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Series GSE249567 Query DataSets for GSE249567
Status Public on Jan 08, 2025
Title Cancer-associated Fibroblast Induces Acinar-to-ductal Cell Transdifferentiation and Pancreatic Cancer Initiation via LAMA5/ITGA4 axis
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 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.
 
Overall design 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.
 
Contributor(s) Parte S, Kaur AB, Nimmakayala RK, Ogunleye AO, Chirravuri R, Vengoji R, Leon F, Nallasamy P, Rauth S, Alsafwani ZW, Lele SM, Cox JL, Bhat I, Singh S, Batra SK, Ponnusamy MP
Citation(s) 38154529
Submission date Dec 06, 2023
Last update date Jan 08, 2025
Contact name Moorthy Palanimuthu Ponnusamy
E-mail(s) mpalanim@unmc.edu
Phone 4022156331
Organization name University of Nebraska Medical Center
Department Biochemistry and Molecular Biology
Lab Dr. Ponnusamy's Lab DRC1 7056
Street address 42nd and Emile
City Omaha
State/province Nebraska
ZIP/Postal code 68198
Country USA
 
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (6)
GSM7950136 266_6_CAF_CM_treated1
GSM7950137 266_6_CAF_CM_treated2
GSM7950138 266_6_CAF_CM_treated3
Relations
BioProject PRJNA1049495

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Supplementary file Size Download File type/resource
GSE249567_CAF_acinar_counts.tsv.gz 767.4 Kb (ftp)(http) TSV
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Raw data are available in SRA

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