Targeting Mechanotransduction in Osteosarcoma: A Comparative Oncology Perspective
Abstract
:1. Introduction
2. Mechanotransduction in Bone
3. Osteosarcoma
4. Mechanotransduction in Cancer
5. Mechanotransduction in Osteosarcoma and Promising Targetable Pathways
5.1. Mechanical Properties of OSA Cells
5.2. Matrix Environments: Response to Environmental Stiffness
6. Hippo Pathway Mediators—TAZ/YAP
6.1. TAZ and YAP in OSA Mechanotransduction
6.2. Inhibitors of TAZ/YAP
6.2.1. Verteporfin
6.2.2. Agave
6.2.3. Repurposed Inhibitors: Dasatinib, Pazopanib, and Simvastatin
7. Myocardin-Related Transcription Factor-A/-B (MRTF-A/-B) (Rho/MRTF/SRF Signalling)
7.1. MRTFs in OSA Mechanotransduction
7.2. Inhibitors of Rho/MRTF/SRF Signaling
8. Ezrin
8.1. Ezrin and Mechanotransduction
8.2. Inhibitors of Ezrin
9. Nuclear Mechanotransduction: Factors for Force Transmission and DNA Repair
10. Unanswered Questions and Possible Avenues for Future Research
- How does the mechanical bone and lung microenvironment change during osteosarcoma progression? Panciera and colleagues (2020) recently found that constitutive oncogenic signalling, specifically by Kirsten rat sarcoma viral oncogene homolog (K-RAS) or HER2, alone, is not enough to reprogram mammary cells into tumour-initiating cells but might additionally require a stiffer-than-normal mechanical microenvironment [191]. Given that calcified collagenous bone is already a stiff microenvironment, it is unclear how, and if, the osteoid production by tumour cells contributes to the stiffness of the microenvironment and what are the implications of such contribution to tumour development and progression. This is also unknown for the lung microenvironment; however, there is indirect evidence to suggest that stromal-tumour interactions within the lung, possibly resulting in enhanced ECM stiffness and subsequent mechanotransduction, favour lung colonisation. Fibroblast growth factor receptor signalling can increase the production of fibronectin by stage-specific embryonic antigen-4 positive (SSEA4+) OSA stem cells and causes a fibrogenic reprogramming. This reprogramming creates a fibrotic-like environment and provides a survival advantage for lung metastasis growth, but not primary bone lesion growth [192]. Although not directly investigated in this study, Liu and colleagues (2015) reported that normal lungs have a median shear modulus of 0.59 kPa, while the fibrotic regions of idiopathic pulmonary fibrosis lungs have a median shear modulus of 5.16 kPa [193]. It will be interesting for future research to determine if this fibrogenic reprogramming of OSA stem cells impacts the mechanical properties of the microenvironment to activate tumour-promoting mechanosignals.
- Do mechanotransduction mechanisms vary in early stage as compared to advanced stage tumour cells? A majority of the research mentioned in this review only included studies that utilised primary OSA cell lines, which makes it difficult to understand any differences in how primary and metastatic OSA cells respond to mechanical cues. Future research could compare paired primary- and metastatic-derived OSA cells in microenvironments with varying stiffnesses to assess the mechanical signalling pathways that are activated and the differences, if any, in functional cell responses.
- Can we identify tumour mechanotransduction signatures to tailor therapy? Most studies that have explored mechanical signatures in epithelial cancer tissue include profiling the stiffness of cancer biopsy tissue ex vivo using indentation techniques [194,195], or using shear wave elastography (SWE) to evaluate the stiffness of the cancer tissue itself and/or surrounding lymph nodes to determine malignancy [196,197]. These methods are helpful as diagnostic and prognostic tools, but do not provide insight into what is actually driving the mechanical signalling. Future studies should explore the possibility of developing a ‘mechanical signature’ in OSA to better predict mechanical signalling and cancer progression. One possible avenue is determining the presence of mechanosignalling mediators in plasma or serum samples from OSA patients. Given the importance of ECM remodelling in cancer, Andriani and colleagues (2018) explored the biomarker potential of collagen type X alpha 1 (COL10A1), collagen type XI alpha 1 (COL11A1) and collagen-binding molecule, secreted protein acidic and rich in cysteine (SPARC) in plasma of lung cancer patients [198]. The levels of COL10A1 and SPARC were significantly higher in lung cancer patients compared to healthy controls. Aside from looking at ECM proteins in plasma, future research could also explore the presence and abundance of mechanical signalling machinery in extracellular vesicles, which are present in high quantities in the circulation of cancer patients and are known to be able to interact with recipient cells and modify behaviour [199,200].
