Intratumoral Heterogeneity Promotes Collective Cancer Invasion through NOTCH1 Variation
Cellular and molecular heterogeneity within tumors has long been associated with the progression of cancer to an aggressive phenotype and a poor prognosis. However, how such intratumoral heterogeneity contributes to the invasiveness of cancer is largely unknown. Here, using a tumor bioengineering ap...
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| Format: | Article |
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MDPI AG
2021-11-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/11/3084 |
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| author | Peter Torab Yue Yan Mona Ahmed Hironobu Yamashita Joshua I. Warrick Jay D. Raman David J. DeGraff Pak Kin Wong |
| author_facet | Peter Torab Yue Yan Mona Ahmed Hironobu Yamashita Joshua I. Warrick Jay D. Raman David J. DeGraff Pak Kin Wong |
| author_sort | Peter Torab |
| collection | DOAJ |
| description | Cellular and molecular heterogeneity within tumors has long been associated with the progression of cancer to an aggressive phenotype and a poor prognosis. However, how such intratumoral heterogeneity contributes to the invasiveness of cancer is largely unknown. Here, using a tumor bioengineering approach, we investigate the interaction between molecular subtypes within bladder microtumors and the corresponding effects on their invasiveness. Our results reveal heterogeneous microtumors formed by multiple molecular subtypes possess enhanced invasiveness compared to individual cells, even when both cells are not invasive individually. To examine the molecular mechanism of intratumoral heterogeneity mediated invasiveness, live single cell biosensing, RNA interference, and CRISPR-Cas9 gene editing approaches were applied to investigate and control the composition of the microtumors. An agent-based computational model was also developed to evaluate the influence of NOTCH1 variation on DLL4 expression within a microtumor. The data indicate that intratumoral variation in NOTCH1 expression can lead to upregulation of DLL4 expression within the microtumor and enhancement of microtumor invasiveness. Overall, our results reveal a novel mechanism of heterogeneity mediated invasiveness through intratumoral variation of gene expression. |
| first_indexed | 2024-03-10T05:36:32Z |
| format | Article |
| id | doaj.art-9fd3d75d6c6547998b2dfb18ad573bc7 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T05:36:32Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-9fd3d75d6c6547998b2dfb18ad573bc72023-11-22T22:51:04ZengMDPI AGCells2073-44092021-11-011011308410.3390/cells10113084Intratumoral Heterogeneity Promotes Collective Cancer Invasion through NOTCH1 VariationPeter Torab0Yue Yan1Mona Ahmed2Hironobu Yamashita3Joshua I. Warrick4Jay D. Raman5David J. DeGraff6Pak Kin Wong7Department of Mechanical Engineering, The Pennsylvania State University, University Park, PA 16802, USADepartment of Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USADepartment of Biomedical Engineering, The Pennsylvania State University, University Park, PA 16802, USADepartment of Pathology and Laboratory Medicine, The Pennsylvania State University, Hershey, PA 17033, USADepartment of Pathology and Laboratory Medicine, The Pennsylvania State University, Hershey, PA 17033, USAPenn State Health Milton S., Hershey Medical Center, Department of Surgery, Hershey, PA 17033, USADepartment of Pathology and Laboratory Medicine, The Pennsylvania State University, Hershey, PA 17033, USADepartment of Mechanical Engineering, The Pennsylvania State University, University Park, PA 16802, USACellular and molecular heterogeneity within tumors has long been associated with the progression of cancer to an aggressive phenotype and a poor prognosis. However, how such intratumoral heterogeneity contributes to the invasiveness of cancer is largely unknown. Here, using a tumor bioengineering approach, we investigate the interaction between molecular subtypes within bladder microtumors and the corresponding effects on their invasiveness. Our results reveal heterogeneous microtumors formed by multiple molecular subtypes possess enhanced invasiveness compared to individual cells, even when both cells are not invasive individually. To examine the molecular mechanism of intratumoral heterogeneity mediated invasiveness, live single cell biosensing, RNA interference, and CRISPR-Cas9 gene editing approaches were applied to investigate and control the composition of the microtumors. An agent-based computational model was also developed to evaluate the influence of NOTCH1 variation on DLL4 expression within a microtumor. The data indicate that intratumoral variation in NOTCH1 expression can lead to upregulation of DLL4 expression within the microtumor and enhancement of microtumor invasiveness. Overall, our results reveal a novel mechanism of heterogeneity mediated invasiveness through intratumoral variation of gene expression.https://www.mdpi.com/2073-4409/10/11/3084single cell analysistumor subtypesbasalluminaltumor-on-chipbiosensing |
| spellingShingle | Peter Torab Yue Yan Mona Ahmed Hironobu Yamashita Joshua I. Warrick Jay D. Raman David J. DeGraff Pak Kin Wong Intratumoral Heterogeneity Promotes Collective Cancer Invasion through NOTCH1 Variation Cells single cell analysis tumor subtypes basal luminal tumor-on-chip biosensing |
| title | Intratumoral Heterogeneity Promotes Collective Cancer Invasion through NOTCH1 Variation |
| title_full | Intratumoral Heterogeneity Promotes Collective Cancer Invasion through NOTCH1 Variation |
| title_fullStr | Intratumoral Heterogeneity Promotes Collective Cancer Invasion through NOTCH1 Variation |
| title_full_unstemmed | Intratumoral Heterogeneity Promotes Collective Cancer Invasion through NOTCH1 Variation |
| title_short | Intratumoral Heterogeneity Promotes Collective Cancer Invasion through NOTCH1 Variation |
| title_sort | intratumoral heterogeneity promotes collective cancer invasion through notch1 variation |
| topic | single cell analysis tumor subtypes basal luminal tumor-on-chip biosensing |
| url | https://www.mdpi.com/2073-4409/10/11/3084 |
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