CD44 alternative splicing in gastric cancer cells is regulated by culture dimensionality and matrix stiffness

C.B. da Cunha, D. D. Klumpers, S.T. Koshy, J.C. Weaver, O. Chaudhuri, R. Seruca, F. Carneiro, Pedro L. Granja, D.J. Mooney

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Two-dimensional (2D) cultures often fail to mimic key architectural and physical features of the tumor microenvironment. Advances in biomaterial engineering allow the design of three-dimensional (3D) cultures within hydrogels that mimic important tumor-like features, unraveling cancer cell behaviors that would not have been observed in traditional 2D plastic surfaces. This study determined how 3D cultures impact CD44 alternative splicing in gastric cancer (GC) cells. In 3D cultures, GC cells lost expression of the standard CD44 isoform (CD44s), while gaining CD44 variant 6 (CD44v6) expression. This splicing switch was reversible, accelerated by nutrient shortage and delayed at lower initial cell densities, suggesting an environmental stress-induced response. It was further shown to be dependent on the hydrogel matrix mechanical properties and accompanied by the upregulation of genes involved in epithelial-mesenchymal transition (EMT), metabolism and angiogenesis. The 3D cultures reported here revealed the same CD44 alternative splicing pattern previously observed in human premalignant and malignant gastric lesions. These findings indicate that fundamental features of 3D cultures such as soluble factors diffusion and mechanical cues influence CD44 expression in GC cells. Moreover, this study provides a new model system to study CD44 dysfunction, whose role in cancer has been in the spotlight for decades. (C) 2016 Elsevier Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)152-162
Number of pages11
JournalBiomaterials
Volume98
DOIs
Publication statusPublished - 2016

Cite this

da Cunha, C. B., Klumpers, D. D., Koshy, S. T., Weaver, J. C., Chaudhuri, O., Seruca, R., ... Mooney, D. J. (2016). CD44 alternative splicing in gastric cancer cells is regulated by culture dimensionality and matrix stiffness. Biomaterials, 98, 152-162. https://doi.org/10.1016/j.biomaterials.2016.04.016
da Cunha, C.B. ; Klumpers, D. D. ; Koshy, S.T. ; Weaver, J.C. ; Chaudhuri, O. ; Seruca, R. ; Carneiro, F. ; Granja, Pedro L. ; Mooney, D.J. / CD44 alternative splicing in gastric cancer cells is regulated by culture dimensionality and matrix stiffness. In: Biomaterials. 2016 ; Vol. 98. pp. 152-162.
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title = "CD44 alternative splicing in gastric cancer cells is regulated by culture dimensionality and matrix stiffness",
abstract = "Two-dimensional (2D) cultures often fail to mimic key architectural and physical features of the tumor microenvironment. Advances in biomaterial engineering allow the design of three-dimensional (3D) cultures within hydrogels that mimic important tumor-like features, unraveling cancer cell behaviors that would not have been observed in traditional 2D plastic surfaces. This study determined how 3D cultures impact CD44 alternative splicing in gastric cancer (GC) cells. In 3D cultures, GC cells lost expression of the standard CD44 isoform (CD44s), while gaining CD44 variant 6 (CD44v6) expression. This splicing switch was reversible, accelerated by nutrient shortage and delayed at lower initial cell densities, suggesting an environmental stress-induced response. It was further shown to be dependent on the hydrogel matrix mechanical properties and accompanied by the upregulation of genes involved in epithelial-mesenchymal transition (EMT), metabolism and angiogenesis. The 3D cultures reported here revealed the same CD44 alternative splicing pattern previously observed in human premalignant and malignant gastric lesions. These findings indicate that fundamental features of 3D cultures such as soluble factors diffusion and mechanical cues influence CD44 expression in GC cells. Moreover, this study provides a new model system to study CD44 dysfunction, whose role in cancer has been in the spotlight for decades. (C) 2016 Elsevier Ltd. All rights reserved.",
author = "{da Cunha}, C.B. and Klumpers, {D. D.} and S.T. Koshy and J.C. Weaver and O. Chaudhuri and R. Seruca and F. Carneiro and Granja, {Pedro L.} and D.J. Mooney",
note = "ISI Document Delivery No.: DQ5XK Times Cited: 2 Cited Reference Count: 69 da Cunha, Cristiana Branco Klumpers, Darinka D. Koshy, Sandeep T. Weaver, James C. Chaudhuri, Ovijit Seruca, Raquel Carneiro, Fatima Granja, Pedro L. Mooney, David J. Carneiro, Fatima/J-6432-2013 Carneiro, Fatima/0000-0002-1964-1006; Koshy, Sandeep/0000-0003-2836-5813; Granja, Pedro/0000-0003-2761-4929; Seruca, Raquel/0000-0002-8851-4166 Portuguese Fundacao para a Ciencia e a Tecnologia (FCT) [SFRH/BD/44982/2008]; Calouste Gulbenkian Foundation (FCG); Luso-American Development Foundation (FLAD); FCT [PTDC/CTM-NAN/120958/2010] We thank Patricia Rogers and Mandy Tam (Harvard University) for assistance with FACS, Anabela Ribeiro Nunes (from the Office for Science Communication at IBMC,INEB) for designing Fig. 7, and Barbara Gomes (IPATIMUP/FMUP) for immunohistochemistry of gastric tumor samples. C.B.C. had research fellowships by the Portuguese Fundacao para a Ciencia e a Tecnologia (FCT) (ref.: SFRH/BD/44982/2008), Calouste Gulbenkian Foundation (FCG) and Luso-American Development Foundation (FLAD). The work herein reported was funded by FCT (PTDC/CTM-NAN/120958/2010). 2 12 27 ELSEVIER SCI LTD OXFORD BIOMATERIALS",
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da Cunha, CB, Klumpers, DD, Koshy, ST, Weaver, JC, Chaudhuri, O, Seruca, R, Carneiro, F, Granja, PL & Mooney, DJ 2016, 'CD44 alternative splicing in gastric cancer cells is regulated by culture dimensionality and matrix stiffness' Biomaterials, vol. 98, pp. 152-162. https://doi.org/10.1016/j.biomaterials.2016.04.016

CD44 alternative splicing in gastric cancer cells is regulated by culture dimensionality and matrix stiffness. / da Cunha, C.B.; Klumpers, D. D.; Koshy, S.T.; Weaver, J.C.; Chaudhuri, O.; Seruca, R.; Carneiro, F.; Granja, Pedro L.; Mooney, D.J.

