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Published on: October 27, 2020
CD73 facilitates EMT progression and promotes lung metastases in triple-negative breast cancer
Nataliia Petruk1,2, Sanni Tuominen1,2,3, Malin Åkerfelt1,2,4
1Institute of Biomedicine, University of Turku, Turku, Finland.
Abstract:
CD73 is a cell surface ecto-5'-nucleotidase, which converts extracellular adenosine monophosphate to adenosine. High tumor CD73 expression is associated with poor outcome among triple-negative breast cancer (TNBC) patients. Here we investigated the mechanisms by which CD73 might contribute to TNBC progression. This was done by inhibiting CD73 with adenosine 5'-(α, β-methylene) diphosphate (APCP) in MDA-MB-231 or 4T1 TNBC cells or through shRNA-silencing (sh-CD73). Effects of such inhibition on cell behavior was then studied in normoxia and hypoxia in vitro and in an orthotopic mouse model in vivo. CD73 inhibition, through shRNA or APCP significantly decreased cellular viability and migration in normoxia. Inhibition of CD73 also resulted in suppression of hypoxia-induced increase in viability and prevented cell protrusion elongation in both normoxia and hypoxia in cancer cells. Sh-CD73 4T1 cells formed significantly smaller and less invasive 3D organoids in vitro, and significantly smaller orthotopic tumors and less lung metastases than control shRNA cells in vivo. CD73 suppression increased E-cadherin and decreased vimentin expression in vitro and in vivo, proposing maintenance of a more epithelial phenotype. In conclusion, our results suggest that CD73 may promote early steps of tumor progression, possibly through facilitating epithelial-mesenchymal transition.
Insights
Inhibiting CD73 in triple-negative breast cancer (TNBC) reduces cancer cell viability and metastasis. Targeting CD73 may hinder tumor progression by maintaining an epithelial cell phenotype.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- CD73, an ecto-5'-nucleotidase, converts extracellular adenosine monophosphate to adenosine.
- High CD73 expression correlates with poor outcomes in triple-negative breast cancer (TNBC).
Purpose of the Study:
- To investigate the mechanisms by which CD73 contributes to TNBC progression.
- To evaluate the effects of CD73 inhibition on TNBC cell behavior in vitro and in vivo.
Main Methods:
- CD73 inhibition using adenosine 5'-(α, β-methylene) diphosphate (APCP) or shRNA-silencing (sh-CD73) in MDA-MB-231 and 4T1 TNBC cells.
- Assessment of cell viability, migration, and protrusion elongation under normoxia and hypoxia.
- Evaluation of 3D organoid invasion, orthotopic tumor growth, and lung metastasis in a mouse model.
- Analysis of E-cadherin and vimentin expression.
Main Results:
- CD73 inhibition significantly decreased cellular viability and migration in normoxia.
- Hypoxia-induced increases in viability were suppressed, and cell protrusion elongation was prevented by CD73 inhibition.
- sh-CD73 cells formed smaller, less invasive 3D organoids, orthotopic tumors, and fewer lung metastases.
- CD73 suppression increased E-cadherin and decreased vimentin expression, suggesting a more epithelial phenotype.
Conclusions:
- CD73 inhibition effectively reduces TNBC cell viability, migration, and metastasis.
- CD73 may promote early tumor progression in TNBC by facilitating epithelial-mesenchymal transition.
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