BMPR1A signalling is linked to tumour progression in dedifferentiated liposarcomas: lessons for rhBMP2 use in spinal surgery
- Published
- Accepted
- Subject Areas
- Bioinformatics, Cell Biology, Genomics, Drugs and Devices, Orthopedics
- Keywords
- Bone Morphogenic Protein, Bone Engineering, Dedifferentiated Liposarcomas, Soft Tissue Sarcomas, Bone Repair, Orthopaedic Surgery, Tissue Engineering
- Copyright
- © 2016 O'Neill et al.
- Licence
- This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ PrePrints) and either DOI or URL of the article must be cited.
- Cite this article
- 2016. BMPR1A signalling is linked to tumour progression in dedifferentiated liposarcomas: lessons for rhBMP2 use in spinal surgery. PeerJ PrePrints 4:e1719v1 https://doi.org/10.7287/peerj.preprints.1719v1
Abstract
Bone Morphogenic Protein 2 (BMP2) is a multipurpose cytokine, important in the development of bone and cartilage, and with a role in tumour initiation and progression. Because of BMP2’s osteogenic properties, a recombinant human version (rhBMP2) has found utility as an adjuvant therapy during surgery for spinal fusions. However, the results of large-scale meta-analysis has highlighted the potential of rhBMP2 to promote new tumour formation, leading to an FDA black box warning. BMP2 signal transduction is dependent on two distinct classes of serine/threonine kinase known as the type I and type II receptors. Although the type I receptors (BMPR1A and BMPR1B) are largely thought to have overlapping functions, we find tissue and cellular compartment specific patterns of expression, suggesting potential for distinct BMP2 signalling outcomes dependent on tissue type. Herein, we utilise large publicly available datasets from The Cancer Genome Atlas (TCGA) and Protein Atlas to define a novel role for BMPR1A-biased BMP2 signalling in soft tissue sarcomas. Using disease free survival as our primary endpoint, we find this BMPR1A-biased BMP2 signalling confers poor overall prognosis compared both to patients with BMPR1B-biased and to the sarcoma dataset as a whole. Through further annotation of the TCGA sarcoma dataset, we localise this effect to dedifferentiated liposarcomas but find overall BMP2/BMP receptor expression is equal across subsets. Finally, through gene set enrichment analysis we link this effect to increased transcriptional activity of the matrisome and general extracellular matrix remodelling. Our study highlights the importance of continued research into the tumorigenic properties of BMP2, the need for extensive patient follow-up and the potential disadvantages of rhBMP2 use. For the first time, we identify BMPR1A-biased BMP2 signalling as a biomarker of disease relapse in dedifferentiated liposarcomas.
Author Comment
Recombinant human BMP2 is often used as an adjuvant in spinal fusion surgery, but has been linked to an increased risk of new cancer events. Here we show that BMP2 signalling through the Type 1a receptor (BMPR1A) is linked to extracellular matrix remodelling and disease progression in soft tissue sarcomas.
This is the first draft of a manuscript submitted to PeerJ for peer review.
Supplemental Information
SuppFig1 - Type1 Receptor tissue expression
Tissue specific protein expression of BMPR1A and BMPR1B based on IHC. Data from the Protein Atlas (Uhlen et al., 2010).
SuppFig2 - Subcellular localisation of BMP receptors
Immunostaining of BMP receptors in three cancer cell lines showing intracellular localisation. U-2 OS is an osteosarcoma, A-431 is an epidermoid carcinoma and U-251/MG is a glioblastoma astrocytoma line. Green is receptor (Antibody CAB019398 for BMPR1A, HPA046821 for BMPR1B and HPA049014 for BMPR2) red is microtubules. Scale bar is 100 μm.
SuppFig3 - Prognostic affects of BMP pathway
Kaplan-Myer disease free survival curves in the TCGA sarcoma dataset (n=263) based on mRNA expression (top 10% and bottom 10% expressors). From top left; BMP2, BMP7, BMPR1A, BMPR1B and BMPR2.
SuppFig4 - Receptor expression by sarcoma subset
Median (± interquartile range) expression of BMPR1A, BMPR1B, BMPR2 and BMP2 in different sarcoma subsets. UPS is Undifferentiated Pleomorphic Sarcoma and LMS is Leiomyosarcoma.
SuppFig5 - BMP2 pan cancer
A: Pan-cancer analysis of BMP2 in several large scale genomics projects. Data from cBioPortal (cbioportal.org) (Cerami et al., 2012; Gao et al., 2013) . B: BMP2 interacting partners, defined in Cytoscape 3.2.1 (cytoscape.org) (Lopes et al., 2010) .
SuppFig6 - BMP2 pathway expression in several tumour types
Detailed waterfall plots for BMP pathway members deregulated (mutation, copy-number, up/down-regulation) in various cancer types. Vertical bars represent individual patients from the following cancer types: Sarcoma (provisional), Prostate (provisional), Breast (T. C. G. A. R. Network, 2012), Ovarian (T. C. G. A. R. Network, 2011), Lung (T. C. G. A. R. Network, 2014) and Head and Neck (T. C. G. A. Network, 2015). Visualisation was cBioPortal (cbioportal.org) (Cerami et al., 2012; Gao et al., 2013).
SuppFig7 - Prognostic ability of BMPR1A signature in other solid tumours
Kaplan-Myer disease free survival curves for BMPR1A-biased, BMPR1B-biased and BMPR2 signalling by high levels of endogenous BMP2. From top left, Prostate (provisional), Pancreatic (provisional), Lung (T. C. G. A. R. Network, 2014) and Ovarian (T. C. G. A. R. Network, 2011) cancers.
SuppTable1 - rhBMP2 new cancer events
Incidence of new cancers from a pivotal, multicentre, randomised controlled trial of patients with degenerative lumbar spine conditions who underwent a single-level instrumented posterolateral arthrodesis with either high-dose rhBMP-2 in a compression-resistant matrix (CRM) (rhBMP-2/CRM; n = 239) or autogenous bone graft (control group; n = 224).
Differential expression analysis from BMPR1A-biased and BMPR1B-biased BMP2 signalling in the TCGA sarcoma dataset
Differential expression analysis from BMPR1A-biased and BMPR1B-biased BMP2 signalling in the TCGA sarcoma dataset.
Differential expression analysis from BMPR1A-biased and BMPR1B-biased BMP2 signalling in dedifferentiated liposarcomas
Differential expression analysis from BMPR1A-biased and BMPR1B-biased BMP2 signalling in dedifferentiated liposarcomas.