Understanding a Molecular Switch Modulating Tumor Metastasis and Chemotherapy Resistance

Disabled 2 (Dab2) expression affects whether a tumor cell undergoes autophagy or apoptosis, according to preclinical research.1

Dab2 is an endocytic adaptor and tumor suppressor whose expression occurs during the epithelial-mesenchymal transition (EMT), which is mediated by transforming growth factor (TGF)-beta. This study sought to understand how Dab2 regulates apoptosis.

Dab2 has a pivotal role in preventing tumor cell survival by blocking autophagy and promoting cell death. These insights provide important information for maximizing the efficacy of existing chemotherapeutic agents.

When TGF-beta mediates EMT, Dab2 is expressed. EMT occurs in normal, healthy cells, but is abnormally activated in tumor cells and contributes to their chemotherapy resistance and metastasis.

"This was an unexpected finding that we followed," explained Philip Howe, PhD, professor and chair of biochemistry and molecular biology and Hans and Helen Koebig Chair in Clinical Oncology at the Medical University of South Carolina in Charleston, and senior author of this study.

"We knew that if you give cells TGF-beta, they go through EMT, and we knew you needed Dab2 for TGF-beta-mediated EMT. But, when we kept adding TGF-beta for more sustained periods (after EMT took place), cells took on a different morphology, and we noticed a loss of Dab2. We investigated this loss of Dab2 and discovered that it was being cleaved and that the cells were undergoing autophagy. Upon sustained TGF-beta treatment, the cells lost their mesenchymal phenotype they'd gained in EMT and entered into an autophagic state."

The research team combined a series of experiments to develop direct insights into molecular mechanisms supporting tumor cell survival and death. Their experiments were conducted in cancer cell lines and mouse models. These insights are crucial for maximizing the effectiveness of existing chemotherapeutic agents.

"This is important because there aren't a whole lot of drugs out there," explained Howe. "Most of what we use today has been around for 20 or 30 years because of a lack of investment in basic science."

The team's next steps are to investigate in vivo models for combination therapies using doxorubicin and an inhibitor of cathepsin B to further illuminate the potential for targeting Dab2 as a means of reducing tumor recurrence and metastasis.

Reference

1. Jiang Y, Woosley AN, Sivalingam N, et al. Cathepsin-B-mediated cleavage of Disabled-2 regulates TGF-β-induced autophagy. Nature Cell Biology. 2016 Jul 11. doi:10.1038/ncb3388. [Epub ahead of print]

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