In: Biomaterials, Vol. 98, 2016, p. 152-162.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - CD44 alternative splicing in gastric cancer cells is regulated by culture dimensionality and matrix stiffness

AU - da Cunha, C.B.

AU - Klumpers, D. D.

AU - Koshy, S.T.

AU - Weaver, J.C.

AU - Chaudhuri, O.

AU - Seruca, R.

AU - Carneiro, F.

AU - Granja, Pedro L.

AU - Mooney, D.J.

N1 - ISI Document Delivery No.: DQ5XK Times Cited: 2 Cited Reference Count: 69 da Cunha, Cristiana Branco Klumpers, Darinka D. Koshy, Sandeep T. Weaver, James C. Chaudhuri, Ovijit Seruca, Raquel Carneiro, Fatima Granja, Pedro L. Mooney, David J. Carneiro, Fatima/J-6432-2013 Carneiro, Fatima/0000-0002-1964-1006; Koshy, Sandeep/0000-0003-2836-5813; Granja, Pedro/0000-0003-2761-4929; Seruca, Raquel/0000-0002-8851-4166 Portuguese Fundacao para a Ciencia e a Tecnologia (FCT) [SFRH/BD/44982/2008]; Calouste Gulbenkian Foundation (FCG); Luso-American Development Foundation (FLAD); FCT [PTDC/CTM-NAN/120958/2010] We thank Patricia Rogers and Mandy Tam (Harvard University) for assistance with FACS, Anabela Ribeiro Nunes (from the Office for Science Communication at IBMC,INEB) for designing Fig. 7, and Barbara Gomes (IPATIMUP/FMUP) for immunohistochemistry of gastric tumor samples. C.B.C. had research fellowships by the Portuguese Fundacao para a Ciencia e a Tecnologia (FCT) (ref.: SFRH/BD/44982/2008), Calouste Gulbenkian Foundation (FCG) and Luso-American Development Foundation (FLAD). The work herein reported was funded by FCT (PTDC/CTM-NAN/120958/2010). 2 12 27 ELSEVIER SCI LTD OXFORD BIOMATERIALS

PY - 2016

Y1 - 2016

N2 - Two-dimensional (2D) cultures often fail to mimic key architectural and physical features of the tumor microenvironment. Advances in biomaterial engineering allow the design of three-dimensional (3D) cultures within hydrogels that mimic important tumor-like features, unraveling cancer cell behaviors that would not have been observed in traditional 2D plastic surfaces. This study determined how 3D cultures impact CD44 alternative splicing in gastric cancer (GC) cells. In 3D cultures, GC cells lost expression of the standard CD44 isoform (CD44s), while gaining CD44 variant 6 (CD44v6) expression. This splicing switch was reversible, accelerated by nutrient shortage and delayed at lower initial cell densities, suggesting an environmental stress-induced response. It was further shown to be dependent on the hydrogel matrix mechanical properties and accompanied by the upregulation of genes involved in epithelial-mesenchymal transition (EMT), metabolism and angiogenesis. The 3D cultures reported here revealed the same CD44 alternative splicing pattern previously observed in human premalignant and malignant gastric lesions. These findings indicate that fundamental features of 3D cultures such as soluble factors diffusion and mechanical cues influence CD44 expression in GC cells. Moreover, this study provides a new model system to study CD44 dysfunction, whose role in cancer has been in the spotlight for decades. (C) 2016 Elsevier Ltd. All rights reserved.

AB - Two-dimensional (2D) cultures often fail to mimic key architectural and physical features of the tumor microenvironment. Advances in biomaterial engineering allow the design of three-dimensional (3D) cultures within hydrogels that mimic important tumor-like features, unraveling cancer cell behaviors that would not have been observed in traditional 2D plastic surfaces. This study determined how 3D cultures impact CD44 alternative splicing in gastric cancer (GC) cells. In 3D cultures, GC cells lost expression of the standard CD44 isoform (CD44s), while gaining CD44 variant 6 (CD44v6) expression. This splicing switch was reversible, accelerated by nutrient shortage and delayed at lower initial cell densities, suggesting an environmental stress-induced response. It was further shown to be dependent on the hydrogel matrix mechanical properties and accompanied by the upregulation of genes involved in epithelial-mesenchymal transition (EMT), metabolism and angiogenesis. The 3D cultures reported here revealed the same CD44 alternative splicing pattern previously observed in human premalignant and malignant gastric lesions. These findings indicate that fundamental features of 3D cultures such as soluble factors diffusion and mechanical cues influence CD44 expression in GC cells. Moreover, this study provides a new model system to study CD44 dysfunction, whose role in cancer has been in the spotlight for decades. (C) 2016 Elsevier Ltd. All rights reserved.

U2 - 10.1016/j.biomaterials.2016.04.016

DO - 10.1016/j.biomaterials.2016.04.016

M3 - Article

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EP - 162

JO - Biomaterials

JF - Biomaterials

SN - 0142-9612

ER -