title: Stemness of the hybrid Epithelial/Mesenchymal State in Breast Cancer and Its Association with Poor Survival.
abstract: Breast cancer stem cells (CSCs) are thought to drive recurrence and metastasis. Their identity has been linked to the epithelial to mesenchymal transition (EMT) but remains highly controversial since--depending on the cell-line studied--either epithelial (E) or mesenchymal (M) markers, alone or together have been associated with stemness. Using distinct transcript expression signatures characterizing the three different E, M and hybrid E/M cell-types, our data support a novel model that links a mixed EM signature with stemness in 1) individual cells, 2) luminal and basal cell lines, 3) in vivo xenograft mouse models, and 4) in all breast cancer subtypes. In particular, we found that co-expression of E and M signatures was associated with poorest outcome in luminal and basal breast cancer patients as well as with enrichment for stem-like cells in both E and M breast cell-lines. This link between a mixed EM expression signature and stemness was explained by two findings: first, mixed cultures of E and M cells showed increased cooperation in mammosphere formation (indicative of stemness) compared to the more differentiated E and M cell-types. Second, single-cell qPCR analysis revealed that E and M genes could be co-expressed in the same cell. These hybrid E/M cells were generated by both E or M cells and had a combination of several stem-like traits since they displayed increased plasticity, self-renewal, mammosphere formation, and produced ALDH1+ progenies, while more differentiated M cells showed less plasticity and E cells showed less self-renewal. Thus, the hybrid E/M state reflecting stemness and its promotion by E-M cooperation offers a dual biological rationale for the robust association of the mixed EM signature with poor prognosis, independent of cellular origin. Together, our model explains previous paradoxical findings that breast CSCs appear to be M in luminal cell-lines but E in basal breast cancer cell-lines. Our results suggest that targeting E/M heterogeneity by eliminating hybrid E/M cells and cooperation between E and M cell-types could improve breast cancer patient survival independent of breast cancer-subtype.
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, United States of America.
authors.forename: Anne
authors.initials: A
authors.lastname: Grosse-Wilde
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, United States of America; Luxembourg Centre for Systems Biomedicine, L-4362 Esch-sur-Alzette, Luxembourg.
authors.forename: Aymeric
authors.initials: A
authors.lastname: Fouquier d'Hérouël
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, United States of America.
authors.forename: Ellie
authors.initials: E
authors.lastname: McIntosh
authors.affiliation: Luxembourg Centre for Systems Biomedicine, L-4362 Esch-sur-Alzette, Luxembourg.
authors.forename: Gökhan
authors.initials: G
authors.lastname: Ertaylan
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, United States of America; Luxembourg Centre for Systems Biomedicine, L-4362 Esch-sur-Alzette, Luxembourg.
authors.forename: Alexander
authors.initials: A
authors.lastname: Skupin
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, United States of America.
authors.forename: Rolf E
authors.initials: RE
authors.lastname: Kuestner
authors.affiliation: Luxembourg Centre for Systems Biomedicine, L-4362 Esch-sur-Alzette, Luxembourg.
authors.forename: Antonio
authors.initials: A
authors.lastname: del Sol
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, United States of America.
authors.forename: Kathie-Anne
authors.initials: KA
authors.lastname: Walters
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, United States of America.
authors.forename: Sui
authors.initials: S
authors.lastname: Huang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate