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ERBB3 is required for metastasis formation of melanoma cells.

Tiwary S, Preziosi M, Rothberg PG, Zeitouni N, Corson N, Xu L - Oncogenesis (2014)

Bottom Line: Consistent with this, the ERBB3 ligand, NRG1, is highly expressed in mouse lungs and induces ERBB3-depdnent phosphorylation of AKT in both MA-2 and 451Lu-R cells in vitro.These findings suggest that ERBB3 may serve as a target for treating metastatic melanomas that are resistant to BIs.In support of this, administration of the pan-ERBB inhibitor, canertinib, significantly suppresses the metastasis formation of BI-resistant melanoma cell lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.

ABSTRACT
Melanoma is curable when it is at an early phase but is lethal once it becomes metastatic. The recent development of BRAF(V600E) inhibitors (BIs) showed great promise in treating metastatic melanoma, but resistance developed quickly in the treated patients, and these inhibitors are not effective on melanomas that express wild-type BRAF. Alternative therapeutic strategies for metastatic melanoma are urgently needed. Here we report that ERBB3, a member of the epidermal growth factor receptor family, is required for the formation of lung metastasis from both the BI-sensitive melanoma cell line, MA-2, and the BI-resistant melanoma cell line, 451Lu-R. Further analyses revealed that ERBB3 does not affect the initial seeding of melanoma cells in lung but is required for their further development into overt metastases, indicating that ERBB3 might be essential for the survival of melanoma cells after they reach the lung. Consistent with this, the ERBB3 ligand, NRG1, is highly expressed in mouse lungs and induces ERBB3-depdnent phosphorylation of AKT in both MA-2 and 451Lu-R cells in vitro. These findings suggest that ERBB3 may serve as a target for treating metastatic melanomas that are resistant to BIs. In support of this, administration of the pan-ERBB inhibitor, canertinib, significantly suppresses the metastasis formation of BI-resistant melanoma cell lines.

No MeSH data available.


Related in: MedlinePlus

ERBB3 is required for the metastasis formation of melanoma cell lines in lung. (a, c). ERBB3 was knocked down by two different shRNAs in MA-2 cells (a) or 451Lu-R cells (c). The efficiency of knockdown was measured by qRT–PCR. (b, d). ERBB3 knockdown led to a significant decrease in the number of lung metastases from MA-2 cells (b) or 451Lu-R cells (d). Student's t-test, ***P<0.001.
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fig2: ERBB3 is required for the metastasis formation of melanoma cell lines in lung. (a, c). ERBB3 was knocked down by two different shRNAs in MA-2 cells (a) or 451Lu-R cells (c). The efficiency of knockdown was measured by qRT–PCR. (b, d). ERBB3 knockdown led to a significant decrease in the number of lung metastases from MA-2 cells (b) or 451Lu-R cells (d). Student's t-test, ***P<0.001.

Mentions: ERBB3 was knocked down in both cell lines via lentiviral expression of shRNAs. The knockdown cells express significantly lower levels of ERBB3 mRNA and protein (Figures 2a and c, 5a and b). These cells, along with control cells expressing the shRNA against green fluorescent protein (GFP), were injected intravenously into the immunodeficient NSG mice. Lungs were harvested, and metastases counted. The knockdowns of ERBB3 resulted in a significant reduction in the number of lung metastases from both cell lines (Figures 2b and d), suggesting that ERBB3 is required for the metastasis formation of human melanoma cells and this effect may be independent of the sensitivity of melanoma cells to BIs.


ERBB3 is required for metastasis formation of melanoma cells.

Tiwary S, Preziosi M, Rothberg PG, Zeitouni N, Corson N, Xu L - Oncogenesis (2014)

ERBB3 is required for the metastasis formation of melanoma cell lines in lung. (a, c). ERBB3 was knocked down by two different shRNAs in MA-2 cells (a) or 451Lu-R cells (c). The efficiency of knockdown was measured by qRT–PCR. (b, d). ERBB3 knockdown led to a significant decrease in the number of lung metastases from MA-2 cells (b) or 451Lu-R cells (d). Student's t-test, ***P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150209&req=5

fig2: ERBB3 is required for the metastasis formation of melanoma cell lines in lung. (a, c). ERBB3 was knocked down by two different shRNAs in MA-2 cells (a) or 451Lu-R cells (c). The efficiency of knockdown was measured by qRT–PCR. (b, d). ERBB3 knockdown led to a significant decrease in the number of lung metastases from MA-2 cells (b) or 451Lu-R cells (d). Student's t-test, ***P<0.001.
Mentions: ERBB3 was knocked down in both cell lines via lentiviral expression of shRNAs. The knockdown cells express significantly lower levels of ERBB3 mRNA and protein (Figures 2a and c, 5a and b). These cells, along with control cells expressing the shRNA against green fluorescent protein (GFP), were injected intravenously into the immunodeficient NSG mice. Lungs were harvested, and metastases counted. The knockdowns of ERBB3 resulted in a significant reduction in the number of lung metastases from both cell lines (Figures 2b and d), suggesting that ERBB3 is required for the metastasis formation of human melanoma cells and this effect may be independent of the sensitivity of melanoma cells to BIs.

Bottom Line: Consistent with this, the ERBB3 ligand, NRG1, is highly expressed in mouse lungs and induces ERBB3-depdnent phosphorylation of AKT in both MA-2 and 451Lu-R cells in vitro.These findings suggest that ERBB3 may serve as a target for treating metastatic melanomas that are resistant to BIs.In support of this, administration of the pan-ERBB inhibitor, canertinib, significantly suppresses the metastasis formation of BI-resistant melanoma cell lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.

ABSTRACT
Melanoma is curable when it is at an early phase but is lethal once it becomes metastatic. The recent development of BRAF(V600E) inhibitors (BIs) showed great promise in treating metastatic melanoma, but resistance developed quickly in the treated patients, and these inhibitors are not effective on melanomas that express wild-type BRAF. Alternative therapeutic strategies for metastatic melanoma are urgently needed. Here we report that ERBB3, a member of the epidermal growth factor receptor family, is required for the formation of lung metastasis from both the BI-sensitive melanoma cell line, MA-2, and the BI-resistant melanoma cell line, 451Lu-R. Further analyses revealed that ERBB3 does not affect the initial seeding of melanoma cells in lung but is required for their further development into overt metastases, indicating that ERBB3 might be essential for the survival of melanoma cells after they reach the lung. Consistent with this, the ERBB3 ligand, NRG1, is highly expressed in mouse lungs and induces ERBB3-depdnent phosphorylation of AKT in both MA-2 and 451Lu-R cells in vitro. These findings suggest that ERBB3 may serve as a target for treating metastatic melanomas that are resistant to BIs. In support of this, administration of the pan-ERBB inhibitor, canertinib, significantly suppresses the metastasis formation of BI-resistant melanoma cell lines.

No MeSH data available.


Related in: MedlinePlus