title: Epithelial mesenchymal-like transition occurs in a subset of cells in castration resistant prostate cancer bone metastases.
abstract: TGFβ is a known driver of epithelial-mesenchymal transition (EMT) which is associated with tumor aggressiveness and metastasis. However, EMT has not been fully explored in clinical specimens of castration-resistant prostate cancer (CRPC) metastases. To assess EMT in CRPC, gene expression analysis was performed on 149 visceral and bone metastases from 62 CRPC patients and immunohistochemical analysis was performed on 185 CRPC bone and visceral metastases from 42 CRPC patients. In addition, to assess the potential of metastases to seed further metastases the mitochondrial genome was sequenced at different metastatic sites in one patient. TGFβ was increased in bone versus visceral metastases. While primarily cytoplasmic; nuclear and cytoplasmic Twist were significantly higher in bone than in visceral metastases. Slug and Zeb1 were unchanged, with the exception of nuclear Zeb1 being significantly higher in visceral metastases. Importantly, nuclear Twist, Slug, and Zeb1 were only present in a subset of epithelial cells that had an EMT-like phenotype. Underscoring the relevance of EMT-like cells, mitochondrial sequencing revealed that metastases could seed additional metastases in the same patient. In conclusion, while TGFβ expression and EMT-associated protein expression is present in a considerable number of CRPC visceral and bone metastases, nuclear Twist, Slug, and Zeb1 localization and an EMT-like phenotype (elongated nuclei and cytoplasmic compartment) was only present in a small subset of CRPC bone metastases. Mitochondrial sequencing from different metastases in a CRPC patient provided evidence for the seeding of metastases from previously established metastases, highlighting the biological relevance of EMT-like behavior in CRPC metastases.
authors.affiliation: Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA.
authors.forename: Maahum
authors.initials: M
authors.lastname: Haider
authors.affiliation: Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA.
authors.forename: Xiaotun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.affiliation: Divison of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Nolan
authors.initials: N
authors.lastname: Ericson
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: True
authors.affiliation: Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA.
authors.forename: Hung-Ming
authors.initials: HM
authors.lastname: Lam
authors.affiliation: Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA.
authors.forename: Lisha G
authors.initials: LG
authors.lastname: Brown
authors.affiliation: Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Ketchanji
authors.affiliation: Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA.
authors.forename: Belinda
authors.initials: B
authors.lastname: Nghiem
authors.affiliation: Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA.
authors.forename: Bryce
authors.initials: B
authors.lastname: Lakely
authors.affiliation: Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Coleman
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Montgomery
authors.affiliation: Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA.|Department of Veterans Affairs Medical Center, Seattle, WA, USA.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Lange
authors.affiliation: Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA.
authors.forename: Martine
authors.initials: M
authors.lastname: Roudier
authors.affiliation: Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA.|Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.affiliation: Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Divison of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Bielas
authors.affiliation: Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA.|Department of Veterans Affairs Medical Center, Seattle, WA, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.affiliation: Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA. cmorriss@u.washington.edu.
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
mesh_terms: D001859:Bone Neoplasms / Q000556:secondary*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D061346:Laser Capture Microdissection; D008297:Male; D009362:Neoplasm Metastasis / Q000473:pathology*; D009687:Nuclear Proteins / Q000096:biosynthesis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000096:biosynthesis; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D051879:Twist-Related Protein 1 / Q000096:biosynthesis; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051879:Twist-Related Protein 1; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1
keywords: Bone metastasis; Epithelial mesenchymal transition; Prostate cancer; TGFβ