Epithelial aPKC deficiency leads to stem cell loss preceding metaplasia in colorectal cancer initiation.

TitleEpithelial aPKC deficiency leads to stem cell loss preceding metaplasia in colorectal cancer initiation.
Publication TypeJournal Article
Year of Publication2024
AuthorsKinoshita H, Martinez-Ordoñez A, Cid-Diaz T, Han Q, Duran A, Muta Y, Zhang X, Linares JF, Nakanishi Y, Kasashima H, Yashiro M, Maeda K, Albaladejo-Gonzalez A, Torres-Moreno D, García-Solano J, Conesa-Zamora P, Inghirami G, Diaz-Meco MT, Moscat J
JournalDev Cell
Volume59
Issue15
Pagination1972-1987.e8
Date Published2024 Aug 05
ISSN1878-1551
KeywordsAdaptor Proteins, Signal Transducing, Animals, Cell Lineage, Cell Transformation, Neoplastic, Colorectal Neoplasms, Epithelial Cells, Humans, Intestinal Mucosa, Isoenzymes, Metaplasia, Mice, Neoplastic Stem Cells, Organoids, Protein Kinase C, Stem Cells, Transcription Factor AP-1, YAP-Signaling Proteins
Abstract

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.

DOI10.1016/j.devcel.2024.05.001
Alternate JournalDev Cell
PubMed ID38815584
PubMed Central IDPMC11303105
Grant ListR50 CA265332 / CA / NCI NIH HHS / United States
R01 CA250025 / CA / NCI NIH HHS / United States
R50 CA283476 / CA / NCI NIH HHS / United States
R01 CA246765 / CA / NCI NIH HHS / United States
R01 CA275846 / CA / NCI NIH HHS / United States
R01 CA265892 / CA / NCI NIH HHS / United States
Related Faculty: 
Maria Angeles Duran, Ph.D. Dr. Xiao Zhang Giorgio Inghirami, M.D. Maria Diaz-Meco Conde, Ph.D. Jorge Moscat, Ph.D.

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