- How do genomic aberrations in OSA impact mechanosignalling? The karyotype of OSA is notoriously complex; genomic analysis of OSA tumours from both human and canine samples show multiple copy number variations and structural variants of certain genes [201,202]. This genomic heterogeneity between and within OSA tumours will undoubtedly challenge the way we understand mechanosignalling and our ability to target it in a patient context. It is imperative that we use a strategic approach to understand how certain mutations can attenuate or potentiate mechanosignalling. One possible way to approach this is to generate and analyse robust datasets from sequenced human and canine OSA tumours and find commonly altered genes [201]. We can then map signalling networks and possibly identify one or more mechanotransduction mediators within these networks. Experiments could use cell lines that bear these mutations or use genetically modified models to create similar mutations and explore their response to mechanical stimuli in both 2D and 3D culture models. Such a link between a mutated gene and mechanotransduction is exemplified by insulin-like growth factor-1 receptor (IGF1R), which has been shown to bear somatic mutations in human OSA [203]. Tahimic and colleagues (2016) found that with mechanical stimulus, IGF1R undergoes activation in an integrin-dependent fashion to activate downstream signalling molecules, such as FAK. In turn, FAK can also mediate response to ligand-dependent IGF1R activation [204]. Given this relationship between IGF1R and mechanical stimulus, further research will be needed to understand how, and if, somatic mutations in IGF1R could potentiate the FAK signalling cascade. Another avenue to explore is understanding how and if mechanosignalling contributes to genomic instability. The mechanical environment can impact cellular processes such as mitosis, chromosome segregation and chromosome architecture, all of which can contribute to abnormal genotypes [205,206]. This really raises the which came first, the chicken-or-the-egg question: do genomic aberrations potentiate mechanosignalling or are genomic aberrations the result of mechanical forces in the environment? In order to address these questions, it is imperative that we utilise a comprehensive human, canine and murine OSA model approach to permit the assessment of clinical relevance side-by-side proof-of-concept experiments, resulting in faster advances in OSA treatment [207].
11. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
OSA | osteosarcoma |
PGE2 | prostaglandin E2 |
COX2 | cyclooxygenase 2 |
ATP | adenosine triphosphate |
cAMP | cyclic adenosine monophosphate |
PKA | protein kinase A |
PI3K | phosphatidylinositol 3-kinase |
GSK3 | glycogen synthase kinase 3 |
CX43 | connexin 43 |
TRPV4 | transient receptor potential vanilloid subfamily member 4 |
ER | endoplasmic reticulum |
P2R | P2 purinergic receptor |
PLC | phospholipase C |
MLCK | myosin light chain kinase |
EV | extracellular vesicle |
RANKL | receptor activator of nuclear factor kappa-B ligand |
OGN | osteoprotegerin |
FAK | focal adhesion kinase |
Rho | Ras homologue |
GTPase | guanosine triphosphatase |
LEF/TCF | lymphoid enhancer-binding factor/T-cell factor |
p38 MAPK | p38 mitogen activated protein kinase |
NF-kappa B | nuclear factor kappa B |
BMP | bone morphogenetic protein |
SMAD | small mothers against decapentaplegic |
ALP | alkaline phosphatase |
OCN | osteocalcin |
COL1 | collagen 1 |
JNK | Jun N-terminal kinase |
HER2 | human epidermal growth factor receptor 2 |
IGF1 | insulin-like growth factor 1 |
mTOR | mammalian target of rapamycin |
ECM | extracellular matrix |
LOX | lysyl oxidase |
ROCK | Rho-associated coiled-coil containing kinase |
kPa | kilo pascals |
PEGDA | polyethylene glycol diacrylate |
ERK | extracellular signal-regulated kinase |
HIF1-alpha | hypoxia inducible factor 1 alpha |
VEGF | vascular endothelial growth factor |
MMP | matrix metalloproteinase |
FNIII A1 | fibronectin III A1 |
TN-C | tenascin C |
4E-BP1 | eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 |
S6K1 | p70 ribosomal protein S6 kinase 1 |
P4H | prolyl 4-hydroxylases |
PLOD | procollagen-lysine, 2-oxoglutarate 5-dioxygenase |
UPS | undifferentiated pleomorphic sarcoma |
TAZ | transcriptional co-activator with a PDZ-binding motif |
YAP | yes-associated protein |
MRTF-A/-B | myocardin-related transcription factor-A/-B |
MST1/2 | mammalian Ste20-like kinase |
LATS1/2 | large animal tumour suppressor 1/2 |
TEAD | TEA domain family member |
CYR61 | cysteine-rich angiogenic inducer 61 |
CTGF | connective tissue growth factor |
