Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells
Metastases are a major cause of cancer mortality. AXL, a receptor tyrosine kinase aberrantly expressed in many tumors, is a potent oncogenic driver of metastatic cell motility and has been identified as broadly relevant in cancer drug resistance. Despite its frequent association with changes in canc...
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American Association for Cancer Research (AACR)
2018
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| Online Access: | http://hdl.handle.net/1721.1/117691 https://orcid.org/0000-0002-3539-3129 https://orcid.org/0000-0001-6284-2711 https://orcid.org/0000-0002-0050-989X |
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| author | French, Cory B. Zweemer, Jacomina M. Mesfin, Joshua Gordonov, Simon Meyer, Aaron Samuel Lauffenburger, Douglas A |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering French, Cory B. Zweemer, Jacomina M. Mesfin, Joshua Gordonov, Simon Meyer, Aaron Samuel Lauffenburger, Douglas A |
| author_sort | French, Cory B. |
| collection | MIT |
| description | Metastases are a major cause of cancer mortality. AXL, a receptor tyrosine kinase aberrantly expressed in many tumors, is a potent oncogenic driver of metastatic cell motility and has been identified as broadly relevant in cancer drug resistance. Despite its frequent association with changes in cancer phenotypes, the precise mechanism leading to AXL activation is incompletely understood. In addition to its ligand growth arrest specific-6 (Gas6), activation of AXL requires the lipid moiety phosphatidylserine (PS). Phosphatidylserine is only available to mediate AXL activation when it is externalized on cell membranes, an event that occurs during certain physiologic processes such as apoptosis. Here, it is reported that exposure of cancer cells to phosphatidylserine-containing vesicles, including synthetic liposomes and apoptotic bodies, contributes to enhanced migration of tumor cells via a PS-Gas6-AXL signaling axis. These findings suggest that anticancer treatments that induce fractional cell killing enhance the motility of surviving cells in AXL-expressing tumors, which may explain the widespread role of AXL in limiting therapeutic efficacy. Implications: This study demonstrates that motility behavior of AXL-expressing tumor cells can be elicited by Gas6-bearing apoptotic bodies generated from tumor treatment with therapeutics that produce killing of a portion of the tumor cells present but not all, hence generating potentially problematic invasive and metastatic behavior of the surviving tumor cells. |
| first_indexed | 2024-09-23T10:45:17Z |
| format | Article |
| id | mit-1721.1/117691 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T10:45:17Z |
| publishDate | 2018 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/1176912022-09-27T14:45:21Z Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells French, Cory B. Zweemer, Jacomina M. Mesfin, Joshua Gordonov, Simon Meyer, Aaron Samuel Lauffenburger, Douglas A Massachusetts Institute of Technology. Department of Biological Engineering Koch Institute for Integrative Cancer Research at MIT Zweemer, Jacomina M. Mesfin, Joshua Gordonov, Simon Meyer, Aaron Samuel Lauffenburger, Douglas A Metastases are a major cause of cancer mortality. AXL, a receptor tyrosine kinase aberrantly expressed in many tumors, is a potent oncogenic driver of metastatic cell motility and has been identified as broadly relevant in cancer drug resistance. Despite its frequent association with changes in cancer phenotypes, the precise mechanism leading to AXL activation is incompletely understood. In addition to its ligand growth arrest specific-6 (Gas6), activation of AXL requires the lipid moiety phosphatidylserine (PS). Phosphatidylserine is only available to mediate AXL activation when it is externalized on cell membranes, an event that occurs during certain physiologic processes such as apoptosis. Here, it is reported that exposure of cancer cells to phosphatidylserine-containing vesicles, including synthetic liposomes and apoptotic bodies, contributes to enhanced migration of tumor cells via a PS-Gas6-AXL signaling axis. These findings suggest that anticancer treatments that induce fractional cell killing enhance the motility of surviving cells in AXL-expressing tumors, which may explain the widespread role of AXL in limiting therapeutic efficacy. Implications: This study demonstrates that motility behavior of AXL-expressing tumor cells can be elicited by Gas6-bearing apoptotic bodies generated from tumor treatment with therapeutics that produce killing of a portion of the tumor cells present but not all, hence generating potentially problematic invasive and metastatic behavior of the surviving tumor cells. 2018-09-10T19:05:59Z 2018-09-10T19:05:59Z 2017-09 2017-08 2018-09-10T13:11:17Z Article http://purl.org/eprint/type/JournalArticle 1541-7786 1557-3125 http://hdl.handle.net/1721.1/117691 Zweemer, Annelien J.M. et al. “Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells.” Molecular Cancer Research 15, 12 (September 2017): 1656–1666 © 2017 American Association for Cancer Research https://orcid.org/0000-0002-3539-3129 https://orcid.org/0000-0001-6284-2711 https://orcid.org/0000-0002-0050-989X http://dx.doi.org/10.1158/1541-7786.MCR-17-0012 Molecular Cancer Research Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research (AACR) PMC |
| spellingShingle | French, Cory B. Zweemer, Jacomina M. Mesfin, Joshua Gordonov, Simon Meyer, Aaron Samuel Lauffenburger, Douglas A Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells |
| title | Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells |
| title_full | Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells |
| title_fullStr | Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells |
| title_full_unstemmed | Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells |
| title_short | Apoptotic Bodies Elicit Gas6-Mediated Migration of AXL-Expressing Tumor Cells |
| title_sort | apoptotic bodies elicit gas6 mediated migration of axl expressing tumor cells |
| url | http://hdl.handle.net/1721.1/117691 https://orcid.org/0000-0002-3539-3129 https://orcid.org/0000-0001-6284-2711 https://orcid.org/0000-0002-0050-989X |
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