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

Abstract

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 state between aberrant Brca1deficient luminal progenitors and growing tumor cells. 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 senescenceassociated 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.

Alpha-6 integrin deletion delays the formation of Brca1/p53-deficient basal-like breast tumors by restricting luminal progenitor cell expansion

“…Furthermore, in agreement with previous studies, we found that, in Brca1/p53-deficient epithelium, a non-negligible fraction of p16 + cells was abnormally cycling, as shown by their Ki67 status (Fig. 5 E; [ 40 , 41 ]. Of interest, we found that the amount of cycling p16 + cells was reduced in Itgα6-deficient glands, predominantly in normal-looking epithelial structures, suggesting cell cycle misregulation in cells expressing p16 in preneoplastic glands (Fig.…”

“…Among invasive breast cancer, basal-like tumors are characterized by the high expression of the cell cycle inhibitor p16 at the transcriptional level [ 40 ]. Moreover, the presence of a p16-expressing luminal cell population in preneoplastic Blg-Cre;Brca1 F/F ;Trp53 F/F mammary tissue has been recently reported [ 41 ]. In agreement with these recent findings, we detected p16 expression in luminal cells (K8 + /α-SMA) from 5-month-old Brca1 mutant mice, but not in control mice (Fig.…”

Multi-modal transcriptomic analysis unravels enrichment of hybrid epithelial/mesenchymal state and enhanced phenotypic heterogeneity in basal breast cancer

“…These trends are further supported by recent experimental observations that luminal progenitors, the proposed cell of origin of basal-like tumors, undergo a pEMT at onset of tumorigenesis (Landragin et al, 2022). Moreover, mammary basal epithelial cells have been shown to exhibit a pEMT state, i.e.…”

“…For instance, mature mammary luminal epithelial cells can give rise to Krt14 and Sox9-expressing basal-like carcinomas that can metastasize (Kern et al, 2022). Similarly, basal-like tumorigenesis involves luminal-to-basal reprogramming with gain in stemness (Christin et al, 2020; Landragin et al, 2022). Further, luminal-basal hybrid cells can express NP63 (basal marker) while maintaining functional levels of ER-alpha (associated with luminal phenotype) (Padua et al, 2018).…”

Cooperative pro-tumorigenic adaptation to oncogenic RAS through epithelial-to-mesenchymal plasticity

“…Our study further highlights a mechanistic link between OIS and EMP during malignant transformation. Strengthening our observations, recent studies have used a pan-cancer scRNA-seq approach to show recurrent signatures associated with EMP and senescence at tumor initiation and over the course of malignant transformation (47)(48)(49). Cellular senescence is a stress response that is generally considered to irreversibly arrest the cell cycle following a variety of intrinsic and extrinsic stressors such as shortening of chromosomal termini, DNA damage, oxidative stress, oncogenic insults, or inactivation of tumor suppressors (50).…”