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Extracellular biophysical cues such as matrix stiffness are key stimuli tuning cell fate and affecting tumor progression in vivo. However, it remains unclear how cancer spheroids in a 3D microenvironment perceive matrix mechanical stiffness stimuli and translate them into intracellular signals driving progression. Mechanosensitive Piezo1 and TRPV4 ion channels, upregulated in many malignancies, are major transducers of such physical stimuli into biochemical responses. Most mechanotransduction studies probing the reception of changing stiffness cues by cells are, however, still limited to 2D culture systems or cell-extracellular matrix models, which lack the major cell–cell interactions prevalent in 3D cancer tumors. Here, we engineered a 3D spheroid culture environment with varying mechanobiological properties to study the effect of static matrix stiffness stimuli on mechanosensitive and malignant phenotypes in oral squamous cell carcinoma spheroids. We find that spheroid growth is enhanced when cultured in stiff extracellular matrix. We show that the protein expression of mechanoreceptor Piezo1 and stemness marker CD44 is upregulated in stiff matrix. We also report the upregulation of a selection of genes with associations to mechanoreception, ion channel transport, extracellular matrix organization, and tumorigenic phenotypes in stiff matrix spheroids. Together, our results indicate that cancer cells in 3D spheroids utilize mechanosensitive ion channels Piezo1 and TRPV4 as means to sense changes in static extracellular matrix stiffness, and that stiffness drives pro-tumorigenic phenotypes in oral squamous cell carcinoma.
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Next-Generation Biomaterials for Culture and Manipulation of Stem Cells
Stem cell fate decisions are informed by physical and chemical cues presented within and by the extracellular matrix. Despite the generally attributed importance of extracellular cues in governing self-renewal, differentiation, and collective behavior, knowledge gaps persist with regard to the individual, synergistic, and competing effects that specific physiochemical signals have on cell function. To better understand basic stem cell biology, as well as to expand opportunities in regenerative medicine and tissue engineering, a growing suite of customizable biomaterials has been developed. These next-generation cell culture materials offer user-defined biochemical and biomechanical properties, increasingly in a manner that can be controlled in time and 3D space. This review highlights recent innovations in this regard, focusing on advances to culture and maintain stemness, direct fate, and to detect stem cell function using biomaterial-based strategies.
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- PAR ID:
- 10160741
- Date Published:
- Journal Name:
- Cold Spring Harbor Perspectives in Biology
- ISSN:
- 1943-0264
- Page Range / eLocation ID:
- a035691
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1101/cshperspect.a035691
