Epithelial presenilin-1 drives colorectal tumour growth by controlling EGFR-COX2 signalling
Menée à l'aide de lignées cellulaires, d'échantillons tumoraux provenant de patients atteints d'un cancer colorectal, d'échantillons témoins, d'organoïdes et de modèles murins, cette étude met en évidence un mécanisme par lequel la préséniline-1 épithéliale favorise la croissance tumorale en augmentant la signalisation du récepteur EGFR et en activant la voie de signalisation
Objective : Psen1 was previously characterised as a crucial factor in the pathogenesis of neurodegeneration in patients with Alzheimer’s disease. Little, if any, is known about its function in the gut. Here, we uncovered an unexpected functional role of Psen1 in gut epithelial cells during intestinal tumourigenesis. Design : Human colorectal cancer (CRC) and control samples were investigated for PSEN1 and proteins of the
γ-secretase complex. Tumour formation was analysed in the AOM-DSS and Apcmin/+ mouse models using newly generated epithelial-specific Psen1 deficient mice. Psen1 deficient human CRC cells were studied in a xenograft tumour model. Tumour-derived organoids were analysed for growth and RNA-Seq was performed to identify Psen1-regulated pathways. Tumouroids were generated to study EGFR activation and evaluation of the influence of prostanoids. Results
:
PSEN1 is expressed in the intestinal epithelium and its level is increased in human CRC. Psen1-deficient mice developed only small tumours and human cancer cell lines deficient in Psen1 had a reduced tumourigenicity. Tumouroids derived from Psen1-deficient Apcmin/+ mice exhibited stunted growth and reduced cell proliferation. On a molecular level, PSEN1 potentiated tumour cell proliferation via enhanced EGFR signalling and COX-2 production. Exogenous administration of PGE2 reversed the slow growth of PSEN1 deficient tumour cells via PGE2 receptor 4 (EP4) receptor signalling. Conclusions
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Psen1 drives tumour development by increasing EGFR signalling via NOTCH1 processing, and by activating the COX-2-PGE2 pathway. PSEN1 inhibition could be a useful strategy in treatment of CRC.
Gut 2022