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.
Clinical & experimental metastasis. 2015 Dec 14 [Epub ahead of print]
Maahum Haider, Xiaotun Zhang, Ilsa Coleman, Nolan Ericson, Lawrence D True, Hung-Ming Lam, Lisha G Brown, Melanie Ketchanji, Belinda Nghiem, Bryce Lakely, Roger Coleman, Bruce Montgomery, Paul H Lange, Martine Roudier, Celestia S Higano, Jason H Bielas, Peter S Nelson, Robert L Vessella, Colm Morrissey
Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA. , Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA. , 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. , Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA. , Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA. , Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA. , Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA. , Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA. , Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. , Department of Medicine, University of Washington, Seattle, WA, USA. , Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA. , Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA. , Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA. , Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. , Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. , Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA. , Genitourinary Cancer Research Laboratory, Department of Urology, University of Washington, Box 356510, Seattle, WA, 98195, USA.