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Serotonin uptake is required for Rac1 activation in Kras‐induced acinar‐to‐ductal metaplasia in the pancreas
Author(s) -
Saponara Enrica,
Visentin Michele,
Baschieri Francesco,
Seleznik Gitta,
Martinelli Paola,
Esposito Irene,
Buschmann Johanna,
Chen Rong,
Parrotta Rossella,
Borgeaud Nathalie,
Bombardo Marta,
Malagola Ermanno,
Caflisch Amedeo,
Farhan Hesso,
Graf Rolf,
Sonda Sabrina
Publication year - 2018
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5147
Subject(s) - cancer research , acinar cell , rac1 , pancreatic cancer , biology , in vivo , pancreas , transdifferentiation , medicine , endocrinology , cancer , microbiology and biotechnology , signal transduction , stem cell
Pancreatic ductal adenocarcinoma (PDAC), which is the primary cause of pancreatic cancer mortality, is poorly responsive to currently available interventions. Identifying new targets that drive PDAC formation and progression is critical for developing alternative therapeutic strategies to treat this lethal malignancy. Using genetic and pharmacological approaches, we investigated in vivo and in vitro whether uptake of the monoamine serotonin [5‐hydroxytryptamine (5‐HT)] is required for PDAC development. We demonstrated that pancreatic acinar cells have the ability to readily take up 5‐HT in a transport‐mediated manner. 5‐HT uptake promoted activation of the small GTPase Ras‐related C3 botulinum toxin substrate 1 (Rac1), which is required for transdifferentiation of acinar cells into acinar‐to‐ductal metaplasia (ADM), a key determinant in PDAC development. Consistent with the central role played by Rac1 in ADM formation, inhibition of the 5‐HT transporter Sert ( Slc6a4 ) with fluoxetine reduced ADM formation both in vitro and in vivo in a cell‐autonomous manner. In addition, fluoxetine treatment profoundly compromised the stromal reaction and affected the proliferation and lipid metabolism of malignant PDAC cells. We propose that Sert is a promising therapeutic target to counteract the early event of ADM, with the potential to stall the initiation and progression of pancreatic carcinogenesis. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.