CCND1 | cyclin D1 |
PCL | poly(ε-caprolactone) |
SCID | severe combined immunodeficiency |
PDGF | platelet derived growth factor |
SCF | stem cell factor |
AMPK | AMP-activated protein kinase |
SRF | serum-response factors |
EMT | epithelial-mesenchymal transition |
ERM | ezrin, radixin, moesin |
FERM | four point one, ezrin radixin, moesin |
ICAM-2 | intercellular adhesion molecule 2 |
PIP2 | phosphatidylinositol 4,5-bisphosphate |
PKC | protein kinase C |
LINC | linker of the nucleoskeleton and cytoskeleton |
NER | nucleotide excision repair |
K-RAS | Kirsten rat sarcoma viral oncogene homolog |
SSEA4+ | stage-specific embryonic antigen-4 positive |
SWE | shear wave elastography |
COL10A1 | collagen type X alpha 1 |
COL11A1 | collagen type XI alpha 1 |
SPARC | secreted protein acidic and rich in cysteine |
IGF1R | insulin-like growth factor-1 receptor |
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Scope of Paper | Cell Line(s) | Model | Key Findings |
---|---|---|---|
Compared mechanical properties of individual mesenchymal stem cell (MSc), osteoblast (NHost) and OSA cells (MG63) [81] | MSc NHost MG63 | 2D | MG63 are smaller, thicker, less stiff and had a rougher membrane compared to MSc and NHost |
Characterised the mechanical properties of U2OS during interphase and telophase of mitosis in two different regions within the cell [90] | U2OS | 2D | U2OS stiffer overall in interphase; periphery of the cell stiffer than nuclear region during interphase and telophase |
Compared the mechanical properties between two paired primary and metastatic OSA cells [82] | SaO2/LM5 HuO9/M132 | 2D | Low metastatic cells had a greater spreading area, focal adhesion count and density; other measured parameters were inconsistent between pairs |
Exposed U2OS cells to different degrees of confinements to determine changes in mechanical properties [86] | U2OS | 1D microlines + Y-shaped PDMS device | U2OS cells soften and YAP is cytoplasmic during confinement in PDMS model but not 1D microline model |
Characterised cell morphology, size and traction forces of bone cells at different differentiation stages [87] | MSC dMSC osteoblasts osteocyte | 2D | Osteoblasts and osteocytes had larger surface area; cell circularity, inverse aspect ratio and traction force generation positively correlated with differentiation |
Scope of Paper | Cell Line(s) | Model | Key Findings |
---|---|---|---|
Isolated tumour cells from human OSA patient and cultured on different substrate rigidities [91] | Primary human OSA cells | 2D collagen-coated PA gels | Cells cultured on 55 kPa was most compatible for growth, cell survival and generated most traction forces |
Cultured sarcospheres in PEGDA gels with various rigidities to determine most optimal environment [92] | U2OS | PEGDA gels | 50 kPa was the most optimal PEGDA gel to form CD133+ and CD44+ sarcospheres |
Investigated the role of integrin beta 1 and FAK signalling in response to mechanical stimulation [93] | MG63 | 2D + mechanical stimulation | Increase in integrin beta 1, pFAK and pERK protein levels with mechanical strain; blockade of integrin beta 1 blunted increase in pFAK and pERK with mechanical stimulation |
Determined how normal osteoblast and osteosarcoma cells respond to microenvironments with varying adhesion ligand density and stiffness [94] | Normal osteoblasts MG63 | PEGDA/GelMa hydrogels | Normal bone cells more responsive to adhesion ligand density of the ECM, while OSA cells more responsive to ECM stiffness; increasing stiffness led to an increase in FA signalling proteins, pro-tumorigenic mRNAs and in vivo tumorigenicity for OSA cells |
Explored the effects of mechanical strain on TN-C FNIII A1 mRNA and protein levels [95] | MG63 | 3D collagen + 0.2 Hz cyclic strain | Increase in TN-C FNIII A1 mRNA and protein upon mechanical strain; silencing of downstream mTOR signalling (4E-BP1 and S6K1) blunts these effects |
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Luu, A.K.; Viloria-Petit, A.M. Targeting Mechanotransduction in Osteosarcoma: A Comparative Oncology Perspective. Int. J. Mol. Sci. 2020, 21, 7595. https://doi.org/10.3390/ijms21207595
Luu AK, Viloria-Petit AM. Targeting Mechanotransduction in Osteosarcoma: A Comparative Oncology Perspective. International Journal of Molecular Sciences. 2020; 21(20):7595. https://doi.org/10.3390/ijms21207595
Chicago/Turabian StyleLuu, Anita K., and Alicia M. Viloria-Petit. 2020. "Targeting Mechanotransduction in Osteosarcoma: A Comparative Oncology Perspective" International Journal of Molecular Sciences 21, no. 20: 7595. https://doi.org/10.3390/ijms21207595