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A decision-point between programmed cell death and transdifferentiation in pancreatic cancer

ABSTRACT: Transdifferentiation and changes of cellular identity are hallmarks of malignant transformation1-3. As such, the process of acinar-to-ductal metaplasia (ADM) represents a fundamental step in pancreatic ductal adenocarcinoma (PDAC) development, but regulatory pathways controlling ADM are not fully understood4,5. Here, we show that murine pancreatic acinar cells upregulate expression of CASPASE3, CASPASE8, RIPK3 and MLKL - key molecules driving both apoptosis and necroptosis6,7 - during transdifferentiation towards a duct-like phenotype. Spontaneous activation of these respective programmed cell death (PCD) pathways during KRAS-driven transdifferentiation is counterbalanced by transforming growth factor (TGF)-β-activated kinase 1 (TAK1), a kinase transmitting inhibitory phosphorylation signals towards the apoptosis- and necroptosis activator RIPK18. Genetic deletion or pharmacological inhibition of TAK1 simultaneously triggered apoptosis and necroptosis and thereby prevented KRAS-driven ADM in vitro as well as KRAS-driven PDAC in vivo. In line, TAK1 expression is upregulated in human PDAC cells, and pharmacological inhibition of TAK1 triggered PCD in organoid and spheroid cells derived from PDAC patients. Collectively, these findings suggest that TAK1 defines a decision point between ADM and PCD in pancreas cells and represents a promising pharmacological target for the prevention and treatment of PDAC patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE223135 | GEO | 2024/11/29

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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A decision-point between programmed cell death and transdifferentiation in pancreatic cancer

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