Epithelial aPKC deficiency leads to stem cell loss preceding metaplasia in colorectal cancer initiation [scRNA-Seq]
The early mechanisms of spontaneous tumor initiation that precede the accumulation of cancer mutations 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 pre-neoplastic lesions, which is perpetuated in colorectal cancers (CRC). Acute inactivation of PKCl/i in vivo and in 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 (ISC), including LGR5+ cells. This is followed by the accumulation of revival stem cells (RSC) at the bottom of the crypt and fetal metaplastic cells (FMC) 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 Overall design: WT (Prkcif/fPrkcif/f, Prkczf/f, and  Prkcif/f mice),   LKO  (Prkcif/f;Villin-Cre),  ZKO (Prkczf/f;Villin-Cre) and DKO (Prkcif/fPrkcif/f;Villin-Cre) mice small intestines were profiled for scRNAseq