The essential clathrin adapter protein complex-2 is tumor suppressive specifically in vivo
Seth P Zimmerman1, Lili B DeGraw1, Christopher M Counter2,3
1Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC, USA.
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.
Insights
Inactivating Adapter Protein complex-2 hinders pancreatic cancer cell growth in vitro but promotes tumor growth in vivo by altering iron transport and integrin signaling, highlighting microenvironment-dependent roles.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- The tumor microenvironment presents novel targets for cancer therapy.
- Identifying genes critical for tumorigenesis is essential for developing new treatment strategies.
Purpose of the Study:
- To screen for genes that uniquely influence pancreatic cancer growth using a targeted single-guide RNA library.
- To investigate the dual role of Adapter Protein complex-2 in cancer cell proliferation and tumor development.
Main Methods:
- Utilized a targeted single-guide RNA library to screen human pancreatic cancer cell lines.
- Assessed gene function in vitro (cell growth, transferrin endocytosis, iron import) and in vivo (tumor growth).
- Analyzed plasma membrane proteome and signaling pathways (e.g., Focal Adhesion Kinase phosphorylation).
Main Results:
- Inactivation of Adapter Protein complex-2 reduced in vitro cell growth by limiting transferrin endocytosis and iron import.
- Conversely, Adapter Protein complex-2 loss promoted in vivo tumor growth.
- This pro-tumor effect was linked to alternative iron transport pathways and reprogramming of the plasma membrane proteome, retaining integrins and activating proliferative signals via Focal Adhesion Kinase.
Conclusions:
- Adapter Protein complex-2 exhibits context-dependent functions in tumorigenesis.
- It acts as an essential gene in vitro, supporting cell fitness through iron import.
- It functions as a tumor suppressor in vivo, regulating integrin trafficking and tumor cell proliferation within the microenvironment.
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