title: TGF-β reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24- cancer cells.
abstract: Many lines of evidence have indicated that both genetic and non-genetic determinants can contribute to intra-tumor heterogeneity and influence cancer outcomes. Among the best described sub-population of cancer cells generated by non-genetic mechanisms are cells characterized by a CD44+/CD24- cell surface marker profile. Here, we report that human CD44+/CD24- cancer cells are genetically highly unstable because of intrinsic defects in their DNA-repair capabilities. In fact, in CD44+/CD24- cells, constitutive activation of the TGF-beta axis was both necessary and sufficient to reduce the expression of genes that are crucial in coordinating DNA damage repair mechanisms. Consequently, we observed that cancer cells that reside in a CD44+/CD24- state are characterized by increased accumulation of DNA copy number alterations, greater genetic diversity and improved adaptability to drug treatment. Together, these data suggest that the transition into a CD44+/CD24- cell state can promote intra-tumor genetic heterogeneity, spur tumor evolution and increase tumor fitness.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.|Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, United States.
authors.forename: Debjani
authors.initials: D
authors.lastname: Pal
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
authors.forename: Anja
authors.initials: A
authors.lastname: Pertot
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.|Graduate Program in Genetics, Stony Brook University, Stony Brook, United States.
authors.forename: Nitin H
authors.initials: NH
authors.lastname: Shirole
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.|Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, United States.
authors.forename: Naishitha
authors.initials: N
authors.lastname: Anaparthy
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.|Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
authors.forename: Tyler
authors.initials: T
authors.lastname: Garvin
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
authors.forename: Hilary
authors.initials: H
authors.lastname: Cox
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Chang
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.|Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
authors.forename: Fred
authors.initials: F
authors.lastname: Rollins
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
authors.forename: Jude
authors.initials: J
authors.lastname: Kendall
authors.affiliation: Huntington Hospital, Northwell Health, Huntington, United States.
authors.forename: Leyla
authors.initials: L
authors.lastname: Edwards
authors.affiliation: Huntington Hospital, Northwell Health, Huntington, United States.
authors.forename: Vijay A
authors.initials: VA
authors.lastname: Singh
authors.affiliation: Huntington Hospital, Northwell Health, Huntington, United States.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Stone
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.|Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Schatz
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.|Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, United States.|Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.|University of Southern California, Los Angeles, United States.
authors.forename: James
authors.initials: J
authors.lastname: Hicks
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.|Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.|Cancer Research UK - Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Hannon
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.|Graduate Program in Genetics, Stony Brook University, Stony Brook, United States.|Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
authors.forename: Raffaella
authors.identifier: 0000-0001-9745-1227
authors.initials: R
authors.lastname: Sordella
mesh_terms: D051927:CD24 Antigen / Q000032:analysis*; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D018628:Gene Dosage; D014644:Genetic Variation; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis*; D009154:Mutation; D009369:Neoplasms / Q000503:physiopathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D016212:Transforming Growth Factor beta
keywords: cancer biology; cell biology; copy number alteration; drug adaptability; genetic diversity; human; intra-tumor heterogeneity; tumor evolution; tumor fitness