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

Dev Cell. 2024 Aug 5;59(15):1972-1987.e8. doi: 10.1016/j.devcel.2024.05.001. Epub 2024 May 29.

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.

Keywords: AP-1; JNK; Yap; aPKC; cell death; colorectal cancer; intestinal stem cell; metaplasia; preneoplasia; tumor initiation.

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Lineage
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / metabolism
  • Colorectal Neoplasms* / pathology
  • Epithelial Cells* / metabolism
  • Epithelial Cells* / pathology
  • Humans
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Isoenzymes / deficiency
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Metaplasia* / metabolism
  • Metaplasia* / pathology
  • Mice
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Organoids / metabolism
  • Organoids / pathology
  • Protein Kinase C* / genetics
  • Protein Kinase C* / metabolism
  • Stem Cells / metabolism
  • Stem Cells / pathology
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism
  • YAP-Signaling Proteins / metabolism

Substances

  • Protein Kinase C
  • protein kinase C lambda
  • PKC-3 protein
  • Transcription Factor AP-1
  • YAP-Signaling Proteins
  • Adaptor Proteins, Signal Transducing
  • Yap1 protein, mouse
  • Isoenzymes