RT Journal Article
SR Electronic
T1 Luminal progenitors undergo partial epithelial-to-mesenchymal transition at the onset of basal-like breast tumorigenesis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.08.494710
DO 10.1101/2022.06.08.494710
A1 Camille Landragin
A1 Melissa Saichi
A1 Pacôme Prompsy
A1 Adeline Durand
A1 Jérémy Mesple
A1 Amandine Trouchet
A1 Marisa Faraldo
A1 Hélène Salmon
A1 Céline Vallot
YR 2022
UL http://biorxiv.org/content/early/2022/06/09/2022.06.08.494710.abstract
AB Defects in double-strand repair mechanisms - both through germline or somatic inactivation of repair genes - is a hallmark of basal-like breast cancers. In this genetically-unstable context, a recurrent shift in cell identity occurs within the mammary epithelium. Basal-like tumors have indeed been proposed to originate from luminal progenitor (LP) cells yet tumor-initiating events remain poorly understood. Here, we map state transitions at the onset of basal-like tumorigenesis, using a Brca-1 deficient mouse model launching tumorigenesis in multiple LP cells. Combining single-cell transcriptomics to spatial multiplex imaging, we identify a population of cycling p16-expressing cells, emerging from the luminal progenitor compartment, undergoing partial epithelial-to-mesenchymal transition and losing luminal identity. Pseudo-temporal analyses position these cells as a transitory pre-tumoral state between aberrant Brca1-deficient luminal progenitors and growing tumor cells. In patients, the p16 pre-tumoral signature is found in early stage basal-like tumors, that rarely recur. Concomitant to p16 activation, we show that LP cells undergo an epigenomic crisis attested by the general re-organization of their heterochromatin. They accumulate multiple H3K27me3 micro-foci - reminiscent of the formation of senescence-associated heterochromatin foci (SAHFs) - and lose their inactive X (Xi). Both p16 activation and heterochromatin reorganization are hallmarks of human basal-like breast tumors; we propose that these events occur during initial LP transformation and are scars of an initial transitory senescent-like state.Competing Interest StatementThe authors have declared no competing interest.