Oscillatory ERK Signaling and Morphology Determine Heterogeneity of Breast Cancer Cell Chemotaxis via MEK-ERK and p38-MAPK Signaling Pathways
Chemotaxis, regulated by oscillatory signals, drives critical processes in cancer metastasis. Crucial chemoattractant molecules in breast cancer, CXCL12 and EGF, drive the activation of ERK and Akt. Regulated by feedback and crosstalk mechanisms, oscillatory signals in ERK and Akt control resultant...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | Bioengineering |
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| Online Access: | https://www.mdpi.com/2306-5354/10/2/269 |
| _version_ | 1827758529829666816 |
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| author | Kenneth K. Y. Ho Siddhartha Srivastava Patrick C. Kinnunen Krishna Garikipati Gary D. Luker Kathryn E. Luker |
| author_facet | Kenneth K. Y. Ho Siddhartha Srivastava Patrick C. Kinnunen Krishna Garikipati Gary D. Luker Kathryn E. Luker |
| author_sort | Kenneth K. Y. Ho |
| collection | DOAJ |
| description | Chemotaxis, regulated by oscillatory signals, drives critical processes in cancer metastasis. Crucial chemoattractant molecules in breast cancer, CXCL12 and EGF, drive the activation of ERK and Akt. Regulated by feedback and crosstalk mechanisms, oscillatory signals in ERK and Akt control resultant changes in cell morphology and chemotaxis. While commonly studied at the population scale, metastasis arises from small numbers of cells that successfully disseminate, underscoring the need to analyze processes that cancer cells use to connect oscillatory signaling to chemotaxis at single-cell resolution. Furthermore, little is known about how to successfully target fast-migrating cells to block metastasis. We investigated to what extent oscillatory networks in single cells associate with heterogeneous chemotactic responses and how targeted inhibitors block signaling processes in chemotaxis. We integrated live, single-cell imaging with time-dependent data processing to discover oscillatory signal processes defining heterogeneous chemotactic responses. We identified that short ERK and Akt waves, regulated by MEK-ERK and p38-MAPK signaling pathways, determine the heterogeneous random migration of cancer cells. By comparison, long ERK waves and the morphological changes regulated by MEK-ERK signaling, determine heterogeneous directed motion. This study indicates that treatments against chemotaxis in consider must interrupt oscillatory signaling. |
| first_indexed | 2024-03-11T09:07:48Z |
| format | Article |
| id | doaj.art-2218fd7753264617bdf794cb49dda7e0 |
| institution | Directory Open Access Journal |
| issn | 2306-5354 |
| language | English |
| last_indexed | 2024-03-11T09:07:48Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Bioengineering |
| spelling | doaj.art-2218fd7753264617bdf794cb49dda7e02023-11-16T19:12:03ZengMDPI AGBioengineering2306-53542023-02-0110226910.3390/bioengineering10020269Oscillatory ERK Signaling and Morphology Determine Heterogeneity of Breast Cancer Cell Chemotaxis via MEK-ERK and p38-MAPK Signaling PathwaysKenneth K. Y. Ho0Siddhartha Srivastava1Patrick C. Kinnunen2Krishna Garikipati3Gary D. Luker4Kathryn E. Luker5Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USADepartment of Mechanical Engineering, University of Michigan, Ann Arbor, MI 48109, USADepartment of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USADepartment of Mechanical Engineering, University of Michigan, Ann Arbor, MI 48109, USADepartment of Radiology, University of Michigan, Ann Arbor, MI 48109, USADepartment of Radiology, University of Michigan, Ann Arbor, MI 48109, USAChemotaxis, regulated by oscillatory signals, drives critical processes in cancer metastasis. Crucial chemoattractant molecules in breast cancer, CXCL12 and EGF, drive the activation of ERK and Akt. Regulated by feedback and crosstalk mechanisms, oscillatory signals in ERK and Akt control resultant changes in cell morphology and chemotaxis. While commonly studied at the population scale, metastasis arises from small numbers of cells that successfully disseminate, underscoring the need to analyze processes that cancer cells use to connect oscillatory signaling to chemotaxis at single-cell resolution. Furthermore, little is known about how to successfully target fast-migrating cells to block metastasis. We investigated to what extent oscillatory networks in single cells associate with heterogeneous chemotactic responses and how targeted inhibitors block signaling processes in chemotaxis. We integrated live, single-cell imaging with time-dependent data processing to discover oscillatory signal processes defining heterogeneous chemotactic responses. We identified that short ERK and Akt waves, regulated by MEK-ERK and p38-MAPK signaling pathways, determine the heterogeneous random migration of cancer cells. By comparison, long ERK waves and the morphological changes regulated by MEK-ERK signaling, determine heterogeneous directed motion. This study indicates that treatments against chemotaxis in consider must interrupt oscillatory signaling.https://www.mdpi.com/2306-5354/10/2/269cancer metastasischemotaxisheterogeneitysingle-cell imagingoscillationCXCR4 signaling |
| spellingShingle | Kenneth K. Y. Ho Siddhartha Srivastava Patrick C. Kinnunen Krishna Garikipati Gary D. Luker Kathryn E. Luker Oscillatory ERK Signaling and Morphology Determine Heterogeneity of Breast Cancer Cell Chemotaxis via MEK-ERK and p38-MAPK Signaling Pathways Bioengineering cancer metastasis chemotaxis heterogeneity single-cell imaging oscillation CXCR4 signaling |
| title | Oscillatory ERK Signaling and Morphology Determine Heterogeneity of Breast Cancer Cell Chemotaxis via MEK-ERK and p38-MAPK Signaling Pathways |
| title_full | Oscillatory ERK Signaling and Morphology Determine Heterogeneity of Breast Cancer Cell Chemotaxis via MEK-ERK and p38-MAPK Signaling Pathways |
| title_fullStr | Oscillatory ERK Signaling and Morphology Determine Heterogeneity of Breast Cancer Cell Chemotaxis via MEK-ERK and p38-MAPK Signaling Pathways |
| title_full_unstemmed | Oscillatory ERK Signaling and Morphology Determine Heterogeneity of Breast Cancer Cell Chemotaxis via MEK-ERK and p38-MAPK Signaling Pathways |
| title_short | Oscillatory ERK Signaling and Morphology Determine Heterogeneity of Breast Cancer Cell Chemotaxis via MEK-ERK and p38-MAPK Signaling Pathways |
| title_sort | oscillatory erk signaling and morphology determine heterogeneity of breast cancer cell chemotaxis via mek erk and p38 mapk signaling pathways |
| topic | cancer metastasis chemotaxis heterogeneity single-cell imaging oscillation CXCR4 signaling |
| url | https://www.mdpi.com/2306-5354/10/2/269 |
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