Melanoma topology reveals a stem-like phenotype that promotes angiogenesis

Junmin Lee, Amr A. Abdeen, Jamila Hedhli, Kathryn L. Wycislo, Iwona T. Dobrucki, Timothy M. Fan, Lawrence W. Dobrucki, Kristopher A. Kilian

Research output: Contribution to journalArticle

Abstract

Tumor angiogenesis provides critical nutrients for cancer progression and may also facilitate pathways for dissemination during the process of metastasis. It is well established that cells that metastasize display characteristics of stem cells; however, the prevailing paradigm points to these stem-like cells residing in the hypoxic niche within the tumor interior. Controlling the geometry at the interface of a population of melanoma cells reveals a role for perimeter topology in promoting a stem-like state with enhanced tumorigenicity. We show that this putative melanoma-initiating cell (MIC) demonstrates significant enhancement in the secretion of proangiogenic molecules. This finding suggests the possibility of an “invasive niche” at the perimeter of a growing tumor that promotes a MIC state with angiogenic activity. Using several in vitro and in vivo models of tumor angiogenesis, we see concurrent stem-like characteristics with initiation of neovascularization. In the absence of hypoxia, precise topological cues induce signaling through integrin a5b1 and downstream extracellular signal–regulated kinase (ERK) signaling to regulate the MIC secretome through the signal transducer and activator of transcription (STAT) and hypoxia-inducible factor 1a (HIF1a) pathways. Inhibiting integrin a5b1 and ERK signaling attenuates both the MIC phenotype and proangiogenic signaling. These results suggest that topological cues in the periphery of malignant melanoma promote the MIC state—using mechanotransduction in lieu of low oxygen—to facilitate the formation of new vasculature for progression and invasion.

Original languageEnglish (US)
Article numbere1701350
JournalScience Advances
Volume3
Issue number10
DOIs
StatePublished - Jan 1 2017

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Melanoma
Phenotype
Neoplasms
Integrins
Cues
Phosphotransferases
Stem Cells
Transducers
Neoplasm Metastasis
Food
Population

ASJC Scopus subject areas

  • General

Cite this

Lee, J., Abdeen, A. A., Hedhli, J., Wycislo, K. L., Dobrucki, I. T., Fan, T. M., ... Kilian, K. A. (2017). Melanoma topology reveals a stem-like phenotype that promotes angiogenesis. Science Advances, 3(10), [e1701350]. https://doi.org/10.1126/sciadv.1701350

Melanoma topology reveals a stem-like phenotype that promotes angiogenesis. / Lee, Junmin; Abdeen, Amr A.; Hedhli, Jamila; Wycislo, Kathryn L.; Dobrucki, Iwona T.; Fan, Timothy M.; Dobrucki, Lawrence W.; Kilian, Kristopher A.

In: Science Advances, Vol. 3, No. 10, e1701350, 01.01.2017.

Research output: Contribution to journalArticle

Lee, J, Abdeen, AA, Hedhli, J, Wycislo, KL, Dobrucki, IT, Fan, TM, Dobrucki, LW & Kilian, KA 2017, 'Melanoma topology reveals a stem-like phenotype that promotes angiogenesis', Science Advances, vol. 3, no. 10, e1701350. https://doi.org/10.1126/sciadv.1701350
Lee J, Abdeen AA, Hedhli J, Wycislo KL, Dobrucki IT, Fan TM et al. Melanoma topology reveals a stem-like phenotype that promotes angiogenesis. Science Advances. 2017 Jan 1;3(10). e1701350. https://doi.org/10.1126/sciadv.1701350
Lee, Junmin ; Abdeen, Amr A. ; Hedhli, Jamila ; Wycislo, Kathryn L. ; Dobrucki, Iwona T. ; Fan, Timothy M. ; Dobrucki, Lawrence W. ; Kilian, Kristopher A. / Melanoma topology reveals a stem-like phenotype that promotes angiogenesis. In: Science Advances. 2017 ; Vol. 3, No. 10.
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