A human breast atlas integrating single-cell proteomics and transcriptomics

Gray, G. Kenneth; Li, Carman Man-Chung; Rosenbluth, Jennifer M.; Selfors, Laura M.; Girnius, Nomeda; Lin, Jia-Ren; Schackmann, Ron C.J.; Goh, Walter L.; Moore, Kaitlin; Shapiro, Hana Kobayashi; Mei, Shaolin; D’Andrea, Kurt; Nathanson, Katherine L.; Sorger, Peter K.; Santagata, Sandro; Regev, Aviv; Garber, Judy E.; Dillon, Deborah; Brugge, Joan S.

doi:10.1016/j.devcel.2022.05.003

Cited by 81 publications

(129 citation statements)

References 193 publications

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“…Among the earliest events to detect, we show the advent of dual expression of basal and luminal markers - supported by multiplex imaging data of isolated p16+ cells detaching from the luminal compartment. A recent study actually shows that alveolar cells with dual basal/luminal markers, and a gene-signature associated with basal-like cancers, accumulate with age in human breast (Gray et al 2022), further highlighting the potential interest of cells with poor lineage definition.…”

Section: Discussionmentioning

confidence: 99%

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

Landragin

Saichi

Prompsy

et al. 2022

Preprint

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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.

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Section: Discussionmentioning

confidence: 99%

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

Landragin

Saichi

Prompsy

et al. 2022

Preprint

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“…Recent studies have suggested that luminal cells with basal cell properties are enriched for gene signatures of basal-like breast cancers and number of cells with this property increase with aging 17 . Whether locally produced IL-6 is responsible for luminal cells acquiring basal phenotype remains to be determined although there is evidence in the literature for IL-6 conferring plasticity to epithelial cells 61 .…”

Section: Discussionmentioning

confidence: 99%

“…PZP:breast epithelial cell communication resulted in elevated expression of IL-6. Furthermore, epithelial cells acquired CD49f + /EpCAMbasal cell characteristics, which has been shown to increase with aging and to increase susceptibility to breast cancer 17,18 . PZP cells, when transformed with oncogenes, generated metaplastic carcinomas in NSG mice suggesting that these cells are cell-of-origin of metaplastic carcinomas of the breast 19 .…”

Section: Introductionmentioning

confidence: 99%

Influence of genetic ancestry on breast stromal cells provides biologic basis for increased incidence of metaplastic breast cancer in women of African descent

Kumar¹,

Batic

Bhat‐Nakshatri

et al. 2022

Preprint

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The biologic basis of genetic ancestry-dependent variability in disease incidence and outcome is just beginning to be explored. We recently reported enrichment of a population of ZEB1-expressing cells located adjacent to the ductal epithelial cells in the normal breast of women of African Ancestry (AA) compared to European Ancestry (EA). By establishing and characterizing cell lines corresponding to these cells and validating in vitro findings with tissue microarrays of healthy breast tissue from AA, EA and Latina Ancestry (LA) women, we demonstrate that these cells have the properties of fibroadipogenic/mesenchymal stromal cells that express PROCR and PDGFRa. PROCR+/ZEB1+/PDGFRa+ cells, hence renamed as PZP cells, are enriched in the normal breast tissues of AA compared to EA or LA women. In vitro, PZP cells trans-differentiated into adipocytes or osteocytes. In co-culture conditions, PZP:epithelial cell communication resulted in luminal epithelial cells acquiring basal/stem cell characteristics and increased expression of IL-6 suggesting the impact of this communication on breast epithelial hierarchy and the microenvironment. Consistent with this possibility, the level of phosphoSTAT3, which is a downstream target of IL-6, was higher in the normal and cancerous breast tissues of AA compared to EA women. PZP cells transformed with HRasG12V ± SV40-T/t antigens generated metaplastic carcinoma in NSG mice suggesting that these cells could be the cell-of-origin of metaplastic breast cancers. Collectively, these results identify a stromal cell component that could influence the biology of breast cancer in AA women.

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“…Co-culturing of epithelial cells with PZP cells caused changes in the phenotype of epithelial cells with a fraction of luminal progenitor cells acquiring basal like properties. Recent studies have suggested that luminal cells with basal cell properties are enriched for gene signatures of basal-like breast cancers and number of cells with this property increase with aging 17 . Whether locally produced IL-6 is responsible for luminal cells acquiring basal phenotype remains to be determined although there is evidence in the literature for IL-6 conferring plasticity to epithelial cells 61 .…”

Section: Discussionmentioning

confidence: 99%

“…PZP:breast epithelial cell communication resulted in elevated expression of IL-6. Furthermore, epithelial cells acquired CD49f + /EpCAM - basal cell characteristics, which has been shown to increase with aging and to increase susceptibility to breast cancer 17, 18 . PZP cells, when transformed with oncogenes, generated metaplastic carcinomas in NSG mice suggesting that these cells are cell-of-origin of metaplastic carcinomas of the breast 19 .…”

Section: Introductionmentioning

confidence: 99%

Influence of genetic ancestry on breast stromal cells provides biologic basis for increased incidence of metaplastic breast cancer in women of African descent

Kumar

Batic

Bhat‐Nakshatri

et al. 2022

Preprint

View full text Add to dashboard Cite

The biologic basis of genetic ancestry-dependent variability in disease incidence and outcome is just beginning to be explored. We recently reported enrichment of a population of ZEB1-expressing cells located adjacent to the ductal epithelial cells in the normal breast of women of African Ancestry (AA) compared to European Ancestry (EA). By establishing and characterizing cell lines corresponding to these cells and validating in vitro findings with tissue microarrays of healthy breast tissue from AA, EA and Latina Ancestry (LA) women, we demonstrate that these cells have the properties of fibroadipogenic/mesenchymal stromal cells that express PROCR and PDGFRalpha;. PROCR+/ZEB1+/PDGFRalpha+ cells, hence renamed as PZP cells, are enriched in the normal breast tissues of AA compared to EA or LA women. In vitro, PZP cells trans-differentiated into adipocytes or osteocytes. In co-culture conditions, PZP:epithelial cell communication resulted in luminal epithelial cells acquiring basal/stem cell characteristics and increased expression of IL-6 suggesting the impact of this communication on breast epithelial hierarchy and the microenvironment. Consistent with this possibility, the level of phospho-STAT3, which is a downstream target of IL-6, was higher in the normal and cancerous breast tissues of AA compared to EA women. PZP cells transformed with HRasG12V with or without SV40-T/t antigens generated metaplastic carcinoma in NSG mice suggesting that these cells could be the cell-of-origin of metaplastic breast cancers. Collectively, these results identify a stromal cell component that could influence the biology of breast cancer in AA women.

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A human breast atlas integrating single-cell proteomics and transcriptomics

Cited by 81 publications

References 193 publications

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

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

Influence of genetic ancestry on breast stromal cells provides biologic basis for increased incidence of metaplastic breast cancer in women of African descent

Influence of genetic ancestry on breast stromal cells provides biologic basis for increased incidence of metaplastic breast cancer in women of African descent

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