Single cells from human primary colorectal tumors exhibit polyfunctional heterogeneity in secretions of ELR+ CXC chemokines
Cancer is an inflammatory disease of tissue that is largely influenced by the interactions between multiple cell types, secreted factors, and signal transduction pathways. While single-cell sequencing continues to refine our understanding of the clonotypic heterogeneity within tumors, the complex in...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Royal Society of Chemistry
2014
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| Online Access: | http://hdl.handle.net/1721.1/91492 https://orcid.org/0000-0003-4555-2485 https://orcid.org/0000-0003-2398-5896 https://orcid.org/0000-0001-5923-3843 https://orcid.org/0000-0003-0921-3144 |
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| author | Adalsteinsson, Viktor A. Tahirova, Narmin Tallapragada, Naren Yao, Xiaosai Campion, Liam Angelini, Alessandro Douce, Thomas B. Bowman, Brittany Williamson, Christina A. Huang, Cindy Y. Kwon, Douglas Wittrup, Karl Dane Love, John C |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Adalsteinsson, Viktor A. Tahirova, Narmin Tallapragada, Naren Yao, Xiaosai Campion, Liam Angelini, Alessandro Douce, Thomas B. Bowman, Brittany Williamson, Christina A. Huang, Cindy Y. Kwon, Douglas Wittrup, Karl Dane Love, John C |
| author_sort | Adalsteinsson, Viktor A. |
| collection | MIT |
| description | Cancer is an inflammatory disease of tissue that is largely influenced by the interactions between multiple cell types, secreted factors, and signal transduction pathways. While single-cell sequencing continues to refine our understanding of the clonotypic heterogeneity within tumors, the complex interplay between genetic variations and non-genetic factors ultimately affects therapeutic outcome. Much has been learned through bulk studies of secreted factors in the tumor microenvironment, but the secretory behavior of single cells has been largely uncharacterized. Here we directly profiled the secretions of ELR+ CXC chemokines from thousands of single colorectal tumor and stromal cells, using an array of subnanoliter wells and a technique called microengraving to characterize both the rates of secretion of several factors at once and the numbers of cells secreting each chemokine. The ELR+ CXC chemokines are highly redundant, pro-angiogenic cytokines that signal via the CXCR1 and CXCR2 receptors, influencing tumor growth and progression. We find that human primary colorectal tumor and stromal cells exhibit polyfunctional heterogeneity in the combinations and magnitudes of secretions for these chemokines. In cell lines, we observe similar variance: phenotypes observed in bulk can be largely absent among the majority of single cells, and discordances exist between secretory states measured and gene expression for these chemokines among single cells. Together, these measures suggest secretory states among tumor cells are complex and can evolve dynamically. Most importantly, this study reveals new insight into the intratumoral phenotypic heterogeneity of human primary tumors. |
| first_indexed | 2024-09-23T08:56:48Z |
| format | Article |
| id | mit-1721.1/91492 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:56:48Z |
| publishDate | 2014 |
| publisher | Royal Society of Chemistry |
| record_format | dspace |
| spelling | mit-1721.1/914922022-09-26T09:22:21Z Single cells from human primary colorectal tumors exhibit polyfunctional heterogeneity in secretions of ELR+ CXC chemokines Adalsteinsson, Viktor A. Tahirova, Narmin Tallapragada, Naren Yao, Xiaosai Campion, Liam Angelini, Alessandro Douce, Thomas B. Bowman, Brittany Williamson, Christina A. Huang, Cindy Y. Kwon, Douglas Wittrup, Karl Dane Love, John C Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Ragon Institute of MGH, MIT and Harvard Koch Institute for Integrative Cancer Research at MIT Adalsteinsson, Viktor A. Tahirova, Narmin Tallapragada, Naren Yao, Xiaosai Angelini, Alessandro Douce, Thomas B. Huang, Cindy Y. Kwon, Douglas Wittrup, Karl Dane Love, J. Christopher Cancer is an inflammatory disease of tissue that is largely influenced by