Notch signaling promotes growth and invasion in uveal melanoma

Laura Asnaghi, Katayoon B. Ebrahimi, Karisa C. Schreck, Eli E. Bar, Michael L. Coonfield, W. Robert Bell, James Handa, Shannath L. Merbs, J. William Harbour, Charles G. Eberhart

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Purpose: To determine whether uveal melanoma, the most common primary intraocular malignancy in adults, requires Notch activity for growth and metastasis. Experimental Design: Expression of Notch pathway members was characterized in primary tumor samples and in cell lines, along with the effects of Notch inhibition or activation on tumor growth and invasion. Results: Notch receptors, ligands, and targets were expressed in all five cell lines examined and in 30 primary uveal melanoma samples. Interestingly, the three lines with high levels of baseline pathway activity (OCM1, OCM3, and OCM8) had their growth reduced by pharmacologic Notch blockade using the γ-secretase inhibitor (GSI) MRK003. In contrast, two uveal melanoma lines (Mel285 and Mel290) with very low expression of Notch targets were insensitive to the GSI. Constitutively active forms of Notch1 and Notch2 promoted growth of uveal melanoma cultures and were able to rescue the inhibitory effects of GSI. MRK003 treatment also inhibited anchorage-independent clonogenic growth and cell invasion and reduced phosphorylation levels of STAT3 and extracellular signal-regulated kinase (Erk)1/2. Suppression of canonical Notch activity using short hairpin RNA targeting Notch2 or CBF1 was also able to reduce tumor growth and invasion. Finally, intraocular xenograft growth was significantly decreased by GSI treatment. Conclusion: Our findings suggest that Notch plays an important role in inducing proliferation and invasion in uveal melanoma and that inhibiting this pathway may be effective in preventing tumor growth and metastasis.

Original languageEnglish
Pages (from-to)654-665
Number of pages12
JournalClinical Cancer Research
Volume18
Issue number3
DOIs
StatePublished - Feb 1 2012
Externally publishedYes

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Growth
Neoplasms
Notch Receptors
Neoplasm Metastasis
Cell Line
Amyloid Precursor Protein Secretases
Mitogen-Activated Protein Kinase 3
Uveal melanoma
Mitogen-Activated Protein Kinase 1
Heterografts
Small Interfering RNA
Research Design
Phosphorylation
Ligands
MRK 003

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Asnaghi, L., Ebrahimi, K. B., Schreck, K. C., Bar, E. E., Coonfield, M. L., Bell, W. R., ... Eberhart, C. G. (2012). Notch signaling promotes growth and invasion in uveal melanoma. Clinical Cancer Research, 18(3), 654-665. https://doi.org/10.1158/1078-0432.CCR-11-1406

Notch signaling promotes growth and invasion in uveal melanoma. / Asnaghi, Laura; Ebrahimi, Katayoon B.; Schreck, Karisa C.; Bar, Eli E.; Coonfield, Michael L.; Bell, W. Robert; Handa, James; Merbs, Shannath L.; William Harbour, J.; Eberhart, Charles G.

In: Clinical Cancer Research, Vol. 18, No. 3, 01.02.2012, p. 654-665.

Research output: Contribution to journalArticle

Asnaghi, L, Ebrahimi, KB, Schreck, KC, Bar, EE, Coonfield, ML, Bell, WR, Handa, J, Merbs, SL, William Harbour, J & Eberhart, CG 2012, 'Notch signaling promotes growth and invasion in uveal melanoma', Clinical Cancer Research, vol. 18, no. 3, pp. 654-665. https://doi.org/10.1158/1078-0432.CCR-11-1406
Asnaghi L, Ebrahimi KB, Schreck KC, Bar EE, Coonfield ML, Bell WR et al. Notch signaling promotes growth and invasion in uveal melanoma. Clinical Cancer Research. 2012 Feb 1;18(3):654-665. https://doi.org/10.1158/1078-0432.CCR-11-1406
Asnaghi, Laura ; Ebrahimi, Katayoon B. ; Schreck, Karisa C. ; Bar, Eli E. ; Coonfield, Michael L. ; Bell, W. Robert ; Handa, James ; Merbs, Shannath L. ; William Harbour, J. ; Eberhart, Charles G. / Notch signaling promotes growth and invasion in uveal melanoma. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 3. pp. 654-665.
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