Extracellular matrix composition defines an ultra-high-risk group of neuroblastoma within the high-risk patient cohort

Tadeo, Irene; Berbegall, Ana P.; Castel, Victoria; García‐Miguel, Purificación; Callaghan, Robert C.; Påhlman, Sven; Navarro, Samuel; Noguera, Rosa

doi:10.1038/bjc.2016.210

Cited by 52 publications

(46 citation statements)

References 52 publications

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“…ECM stiffening is increasingly recognized as a major mechanical signal, which alters cell behavior and in part confers cancer cell hallmark capabilities including sustained growth, invasion, and metastasis (6,7,(37)(38)(39)(40)(41)(42). ECM stiffening is also associated with increased solid stress and IFP, two other hallmarks of tumor mechanobiology that induce blood and lymphatic vessel compression and reduce transcapillary transport, respectively, and that impair effective drug delivery (3).…”

Section: Discussionmentioning

confidence: 99%

Investigating the Contribution of Collagen to the Tumor Biomechanical Phenotype with Noninvasive Magnetic Resonance Elastography

et al. 2019

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Increased stiffness in the extracellular matrix (ECM) contributes to tumor progression and metastasis. Therefore, stromal modulating therapies and accompanying biomarkers are being developed to target ECM stiffness. Magnetic resonance (MR) elastography can noninvasively and quantitatively map the viscoelastic properties of tumors in vivo and thus has clear clinical applications. Herein, we used MR elastography, coupled with computational histopathology, to interrogate the contribution of collagen to the tumor biomechanical phenotype and to evaluate its sensitivity to collagenase-induced stromal modulation. Elasticity (G d) and viscosity (G l) were significantly greater for orthotopic BT-474 (G d ¼ 5.9 AE 0.2 kPa, G l ¼ 4.7 AE 0.2 kPa, n ¼ 7) and luc-MDA-MB-231-LM2-4 (G d ¼ 7.9 AE 0.4 kPa, G l ¼ 6.0 AE 0.2 kPa, n ¼ 6) breast cancer xenografts, and luc-PANC1 (G d ¼ 6.9 AE 0.3 kPa, G l ¼ 6.2 AE 0.2 kPa, n ¼ 7) pancreatic cancer xenografts, compared with tumors associated with the nervous system, including GTML/Trp53 KI/KI medulloblastoma (G d ¼ 3.5 AE 0.2 kPa, G l ¼ 2.3 AE 0.2 kPa, n ¼ 7), orthotopic luc-D-212-MG (G d ¼ 3.5 AE 0.2 kPa, G l ¼ 2.3 AE 0.2 kPa, n ¼ 7), luc-RG2 (G d ¼ 3.5 AE 0.2 kPa, G l ¼ 2.3 AE 0.2 kPa, n ¼ 5), and luc-U-87-MG (G d ¼ 3.5 AE 0.2 kPa, G l ¼ 2.3 AE 0.2 kPa, n ¼ 8) glioblastoma xenografts, intracranially propagated luc-MDA-MB-231-LM2-4 (G d ¼ 3.7 AE 0.2 kPa, G l ¼ 2.2 AE 0.1 kPa, n ¼ 7) breast cancer xenografts, and Th-MYCN neuroblastomas (G d ¼ 3.5 AE 0.2 kPa, G l ¼ 2.3 AE 0.2 kPa, n ¼ 5). Positive correlations between both elasticity (r ¼ 0.72, P < 0.0001) and viscosity (r ¼ 0.78, P < 0.0001) were determined with collagen fraction, but not with cellular or vascular density. Treatment with collagenase significantly reduced G d (P ¼ 0.002) and G l (P ¼ 0.0006) in orthotopic breast tumors. Texture analysis of extracted images of picrosirius red staining revealed significant negative correlations of entropy with G d (r ¼ À0.69, P < 0.0001) and G l (r ¼ À0.76, P < 0.0001), and positive correlations of fractal dimension with G d (r ¼ 0.75, P < 0.0001) and G l (r ¼ 0.78, P < 0.0001). MR elastography can thus provide sensitive imaging biomarkers of tumor collagen deposition and its therapeutic modulation. Significance: MR elastography enables noninvasive detection of tumor stiffness and will aid in the development of ECM-targeting therapies.