the interactions between multiple cell types, secreted factors, and signal transduction pathways. While single-cell sequencing continues to refine our understanding of the clonotypic heterogeneity within tumors, the complex interplay between genetic variations and non-genetic factors ultimately affects therapeutic outcome. Much has been learned through bulk studies of secreted factors in the tumor microenvironment, but the secretory behavior of single cells has been largely uncharacterized. Here we directly profiled the secretions of ELR+ CXC chemokines from thousands of single colorectal tumor and stromal cells, using an array of subnanoliter wells and a technique called microengraving to characterize both the rates of secretion of several factors at once and the numbers of cells secreting each chemokine. The ELR+ CXC chemokines are highly redundant, pro-angiogenic cytokines that signal via the CXCR1 and CXCR2 receptors, influencing tumor growth and progression. We find that human primary colorectal tumor and stromal cells exhibit polyfunctional heterogeneity in the combinations and magnitudes of secretions for these chemokines. In cell lines, we observe similar variance: phenotypes observed in bulk can be largely absent among the majority of single cells, and discordances exist between secretory states measured and gene expression for these chemokines among single cells. Together, these measures suggest secretory states among tumor cells are complex and can evolve dynamically. Most importantly, this study reveals new insight into the intratumoral phenotypic heterogeneity of human primary tumors. Janssen Pharmaceutical Ltd. National Cancer Institute (U.S.) (Cancer Center Support (Core) Grant P30-CA14051) National Science Foundation (U.S.). Graduate Research Fellowship Singapore. Agency for Science, Technology and Research Swiss National Science Foundation (Fellowship for Advanced Researchers PA00P3 139659) 2014-11-07T15:19:38Z 2014-11-07T15:19:38Z 2013-08 2013-03 Article http://purl.org/eprint/type/JournalArticle 1757-9694 1757-9708 http://hdl.handle.net/1721.1/91492 Adalsteinsson, Viktor A., Narmin Tahirova, Naren Tallapragada, Xiaosai Yao, Liam Campion, Alessandro Angelini, Thomas B. Douce, et al. “Single Cells from Human Primary Colorectal Tumors Exhibit Polyfunctional Heterogeneity in Secretions of ELR+ CXC Chemokines.” Integr. Biol. 5, no. 10 (2013): 1272. https://orcid.org/0000-0003-4555-2485 https://orcid.org/0000-0003-2398-5896 https://orcid.org/0000-0001-5923-3843 https://orcid.org/0000-0003-0921-3144 en_US http://dx.doi.org/10.1039/c3ib40059j Integrative Biology Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Royal Society of Chemistry PMC |
| spellingShingle | Adalsteinsson, Viktor A. Tahirova, Narmin Tallapragada, Naren Yao, Xiaosai Campion, Liam Angelini, Alessandro Douce, Thomas B. Bowman, Brittany Williamson, Christina A. Huang, Cindy Y. Kwon, Douglas Wittrup, Karl Dane Love, John C Single cells from human primary colorectal tumors exhibit polyfunctional heterogeneity in secretions of ELR+ CXC chemokines |
| title | Single cells from human primary colorectal tumors exhibit polyfunctional heterogeneity in secretions of ELR+ CXC chemokines |
| title_full | Single cells from human primary colorectal tumors exhibit polyfunctional heterogeneity in secretions of ELR+ CXC chemokines |
| title_fullStr | Single cells from human primary colorectal tumors exhibit polyfunctional heterogeneity in secretions of ELR+ CXC chemokines |
| title_full_unstemmed | Single cells from human primary colorectal tumors exhibit polyfunctional heterogeneity in secretions of ELR+ CXC chemokines |
| title_short | Single cells from human primary colorectal tumors exhibit polyfunctional heterogeneity in secretions of ELR+ CXC chemokines |
| title_sort | single cells from human primary colorectal tumors exhibit polyfunctional heterogeneity in secretions of elr cxc chemokines |
| url | http://hdl.handle.net/1721.1/91492 https://orcid.org/0000-0003-4555-2485 https://orcid.org/0000-0003-2398-5896 https://orcid.org/0000-0001-5923-3843 https://orcid.org/0000-0003-0921-3144 |
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