Keratin 13 expression reprograms bone and brain metastases of human prostate cancer cells.
Lethal progression of prostate cancer metastasis can be improved by developing animal models that recapitulate the clinical conditions. We report here that cytokeratin 13 (KRT13), an intermediate filament protein, plays a directive role in prostate cancer bone, brain, and soft tissue metastases. KRT13 expression was elevated in bone, brain, and soft tissue metastatic prostate cancer cell lines and in primary and metastatic clinical prostate, lung, and breast cancer specimens. When KRT13 expression was determined at a single cell level in primary tumor tissues of 44 prostate cancer cases, KRT13 level predicted bone metastasis and the overall survival of prostate cancer patients. Genetically enforced KRT13 expression in human prostate cancer cell lines drove metastases toward mouse bone, brain and soft tissues through a RANKL-independent mechanism, as KRT13 altered the expression of genes associated with EMT, stemness, neuroendocrine/neuromimicry, osteomimicry, development, and extracellular matrices, but not receptor activator NF-κB ligand (RANKL) signaling networks in prostate cancer cells. Our results suggest new inhibitors targeting RANKL-independent pathways should be developed for the treatment of prostate cancer bone and soft tissue metastases.
Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Current address: Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Qinlong
Q
Li
Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Lijuan
L
Yin
Urological Research, Huntington Medical Research Institutes, Huntington Memorial Hospital, Pasadena, CA, USA.
Lawrence W
LW
Jones
Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Gina C-Y
GC
Chu
Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Jason B-Y
JB
Wu
Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Jen-Ming
JM
Huang
Biostatistics and Bioinformatics, Department of Medicine, Los Angeles, CA, USA.
Quanlin
Q
Li
Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Sungyong
S
You
Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Jayoung
J
Kim
John H. Stroger, Jr. Hospital of Cook County, Chicago, IL, USA.
Yi-Tsung
YT
Lu
Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Stefan
S
Mrdenovic
Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Ruoxiang
R
Wang
Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Michael R
MR
Freeman
Department of Urology and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA and Division of Urology, Greater Los Angeles Veteran's Affairs Healthcare System, Los Angeles, CA, USA.
Isla
I
Garraway
Sepulveda Research Corporation VA Medical Center, Los Angeles, CA, USA.
Michael S
MS
Lewis
Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Leland W K
LW
Chung
Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Haiyen E
HE
Zhau
D000230:Adenocarcinoma / Q000378:metabolism* / Q000556:secondary; D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000556:secondary; D001932:Brain Neoplasms / Q000378:metabolism* / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D065150:Cellular Reprogramming; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053535:Keratin-13 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D053245:RANK Ligand / Q000378:metabolism; D016019:Survival Analysis; D059467:Transcriptome; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
C507426:KRT13 protein, human; D053535:Keratin-13; D053245:RANK Ligand
RANKL-independent; biomarker; bone and brain metastases; cell signal network; targeting