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Section: Discussionmentioning

confidence: 99%

Investigating the Contribution of Collagen to the Tumor Biomechanical Phenotype with Noninvasive Magnetic Resonance Elastography

et al. 2019

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“…The adaptation process was faster in VN-KO tumor cells but less manageable than in hydrogels. Furthermore, cells grown in rigid 3D hydrogels showed faster selection for SCAs and less presence of intratumoral heterogeneity than those cells with long and soft 3D growth, which could re ect a more e cient adaptation to niche [39] as occurs in aggressive patients tumors with rigid ECMs [58].…”

Section: Discussionmentioning

confidence: 94%

Impact of extracellular matrix properties on neuroblastoma genomic heterogeneity

López-Carrasco¹,

Martín-Vañó²,

Burgos‐Panadero³

et al. 2020

Preprint

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Background Increased tissue stiffness is a common feature of malignant solid tumors, often associated with metastasis and poor patient outcomes. Vitronectin, as an extracellular matrix anchorage glycoprotein related to a stiff matrix, is present in a particularly increased quantity and specific distribution in high-risk neuroblastoma. Furthermore, as cells can sense and transform the proprieties of the extracellular matrix into chemical signals through mechanotransduction, genotypic changes related to stiffness are possible. Methods We have applied high density SNPa and NGS techniques to in vivo and in vitro models (orthotropic xenograft vitronectin knock-out mice and 3D bioprinted hydrogels with different stiffness) using two representative neuroblastoma cell lines (the MYCN amplified SK-N-BE(2) and the ALK mutated SH-SY5Y), to discern how tumor genomics patterns and clonal heterogeneity of both cell lines are affected. Results We describe a remarkable subclonal selection of some genomic aberrations in SK-N-BE(2) cells grown in knock-out vitronectin xenograft mice that also emerged when cultured for long times in stiff hydrogels. Specially, we detected an enlarged subclonal cell population with chromosome 9 aberrations in both models. Similar abnormalities were found in human high-risk neuroblastoma with MYCN amplification. Genomics of the SH-SY5Y cell line remained stable when cultured in both models. Conclusions Focus on heterogeneous intratumor segmental chromosome aberrations and mutations, as a mirror image of tumor microenvironment, is a vital area of future research.

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“…In accordance with current knowledge of biology and cell cultures, we expected that cell cluster density and occupancy would increase over time in our 3D models, due to cell migration and proliferation 52 . Moreover, given that ECM with high stiffness has been associated with aggressiveness in NB 38 , we predicted cell cluster density and occupancy would increase with stiffness. We found growth in cell cluster occupancy, but density tended to decrease over time, meaning that cluster generation processes like cell migration and cluster division were underrepresented compared to cell cluster growth, death and detachment processes.…”

Section: Discussionmentioning

confidence: 99%

A three-dimensional bioprinted model to evaluate the effect of stiffness on neuroblastoma cell cluster dynamics and behavior

Monferrer

Martín-Vañó

Carretero

et al. 2020

Sci Rep

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Three-dimensional (3D) bioprinted culture systems allow to accurately control microenvironment components and analyze their effects at cellular and tissue levels. The main objective of this study was to identify, quantify and localize the effects of physical-chemical communication signals between tumor cells and the surrounding biomaterial stiffness over time, defining how aggressiveness increases in SK-N-BE(2) neuroblastoma (NB) cell line. Biomimetic hydrogels with SK-N-BE(2) cells, methacrylated gelatin and increasing concentrations of methacrylated alginate (AlgMA 0%, 1% and 2%) were used. Young's modulus was used to define the stiffness of bioprinted hydrogels and NB tumors. Stained sections of paraffin-embedded hydrogels were digitally quantified. Human NB and 1% AlgMA hydrogels presented similar Young´s modulus mean, and orthotopic NB mice tumors were equally similar to 0% and 1% AlgMA hydrogels. Porosity increased over time; cell cluster density decreased over time and with stiffness, and cell cluster occupancy generally increased with time and decreased with stiffness. In addition, cell proliferation, mRNA metabolism and antiapoptotic activity advanced over time and with stiffness. Together, this rheological, optical and digital data show the potential of the 3D in vitro cell model described herein to infer how intercellular space stiffness patterns drive the clinical behavior associated with NB patients.

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Extracellular matrix composition defines an ultra-high-risk group of neuroblastoma within the high-risk patient cohort

Cited by 52 publications

References 52 publications

Investigating the Contribution of Collagen to the Tumor Biomechanical Phenotype with Noninvasive Magnetic Resonance Elastography

Investigating the Contribution of Collagen to the Tumor Biomechanical Phenotype with Noninvasive Magnetic Resonance Elastography

Impact of extracellular matrix properties on neuroblastoma genomic heterogeneity

A three-dimensional bioprinted model to evaluate the effect of stiffness on neuroblastoma cell cluster dynamics and behavior

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