Combinatorial Microenvironments Impose a Continuum of Cellular Responses to a Single Pathway-Targeted Anti-cancer Compound
Summary: Tumor microenvironments are a driver of resistance to anti-cancer drugs. Dissecting cell-microenvironment interactions into tractable units of study presents a challenge. Here, we assess the impact of hundreds of tumor-inspired microenvironments, in parallel, on lapatinib responses in four...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-10-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717313487 |
| _version_ | 1819010268956459008 |
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| author | Chun-Han Lin Tiina Jokela Joe Gray Mark A. LaBarge |
| author_facet | Chun-Han Lin Tiina Jokela Joe Gray Mark A. LaBarge |
| author_sort | Chun-Han Lin |
| collection | DOAJ |
| description | Summary: Tumor microenvironments are a driver of resistance to anti-cancer drugs. Dissecting cell-microenvironment interactions into tractable units of study presents a challenge. Here, we assess the impact of hundreds of tumor-inspired microenvironments, in parallel, on lapatinib responses in four cancer cell lines. Combinations of ECM and soluble factors were printed on stiffness-tunable substrata to generate a collection of controlled microenvironments in which to explore cell-based functional responses. Proliferation, HER2 protein expression and phosphorylation, and morphology were measured in single cells. Using dimension reduction and linear modeling, the effects of microenvironment constituents were identified and then validated empirically. Each of the cell lines exhibits unique microenvironment-response patterns. Fibronectin, type IV collagen, and matrix rigidity are significant regulators of lapatinib resistance in HER2-amplified breast cancer cells. Small-molecule inhibitors were identified that could attenuate microenvironment-imposed resistance. Thus, we demonstrate a strategy to identify resistance- and sensitivity-driving microenvironments to improve the efficacy of anti-cancer therapeutics. : Tumor microenvironments are a driver of anti-cancer drug resistance. Lin et al. use microenvironment microarrays and a cell-based functional approach to identify microenvironment components that modulate lapatinib responses in isogenic cells. They demonstrate a strategy to identify resistance- and sensitivity-driving microenvironments that may improve the understanding and efficacy of anti-cancer therapeutics. Keywords: microenvironment, microenvironment microarray, MEMA, HER2, lapatinib, verteporfin, AZD0530, YAP, fibronectin, breast cancer, drug resistance |
| first_indexed | 2024-12-21T01:09:34Z |
| format | Article |
| id | doaj.art-1672c91d90dc48838b513246a5c203b2 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-21T01:09:34Z |
| publishDate | 2017-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-1672c91d90dc48838b513246a5c203b22022-12-21T19:20:57ZengElsevierCell Reports2211-12472017-10-01212533545Combinatorial Microenvironments Impose a Continuum of Cellular Responses to a Single Pathway-Targeted Anti-cancer CompoundChun-Han Lin0Tiina Jokela1Joe Gray2Mark A. LaBarge3Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USADepartment of Population Sciences, City of Hope, Duarte, CA 91010, USA; Center for Cancer Biomarkers, University of Bergen, Bergen 5009, NorwayDepartment of Bioengineering, Oregon Health & Science University, Portland, OR 97201, USADepartment of Population Sciences, City of Hope, Duarte, CA 91010, USA; Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Center for Cancer Biomarkers, University of Bergen, Bergen 5009, Norway; Corresponding authorSummary: Tumor microenvironments are a driver of resistance to anti-cancer drugs. Dissecting cell-microenvironment interactions into tractable units of study presents a challenge. Here, we assess the impact of hundreds of tumor-inspired microenvironments, in parallel, on lapatinib responses in four cancer cell lines. Combinations of ECM and soluble factors were printed on stiffness-tunable substrata to generate a collection of controlled microenvironments in which to explore cell-based functional responses. Proliferation, HER2 protein expression and phosphorylation, and morphology were measured in single cells. Using dimension reduction and linear modeling, the effects of microenvironment constituents were identified and then validated empirically. Each of the cell lines exhibits unique microenvironment-response patterns. Fibronectin, type IV collagen, and matrix rigidity are significant regulators of lapatinib resistance in HER2-amplified breast cancer cells. Small-molecule inhibitors were identified that could attenuate microenvironment-imposed resistance. Thus, we demonstrate a strategy to identify resistance- and sensitivity-driving microenvironments to improve the efficacy of anti-cancer therapeutics. : Tumor microenvironments are a driver of anti-cancer drug resistance. Lin et al. use microenvironment microarrays and a cell-based functional approach to identify microenvironment components that modulate lapatinib responses in isogenic cells. They demonstrate a strategy to identify resistance- and sensitivity-driving microenvironments that may improve the understanding and efficacy of anti-cancer therapeutics. Keywords: microenvironment, microenvironment microarray, MEMA, HER2, lapatinib, verteporfin, AZD0530, YAP, fibronectin, breast cancer, drug resistancehttp://www.sciencedirect.com/science/article/pii/S2211124717313487 |
| spellingShingle | Chun-Han Lin Tiina Jokela Joe Gray Mark A. LaBarge Combinatorial Microenvironments Impose a Continuum of Cellular Responses to a Single Pathway-Targeted Anti-cancer Compound Cell Reports |
| title | Combinatorial Microenvironments Impose a Continuum of Cellular Responses to a Single Pathway-Targeted Anti-cancer Compound |
| title_full | Combinatorial Microenvironments Impose a Continuum of Cellular Responses to a Single Pathway-Targeted Anti-cancer Compound |
| title_fullStr | Combinatorial Microenvironments Impose a Continuum of Cellular Responses to a Single Pathway-Targeted Anti-cancer Compound |
| title_full_unstemmed | Combinatorial Microenvironments Impose a Continuum of Cellular Responses to a Single Pathway-Targeted Anti-cancer Compound |
| title_short | Combinatorial Microenvironments Impose a Continuum of Cellular Responses to a Single Pathway-Targeted Anti-cancer Compound |
| title_sort | combinatorial microenvironments impose a continuum of cellular responses to a single pathway targeted anti cancer compound |
| url | http://www.sciencedirect.com/science/article/pii/S2211124717313487 |
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