Melanoma topology reveals a stem-like phenotype that promotes angiogenesis.

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 α5β1 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 1α (HIF1α) pathways. Inhibiting integrin α5β1 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.

journal_name

Sci Adv

journal_title

Science advances

authors

Lee J,Abdeen AA,Hedhli J,Wycislo KL,Dobrucka IT,Fan TM,Dobrucki LW,Kilian KA

doi

10.1126/sciadv.1701350

subject

Has Abstract

pub_date

2017-10-25 00:00:00

pages

e1701350

issue

10

issn

2375-2548

pii

1701350

journal_volume

3

pub_type

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