RESUMEN
Metastasis is the principal cause of cancer death, yet we lack an understanding of metastatic cell states, their relationship to primary tumor states, and the mechanisms by which they transition. In a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that while primary tumors largely adopt LGR5 + intestinal stem-like states, metastases display progressive plasticity. Loss of intestinal cell states is accompanied by reprogramming into a highly conserved fetal progenitor state, followed by non-canonical differentiation into divergent squamous and neuroendocrine-like states, which is exacerbated by chemotherapy and associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cancer cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues than their intestinal lineage-restricted primary tumor counterparts. We identify PROX1 as a stabilizer of intestinal lineage in the fetal progenitor state, whose downregulation licenses non-canonical reprogramming.
RESUMEN
Positional information is pivotal for establishing developmental patterning in plants, but little is known about the underlying signalling mechanisms. The Arabidopsis root radial pattern is generated through stereotyped division of initial cells and the subsequent acquisition of cell fate. short-root (shr) mutants do not undergo the longitudinal cell division of the cortex/endodermis initial daughter cell, resulting in a single cell layer with only cortex attributes. Thus, SHR is necessary for both cell division and endodermis specification. SHR messenger RNA is found exclusively in the stele cells internal to the endodermis and cortex, indicating that it has a non-cell-autonomous mode of action. Here we show that the SHR protein, a putative transcription factor, moves from the stele to a single layer of adjacent cells, where it enters the nucleus. Ectopic expression of SHR driven by the promoter of the downstream gene SCARECROW (SCR) results in autocatalytic reinforcement of SHR signalling, producing altered cell fates and multiplication of cell layers. These results support a model in which SHR protein acts both as a signal from the stele and as an activator of endodermal cell fate and SCR-mediated cell division.
