The essential clathrin adapter protein complex-2 is tumor suppressive specifically in vivo
Abstract The microenvironment is a rich source of new cancer targets. We thus used a targeted single-guide RNA library to screen a panel of human pancreatic cancer lines for genes uniquely affecting tumorigenesis. Here we show inactivation of the Adapter Protein complex-2 of clathrin-mediated endocy...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57521-2 |
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| author | Seth P. Zimmerman Lili B. DeGraw Christopher M. Counter |
| author_facet | Seth P. Zimmerman Lili B. DeGraw Christopher M. Counter |
| author_sort | Seth P. Zimmerman |
| collection | DOAJ |
| description | Abstract The microenvironment is a rich source of new cancer targets. We thus used a targeted single-guide RNA library to screen a panel of human pancreatic cancer lines for genes uniquely affecting tumorigenesis. Here we show inactivation of the Adapter Protein complex-2 of clathrin-mediated endocytosis reduces cell growth in vitro, but completely oppositely, promotes tumor growth in vivo. In culture, loss of the complex reduces transferrin endocytosis and iron import required for cell fitness. In tumors, alternative iron transport pathways allow pro-tumor effects of Adapter Protein complex-2 loss to manifest. In the most sensitive case, this is attributed to reprogramming the plasma membrane proteome, retaining integrins on the surface leading to Focal Adhesion Kinase phosphorylation and induction of proliferative signals. Adapter Protein complex-2 function in tumorigenesis is thus dependent upon the microenvironment, behaving as a common essential gene in culture via iron import, but as a tumor suppressor in tumors via integrin trafficking. |
| format | Article |
| id | doaj-art-a83e900bb33649968c85dfdd293a0a4a |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a83e900bb33649968c85dfdd293a0a4a2025-08-20T03:06:01ZengNature PortfolioNature Communications2041-17232025-03-0116111810.1038/s41467-025-57521-2The essential clathrin adapter protein complex-2 is tumor suppressive specifically in vivoSeth P. Zimmerman0Lili B. DeGraw1Christopher M. Counter2Department of Pharmacology & Cancer Biology, Duke University Medical CenterDepartment of Pharmacology & Cancer Biology, Duke University Medical CenterDepartment of Pharmacology & Cancer Biology, Duke University Medical CenterAbstract The microenvironment is a rich source of new cancer targets. We thus used a targeted single-guide RNA library to screen a panel of human pancreatic cancer lines for genes uniquely affecting tumorigenesis. Here we show inactivation of the Adapter Protein complex-2 of clathrin-mediated endocytosis reduces cell growth in vitro, but completely oppositely, promotes tumor growth in vivo. In culture, loss of the complex reduces transferrin endocytosis and iron import required for cell fitness. In tumors, alternative iron transport pathways allow pro-tumor effects of Adapter Protein complex-2 loss to manifest. In the most sensitive case, this is attributed to reprogramming the plasma membrane proteome, retaining integrins on the surface leading to Focal Adhesion Kinase phosphorylation and induction of proliferative signals. Adapter Protein complex-2 function in tumorigenesis is thus dependent upon the microenvironment, behaving as a common essential gene in culture via iron import, but as a tumor suppressor in tumors via integrin trafficking.https://doi.org/10.1038/s41467-025-57521-2 |
| spellingShingle | Seth P. Zimmerman Lili B. DeGraw Christopher M. Counter The essential clathrin adapter protein complex-2 is tumor suppressive specifically in vivo Nature Communications |
| title | The essential clathrin adapter protein complex-2 is tumor suppressive specifically in vivo |
| title_full | The essential clathrin adapter protein complex-2 is tumor suppressive specifically in vivo |
| title_fullStr | The essential clathrin adapter protein complex-2 is tumor suppressive specifically in vivo |
| title_full_unstemmed | The essential clathrin adapter protein complex-2 is tumor suppressive specifically in vivo |
| title_short | The essential clathrin adapter protein complex-2 is tumor suppressive specifically in vivo |
| title_sort | essential clathrin adapter protein complex 2 is tumor suppressive specifically in vivo |
| url | https://doi.org/10.1038/s41467-025-57521-2 |
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