title: Cell-state transitions regulated by SLUG are critical for tissue regeneration and tumor initiation.
abstract: Perturbations in stem cell activity and differentiation can lead to developmental defects and cancer. We use an approach involving a quantitative model of cell-state transitions in vitro to gain insights into how SLUG/SNAI2, a key developmental transcription factor, modulates mammary epithelial stem cell activity and differentiation in vivo. In the absence of SLUG, stem cells fail to transition into basal progenitor cells, while existing basal progenitor cells undergo luminal differentiation; together, these changes result in abnormal mammary architecture and defects in tissue function. Furthermore, we show that in the absence of SLUG, mammary stem cell activity necessary for tissue regeneration and cancer initiation is lost. Mechanistically, SLUG regulates differentiation and cellular plasticity by recruiting the chromatin modifier lysine-specific demethylase 1 (LSD1) to promoters of lineage-specific genes to repress transcription. Together, these results demonstrate that SLUG plays a dual role in repressing luminal epithelial differentiation while unlocking stem cell transitions necessary for tumorigenesis.
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA ; Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Phillips
authors.affiliation: Translational Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain.
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA ; Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
authors.forename: Maja
authors.initials: M
authors.lastname: Sedic
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge MA, 02142, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Proia
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA ; Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
authors.forename: Ania
authors.initials: A
authors.lastname: Wronski
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
authors.forename: Sohini
authors.initials: S
authors.lastname: Mazumdar
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA ; Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Skibinski
authors.affiliation: Department of Molecular Carcinogenesis, Science Park - Research Division, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Shirley
authors.affiliation: Department of Genetics and Pathology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27514, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Gill
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge MA, 02142, USA ; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Piyush B
authors.initials: PB
authors.lastname: Gupta
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA ; Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kuperwasser
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic; D018572:Disease-Free Survival; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009369:Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012038:Regeneration; D000071250:Snail Family Transcription Factors; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D006657:Histones; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors