Luminal progenitors undergo partial epithelial-to-mesenchymal transition at the onset of basal-like breast tumorigenesis

Camille Landragin (1) , Melissa Saichi (1) , Pacôme Prompsy (1) , Adeline Durand (1) , Jérémy Mesple (1) , Amandine Trouchet (1) , Marisa Faraldo (1) , Hélène Salmon (1) , Céline Vallot (1)

1 Institut Curie [Paris]

SUMMARY 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.

Domaines: Sciences du Vivant [q-bio]

Camille Landragin, Melissa Saichi, Pacôme Prompsy, Adeline Durand, Jérémy Mesple, et al.. Luminal progenitors undergo partial epithelial-to-mesenchymal transition at the onset of basal-like breast tumorigenesis. 2022. ⟨hal-03860732⟩