Flow-based pipeline for systematic modulation and analysis of 3D tumor microenvironments
The cancer microenvironment, which incorporates interactions with stromal cells, extracellular matrix (ECM), and other tumor cells in a 3-dimensional (3D) context, has been implicated in every stage of cancer development, including growth of the primary tumor, metastatic spread, and response to trea...
| Main Authors: | , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
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Royal Society of Chemistry, The
2013
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| Online Access: | http://hdl.handle.net/1721.1/82618 https://orcid.org/0000-0002-1293-2097 |
| _version_ | 1826211589365170176 |
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| author | Li, Cheri Yingjie Wood, David K. Huang, Joanne Bhatia, Sangeeta N. |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology Li, Cheri Yingjie Wood, David K. Huang, Joanne Bhatia, Sangeeta N. |
| author_sort | Li, Cheri Yingjie |
| collection | MIT |
| description | The cancer microenvironment, which incorporates interactions with stromal cells, extracellular matrix (ECM), and other tumor cells in a 3-dimensional (3D) context, has been implicated in every stage of cancer development, including growth of the primary tumor, metastatic spread, and response to treatment. Our understanding of the tumor microenvironment and our ability to develop new therapies would greatly benefit from tools that allow us to systematically probe microenvironmental cues within a 3D context. Here, we leveraged recent advances in microfluidic technology to develop a platform for high-throughput fabrication of tunable cellular microniches (“microtissues”) that allow us to probe tumor cell response to a range of microenvironmental cues, including ECM, soluble factors, and stromal cells, all in 3D. We further combine this tunable microniche platform with rapid, flow-based population level analysis (n > 500), which permits analysis and sorting of microtissue populations both pre- and post-culture by a range of parameters, including proliferation and homotypic or heterotypic cell density. We used this platform to demonstrate differential responses of lung adenocarcinoma cells to a selection of ECM molecules and soluble factors. The cells exhibited enhanced or reduced proliferation when encapsulated in fibronectin- or collagen-1-containing microtissues, respectively, and they showed reduced proliferation in the presence of TGF-β, an effect that we did not observe in monolayer culture. We also measured tumor cell response to a panel of drug targets and found, in contrast to monolayer culture, specific sensitivity of tumor cells to TGFβR2 inhibitors, implying that TGF-β has an anti-proliferative affect that is unique to the 3D context and that this effect is mediated by TGFβR2. These findings highlight the importance of the microenvironmental context in therapeutic development and that the platform we present here allows the high-throughput study of tumor response to drugs as well as basic tumor biology in well-defined microenvironmental niches. |
| first_indexed | 2024-09-23T15:08:23Z |
| format | Article |
| id | mit-1721.1/82618 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:08:23Z |
| publishDate | 2013 |
| publisher | Royal Society of Chemistry, The |
| record_format | dspace |
| spelling | mit-1721.1/826182022-09-29T12:56:22Z Flow-based pipeline for systematic modulation and analysis of 3D tumor microenvironments Li, Cheri Yingjie Wood, David K. Huang, Joanne Bhatia, Sangeeta N. Harvard University--MIT Division of Health Sciences and Technology Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Koch Institute for Integrative Cancer Research at MIT Li, Cheri Yingjie Wood, David K. Huang, Joanne Bhatia, Sangeeta N. The cancer microenvironment, which incorporates interactions with stromal cells, extracellular matrix (ECM), and other tumor cells in a 3-dimensional (3D) context, has been implicated in every stage of cancer development, including growth of the primary tumor, metastatic spread, and response to treatment. Our understanding of the tumor microenvironment and our ability to develop new therapies would greatly benefit from tools that allow us to systematically probe microenvironmental cues within a 3D context. Here, we leveraged recent advances in microfluidic technology to develop a platform for high-throughput fabrication of tunable cellular microniches (“microtissues”) that allow us to probe tumor cell response to a range of microenvironmental cues, including ECM, soluble factors, and stromal cells, all in 3D. We further combine this tunable microniche platform with rapid, flow-based population level analysis (n > 500), which permits analysis and sorting of microtissue populations both pre- and post-culture by a range of parameters, including proliferation and homotypic or heterotypic cell density. We used this platform to demonstrate differential responses of lung adenocarcinoma cells to a selection of ECM molecules and soluble factors. The cells exhibited enhanced or reduced proliferation when encapsulated in fibronectin- or collagen-1-containing microtissues, respectively, and they showed reduced proliferation in the presence of TGF-β, an effect that we did not observe in monolayer culture. We also measured tumor cell response to a panel of drug targets and found, in contrast to monolayer culture, specific sensitivity of tumor cells to TGFβR2 inhibitors, implying that TGF-β has an anti-proliferative affect that is unique to the 3D context and that this effect is mediated by TGFβR2. These findings highlight the importance of the microenvironmental context in therapeutic development and that the platform we present here allows the high-throughput study of tumor response to drugs as well as basic tumor biology in well-defined microenvironmental niches. American Association for Cancer Research (Stand Up to Cancer Charitable Initiative) National Institute for Biomedical Imaging and Bioengineering (U.S.) (National Research Service Award Fellowship) National Science Foundation (U.S.) (Graduate Research Fellowship Program Grant 1122374) Howard Hughes Medical Institute 2013-12-02T17:27:56Z 2013-12-02T17:27:56Z 2013-03 2012-11 Article http://purl.org/eprint/type/JournalArticle 1473-0197 1473-0189 http://hdl.handle.net/1721.1/82618 Li, Cheri Y., David K. Wood, Joanne H. Huang, and Sangeeta N. Bhatia. “Flow-based pipeline for systematic modulation and analysis of 3D tumor microenvironments.” Lab on a Chip 13, no. 10 (2013): 1969. © Royal Society of Chemistry 2013 https://orcid.org/0000-0002-1293-2097 en_US http://dx.doi.org/10.1039/c3lc41300d Lab on a Chip http://creativecommons.org/licenses/by-nc/3.0/ application/pdf Royal Society of Chemistry, The PMC |
| spellingShingle | Li, Cheri Yingjie Wood, David K. Huang, Joanne Bhatia, Sangeeta N. Flow-based pipeline for systematic modulation and analysis of 3D tumor microenvironments |
| title | Flow-based pipeline for systematic modulation and analysis of 3D tumor microenvironments |
| title_full | Flow-based pipeline for systematic modulation and analysis of 3D tumor microenvironments |
| title_fullStr | Flow-based pipeline for systematic modulation and analysis of 3D tumor microenvironments |
| title_full_unstemmed | Flow-based pipeline for systematic modulation and analysis of 3D tumor microenvironments |
| title_short | Flow-based pipeline for systematic modulation and analysis of 3D tumor microenvironments |
| title_sort | flow based pipeline for systematic modulation and analysis of 3d tumor microenvironments |
| url | http://hdl.handle.net/1721.1/82618 https://orcid.org/0000-0002-1293-2097 |
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