC initiation. Mouse and human acinar cell organoids, acinar cells cocultured with CAFs and exposed to CAF-conditioned media (CAF-CM), acinar cell explants, and CAF cocultures, etc., were examined by qRT-PCR, RNA-seq, immunoblotting and confocal microscopy. Data from LC-MS/MS analysis of CAF CM and RNAseq data of acinar cells post-CM exposure were integrated using bioinformatics tools to identify molecular mechanism for CAF-induced ADM. Using confocal microscopy, immunoblotting, and qRT-PCR analysis, we validated the depletion of key signaling axis in cell-line, acinar explant coculture, and mCAFs. Close association of acino-ductal (UEA1, Amylase, Ck19) markers and mCAFs (α-SMA) in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1Cre (KPC) and LSL-KrasG12D/+; Pdx1Cre (KC) autochthonous progression tumor tissue was observed. Caerulein treatment-induced mCAFs increased Ck19 and decreased Amylase in wild-type (WT) and KC pancreas. Likewise, acinar-mCAF cocultures revealed induction of ductal transdifferentiation in cell-line, acinar-organoid, and explant coculture formats in WT and KC mice pancreas. Proteomic and transcriptomic data integration revealed a novel Laminin5/Integrinα4/Stat3 axis responsible for CAF-mediated acinar to ductal cell transdifferentiation. Results collectively suggest the first evidence for CAF-influenced acino-ductal phenotypic switchover, thus highlighting the role of the tumor micro-environment in the inception of pancreatic carcinogenesis.

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Single-cell resolution spatial analysis of antigen-presenting cancer-associated fibroblast niches [Xenium PDAC]

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