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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 affects the formation of 451Lu-R metastases in the lung at later time points. ERBB3 knockdown did not reduce the number of 451Lu-R cells in the lungs at 24 h or 1 week after injections but led to a significant reduction in lung metastases at the 3-week time point. (a) Representative images of lung sections at 24 h, 1 week or 3 weeks after intravenous injections of 451Lu-R(shGFP), 451Lu-R(shERBB3#1) and 451Lu-R(shERBB3#2) cells. (b) Quantitation of lung metastases at each time point. NS: not significant. *P<0.05. **P<0.01.
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fig4: ERBB3 affects the formation of 451Lu-R metastases in the lung at later time points. ERBB3 knockdown did not reduce the number of 451Lu-R cells in the lungs at 24 h or 1 week after injections but led to a significant reduction in lung metastases at the 3-week time point. (a) Representative images of lung sections at 24 h, 1 week or 3 weeks after intravenous injections of 451Lu-R(shGFP), 451Lu-R(shERBB3#1) and 451Lu-R(shERBB3#2) cells. (b) Quantitation of lung metastases at each time point. NS: not significant. *P<0.05. **P<0.01.

Mentions: We performed similar analyses in 451Lu-R cells, except that the 451Lu-R cells were not labeled with CMFDA before injections. Mouse lungs were collected at different time points after injections, sectioned and stained with a human-specific anti-vimentin antibody to detect the human melanoma cells (Figure 4a, black arrows; see Materials and methods). In contrast to the MA-2 cells, knocking down of ERBB3 did not lead to any reduction of 451Lu-R cells in the mouse lung 24 h after injections (Figure 4b), arguing that ERBB3 does not affect the seeding of 451Lu-R cells and their initial survival in the lung. The metastasis formation from these cells was then traced over a course of 3 weeks. No difference in metastasis formation was observed at the 1-week time point (Figure 4b), but at the 3-week time point, a significant reduction of metastases was observed in ERBB3-knockdown cells (Figure 4b). These findings suggest that, although ERBB3 might not be required for the survival of 451Lu-R cells immediately after their seeding in the lung, it is required for their persistent survival and/or proliferation later on to form overt metastases (Figure 3a; steps 2 and 3).


ERBB3 is required for metastasis formation of melanoma cells.

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

ERBB3 affects the formation of 451Lu-R metastases in the lung at later time points. ERBB3 knockdown did not reduce the number of 451Lu-R cells in the lungs at 24 h or 1 week after injections but led to a significant reduction in lung metastases at the 3-week time point. (a) Representative images of lung sections at 24 h, 1 week or 3 weeks after intravenous injections of 451Lu-R(shGFP), 451Lu-R(shERBB3#1) and 451Lu-R(shERBB3#2) cells. (b) Quantitation of lung metastases at each time point. NS: not significant. *P<0.05. **P<0.01.
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Related In: Results  -  Collection

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fig4: ERBB3 affects the formation of 451Lu-R metastases in the lung at later time points. ERBB3 knockdown did not reduce the number of 451Lu-R cells in the lungs at 24 h or 1 week after injections but led to a significant reduction in lung metastases at the 3-week time point. (a) Representative images of lung sections at 24 h, 1 week or 3 weeks after intravenous injections of 451Lu-R(shGFP), 451Lu-R(shERBB3#1) and 451Lu-R(shERBB3#2) cells. (b) Quantitation of lung metastases at each time point. NS: not significant. *P<0.05. **P<0.01.
Mentions: We performed similar analyses in 451Lu-R cells, except that the 451Lu-R cells were not labeled with CMFDA before injections. Mouse lungs were collected at different time points after injections, sectioned and stained with a human-specific anti-vimentin antibody to detect the human melanoma cells (Figure 4a, black arrows; see Materials and methods). In contrast to the MA-2 cells, knocking down of ERBB3 did not lead to any reduction of 451Lu-R cells in the mouse lung 24 h after injections (Figure 4b), arguing that ERBB3 does not affect the seeding of 451Lu-R cells and their initial survival in the lung. The metastasis formation from these cells was then traced over a course of 3 weeks. No difference in metastasis formation was observed at the 1-week time point (Figure 4b), but at the 3-week time point, a significant reduction of metastases was observed in ERBB3-knockdown cells (Figure 4b). These findings suggest that, although ERBB3 might not be required for the survival of 451Lu-R cells immediately after their seeding in the lung, it is required for their persistent survival and/or proliferation later on to form overt metastases (Figure 3a; steps 2 and 3).

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