title: A self-enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells.
abstract: Invasion and metastasis of carcinomas are often activated by induction of aberrant epithelial-mesenchymal transition (EMT). This is mainly driven by the transcription factor ZEB1, promoting tumor-initiating capacity correlated with increased expression of the putative stem cell marker CD44. However, the direct link between ZEB1, CD44 and tumourigenesis is still enigmatic. Remarkably, EMT-induced repression of ESRP1 controls alternative splicing of CD44, causing a shift in the expression from the variant CD44v to the standard CD44s isoform. We analyzed whether CD44 and ZEB1 regulate each other and show that ZEB1 controls CD44s splicing by repression of ESRP1 in breast and pancreatic cancer. Intriguingly, CD44s itself activates the expression of ZEB1, resulting in a self-sustaining ZEB1 and CD44s expression. Activation of this novel CD44s-ZEB1 regulatory loop has functional impact on tumor cells, as evident by increased tumor-sphere initiation capacity, drug-resistance and tumor recurrence. In summary, we identified a self-enforcing feedback loop that employs CD44s to activate ZEB1 expression. This renders tumor cell stemness independent of external stimuli, as ZEB1 downregulates ESRP1, further promoting CD44s isoform synthesis.
authors.affiliation: Department of Visceral Surgery, University Medical Center Freiburg, D-79106, Freiburg, Germany.|Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: Bogdan-Tiberius
authors.initials: BT
authors.lastname: Preca
authors.affiliation: Department of Visceral Surgery, University Medical Center Freiburg, D-79106, Freiburg, Germany.|Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: Karolina
authors.initials: K
authors.lastname: Bajdak
authors.affiliation: Department of Visceral Surgery, University Medical Center Freiburg, D-79106, Freiburg, Germany.|Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Mock
authors.affiliation: Department of Visceral Surgery, University Medical Center Freiburg, D-79106, Freiburg, Germany.|Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.|Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, Germany.
authors.forename: Vignesh
authors.initials: V
authors.lastname: Sundararajan
authors.affiliation: Department of Visceral Surgery, University Medical Center Freiburg, D-79106, Freiburg, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Pfannstiel
authors.affiliation: Department of Visceral Surgery, University Medical Center Freiburg, D-79106, Freiburg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Maurer
authors.affiliation: Department of Surgery, University Medical Center Schleswig-Holstein, Campus Lübeck, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wellner
authors.affiliation: Department of Visceral Surgery, University Medical Center Freiburg, D-79106, Freiburg, Germany.
authors.forename: Ulrich T
authors.initials: UT
authors.lastname: Hopt
authors.affiliation: Institute for Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Germany.|BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Germany.|Comprehensive Cancer Center Freiburg, University Medical Center Freiburg, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Brummer
authors.affiliation: Department of Visceral Surgery, University Medical Center Freiburg, D-79106, Freiburg, Germany.|Department of Experimental Medicine I, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, D-91054, Erlangen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Brabletz
authors.affiliation: Department of Experimental Medicine I, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, D-91054, Erlangen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brabletz
authors.affiliation: Department of Visceral Surgery, University Medical Center Freiburg, D-79106, Freiburg, Germany.|Department of Experimental Medicine I, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, D-91054, Erlangen, Germany.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Stemmler
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics*; D061986:MCF-7 Cells; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D016601:RNA-Binding Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: C497483:CD44 protein, human; C539364:ESRP1 protein, human; D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1
keywords: cancer stem cells; differential splicing; drug resistance; epithelial-mesenchymal transition (EMT); metastasis