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Publications of the Week

Cx43 Phosphorylation Sites Regulate Pancreatic Cancer Metastasis

By March 4, 2021March 15th, 2021No Comments

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This week we profile a recent publication in Oncogene from the laboratory of Dr. Paul Lampe at Fred Hutch. Pictured are Joell L. Solan (right) and Paul D. Lampe (left).

Can you provide a brief overview of your lab’s current research focus?

The work discussed here highlights our work on gap junctions. Gap junctions are highly organized membrane domains, consisting of thousands of intercellular channels, made up of connexin proteins. The cytoplasmic tails of these proteins interact with a wide variety of kinases and signaling molecules providing a scaffold function at the plasma membrane. Thus, gap junctions can couple intercellular communication with intracellular signaling. Our lab has studied how post-translational modification of the gap junction protein Connexin 43 (Cx43) can alter biological responses in a variety of pathologies, including pancreatic cancer, cardiac ischemia and epidermal wounding.

What is the significance of the findings in this publication?

Progression of pancreatic cancer is characterized by dynamic interactions between multiple cell types that promote a complex tumor microenvironment (TME). This results in tumors that are particularly refractory to treatment, resulting in a 5-year survival rate of just 9%, thus treatments that target the TME are a promising and active target of investigation in pancreatic and other cancers. These studies show that phosphorylation of Cx43 regulates tissue remodeling throughout tumor progression, including the ability of the tumor to metastasize. Gap junctions in cancer associated fibroblasts (CAFs) appear to promote metastasis while downregulation of gap junctions can diminish metastases. CAF phenotypes are heterogeneous and dynamic and serve multiple functions that can regulate, promote or inhibit tumorigenesis. Data presented here and from other fields indicate that Cx43 can regulate fibroblast phenotypes in response to environmental cues. These data suggest that post-translational modification of Cx43 is a target that could skew CAF phenotypes towards a tumor inhibiting phenotype and/or render the tumor susceptible to treatment.

This work was funded by:

Grants R21CA149554 and GM55632 from the National Institutes of Health.

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