RESUMEN
The early mechanisms of spontaneous tumor initiation that precede malignancy are largely unknown. We show that reduced aPKC levels correlate with stem cell loss and the induction of revival and metaplastic programs in serrated- and conventional-initiated premalignant lesions, which is perpetuated in colorectal cancers (CRCs). Acute inactivation of PKCλ/ι in vivo and in mouse organoids is sufficient to stimulate JNK in non-transformed intestinal epithelial cells (IECs), which promotes cell death and the rapid loss of the intestinal stem cells (ISCs), including those that are LGR5+. This is followed by the accumulation of revival stem cells (RSCs) at the bottom of the crypt and fetal-metaplastic cells (FMCs) at the top, creating two spatiotemporally distinct cell populations that depend on JNK-induced AP-1 and YAP. These cell lineage changes are maintained during cancer initiation and progression and determine the aggressive phenotype of human CRC, irrespective of their serrated or conventional origin.
Asunto(s)
Neoplasias Colorrectales , Células Epiteliales , Metaplasia , Proteína Quinasa C , Animales , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Proteína Quinasa C/metabolismo , Proteína Quinasa C/genética , Metaplasia/patología , Metaplasia/metabolismo , Ratones , Humanos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Células Madre/metabolismo , Células Madre/patología , Factor de Transcripción AP-1/metabolismo , Factor de Transcripción AP-1/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Proteínas Señalizadoras YAP/metabolismo , Transformación Celular Neoplásica/patología , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Organoides/metabolismo , Organoides/patología , Linaje de la Célula , Isoenzimas/metabolismo , Isoenzimas/genética , Isoenzimas/deficiencia , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/metabolismoRESUMEN
The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.