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

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. [Display omitted] • aPKC deficiency acutely drives intrinsic stem cell loss in the intestinal epithelium • Stem cells are lost before metaplasia and in aPKC-low dysplasia and CRC • Revival stem and fetal metaplasia cells are two spatiotemporally distinct populations • JNK activation by low aPKC leads to stem cell loss and metaplasia through AP-1/YAP Kinoshita and Martinez-Ordoñez et al. demonstrate that aPKC loss is an early event in the initiation of colorectal cancer through the conventional and serrated pathways. This is associated with impaired intestinal stem cells, preceding the activation of the revival and metaplastic cell programs through a JNK-driven AP-1/YAP cascade. [ABSTRACT FROM AUTHOR]