RANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonization.
Prostate cancer (PCa) metastasis to bone is lethal and there is no adequate animal model for studying the mechanisms underlying the metastatic process. Here, we report that receptor activator of NF-κB ligand (RANKL) expressed by PCa cells consistently induced colonization or metastasis to bone in animal models. RANK-mediated signaling established a premetastatic niche through a feed-forward loop, involving the induction of RANKL and c-Met, but repression of androgen receptor (AR) expression and AR signaling pathways. Site-directed mutagenesis and transcription factor (TF) deletion/interference assays identified common TF complexes, c-Myc/Max, and AP4 as critical regulatory nodes. RANKL-RANK signaling activated a number of master regulator TFs that control the epithelial-to-mesenchymal transition (Twist1, Slug, Zeb1, and Zeb2), stem cell properties (Sox2, Myc, Oct3/4, and Nanog), neuroendocrine differentiation (Sox9, HIF1α, and FoxA2), and osteomimicry (c-Myc/Max, Sox2, Sox9, HIF1α, and Runx2). Abrogating RANK or its downstream c-Myc/Max or c-Met signaling network minimized or abolished skeletal metastasis in mice. RANKL-expressing LNCaP cells recruited and induced neighboring non metastatic LNCaP cells to express RANKL, c-Met/activated c-Met, while downregulating AR expression. These initially non-metastatic cells, once retrieved from the tumors, acquired the potential to colonize and grow in bone. These findings identify a novel mechanism of tumor growth in bone that involves tumor cell reprogramming via RANK-RANKL signaling, as well as a form of signal amplification that mediates recruitment and stable transformation of non-metastatic bystander dormant cells.
Uro-Oncology Research, Department of Medicine, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, 8750 Beverly Blvd., Atrium 103, Los Angeles, California 90048, USA Departments of Surgery Biomedical Sciences Biostatistics and Bioinformatics Center, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California, USA Department of Pathology, School of Medicine, University of Alabama, Birmingham, Alabama, USA Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Biochemistry and Cell Biology, Rice University, Houston, Texas, USA.
Gina Chia-Yi
GC
Chu
Haiyen E
HE
Zhau
Ruoxiang
R
Wang
André
A
Rogatko
Xu
X
Feng
Majd
M
Zayzafoon
Youhua
Y
Liu
Mary C
MC
Farach-Carson
Sungyong
S
You
Jayoung
J
Kim
Michael R
MR
Freeman
Leland W K
LW
Chung
D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D046888:Tissue Array Analysis
D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
RANK; RANKL; c-Met; cancer dormancy; metastasis; prostate cancer