Myoepithelial progenitors as founder cells of hyperplastic human breast lesions upon PIK3CA transformation
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Dokumenter
- Fulltext
Forlagets udgivne version, 3,13 MB, PDF-dokument
The myoepithelial (MEP) lineage of human breast comprises bipotent and multipotent progenitors in ducts and terminal duct lobular units (TDLUs). We here assess whether this heterogeneity impacts on oncogenic PIK3CA transformation. Single cell RNA sequencing (scRNA-seq) and multicolor imaging reveal that terminal ducts represent the most enriched source of cells with ductal MEP markers including α-smooth muscle actin (α-SMA), keratin K14, K17 and CD200. Furthermore, we find neighboring CD200high and CD200low progenitors within terminal ducts. When sorted and kept in ground state conditions, their CD200low and CD200high phenotypes are preserved. Upon differentiation, progenitors remain multipotent and bipotent, respectively. Immortalized progenitors are transduced with mutant PIK3CA on an shp53 background. Upon transplantation, CD200low MEP progenitors distinguish from CD200high by the formation of multilayered structures with a hyperplastic inner layer of luminal epithelial cells. We suggest a model with spatially distributed MEP progenitors as founder cells of biphasic breast lesions with implications for early detection and prevention strategies.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 219 |
| Tidsskrift | Communications Biology |
| Vol/bind | 5 |
| Udgave nummer | 1 |
| Antal sider | 13 |
| ISSN | 2399-3642 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
We gratefully acknowledge the expert technical assistance from Tove Marianne Lund, Lena Kristensen, and Anita Sharma Friismose. Capio CFR Hospitaler (Benedikte Thuesen and Trine Foged Henriksen) and the donors are acknowledged for providing breast biopsy material. The Core Facility for Integrated Microscopy (University of Copenhagen) is acknowledged for confocal microscope accessibility. We thank Gelo Dela Cruz and the DanStem Flow Cytometry Platform for access to FCS Express to analyze flow cytometry data. Furthermore, we thank Helen Neil and the DanStem Genomics Platform for technical expertise, support, and the use of instruments. Finally, we acknowledge Konstantin Khodosevich, Ulrich Pfisterer, and Andrea Asenjo Martinez for access to and support with scRNA-seq equipment and Samuel Demharter and Katharina Theresa Kohler for assistance with bioinformatics analyses. This work was supported by Novo Nordisk Fonden (NNF17CC0027852) and Danish Research Council grant 10-092798 (to DanStem), Familien Erichsens Mindefond and Vera og Carl Johan Michaelsens Legat (to J.K.), Toyota-Fonden Denmark and Anita og Tage Therkelsens Fond (to R.V.), Harboefonden, Else og Mogens Wedell-Wedellborgs Fond, Danish Cancer Society Grant R146-A9257 and Dagmar Marshalls Fond (to L.R.-J.), Novo Nordisk Fonden (NNF18CC0033666 (to N.G.), and the Kirsten and Freddy Johansens Fond (to O.W.P).
Funding Information:
We gratefully acknowledge the expert technical assistance from Tove Marianne Lund, Lena Kristensen, and Anita Sharma Friismose. Capio CFR Hospitaler (Benedikte Thuesen and Trine Foged Henriksen) and the donors are acknowledged for providing breast biopsy material. The Core Facility for Integrated Microscopy (University of Copenhagen) is acknowledged for confocal microscope accessibility. We thank Gelo Dela Cruz and the DanStem Flow Cytometry Platform for access to FCS Express to analyze flow cytometry data. Furthermore, we thank Helen Neil and the DanStem Genomics Platform for technical expertise, support, and the use of instruments. Finally, we acknowledge Konstantin Khodosevich, Ulrich Pfisterer, and Andrea Asenjo Martinez for access to and support with scRNA-seq equipment and Samuel Demharter and Katharina Theresa Kohler for assistance with bioinformatics analyses. This work was supported by Novo Nordisk Fonden (NNF17CC0027852) and Danish Research Council grant 10-092798 (to DanStem), Familien Erichsens Mindefond and Vera og Carl Johan Michaelsens Legat (to J.K.), Toyota-Fonden Denmark and Anita og Tage Therkelsens Fond (to R.V.), Harboefonden, Else og Mogens Wedell-Wedellborgs Fond, Danish Cancer Society Grant R146-A9257 and Dagmar Marshalls Fond (to L.R.-J.), Novo Nordisk Fonden (NNF18CC0033666 (to N.G.), and the Kirsten and Freddy Johansens Fond (to O.W.P).
Publisher Copyright:
© 2022, The Author(s).
Antal downloads er baseret på statistik fra Google Scholar og www.ku.dk
ID: 301138743