title: Androgen-Regulated SPARCL1 in the Tumor Microenvironment Inhibits Metastatic Progression.
abstract: Prostate cancer is a leading cause of cancer death in men due to the subset of cancers that progress to metastasis. Prostate cancers are thought to be hardwired to androgen receptor (AR) signaling, but AR-regulated changes in the prostate that facilitate metastasis remain poorly understood. We previously noted a marked reduction in secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) expression during invasive phases of androgen-induced prostate growth, suggesting that this may be a novel invasive program governed by AR. Herein, we show that SPARCL1 loss occurs concurrently with AR amplification or overexpression in patient-based data. Mechanistically, we demonstrate that SPARCL1 expression is directly suppressed by androgen-induced AR activation and binding at the SPARCL1 locus via an epigenetic mechanism, and these events can be pharmacologically attenuated with either AR antagonists or HDAC inhibitors. We establish using the Hi-Myc model of prostate cancer that in Hi-Myc/Sparcl1(-/-) mice, SPARCL1 functions to suppress cancer formation. Moreover, metastatic progression of Myc-CaP orthotopic allografts is restricted by SPARCL1 in the tumor microenvironment. Specifically, we show that SPARCL1 both tethers to collagen in the extracellular matrix (ECM) and binds to the cell's cytoskeleton. SPARCL1 directly inhibits the assembly of focal adhesions, thereby constraining the transmission of cell traction forces. Our findings establish a new insight into AR-regulated prostate epithelial movement and provide a novel framework whereby SPARCL1 in the ECM microenvironment restricts tumor progression by regulating the initiation of the network of physical forces that may be required for metastatic invasion of prostate cancer.
authors: The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland. The Department of Oncology, Johns Hopkins University, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland. phurley2@jhmi.edu.
authors: Paula J
authors: PJ
authors: Hurley
authors: The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
authors: Robert M
authors: RM
authors: Hughes
authors: The Department of Comparative Pathobiology, Johns Hopkins University, Baltimore, Maryland.
authors: Brian W
authors: BW
authors: Simons
authors: The Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors: Jessie
authors: J
authors: Huang
authors: The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
authors: Rebecca M
authors: RM
authors: Miller
authors: The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
authors: Brian
authors: B
authors: Shinder
authors: The Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
authors: Michael C
authors: MC
authors: Haffner
authors: The Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
authors: David
authors: D
authors: Esopi
authors: The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
authors: Yasunori
authors: Y
authors: Kimura
authors: The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
authors: Javaneh
authors: J
authors: Jabbari
authors: The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland. The Department of Oncology, Johns Hopkins University, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland. The Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors: Ashley E
authors: AE
authors: Ross
authors: Genome Dx Biosciences Inc., Vancouver, British Columbia, Canada.
authors: Nicholas
authors: N
authors: Erho
authors: Genome Dx Biosciences Inc., Vancouver, British Columbia, Canada.
authors: Ismael A
authors: IA
authors: Vergara
authors: The Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors: Sheila F
authors: SF
authors: Faraj
authors: Genome Dx Biosciences Inc., Vancouver, British Columbia, Canada.
authors: Elai
authors: E
authors: Davicioni
authors: The Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors: George J
authors: GJ
authors: Netto
authors: The Department of Oncology, Johns Hopkins University, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors: Srinivasan
authors: S
authors: Yegnasubramanian
authors: The Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. The Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland. Physical Sciences-Oncology Center, Johns Hopkins University, Baltimore, Maryland.
authors: Steven S
authors: SS
authors: An
authors: The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland. The Department of Oncology, Johns Hopkins University, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors: Edward M
authors: EM
authors: Schaeffer
mesh_terms: D000107:Acetylation; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D000728:Androgens; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D006657:Histones; C503126:SPARCL1 protein, human; D003094:Collagen