NUMB as a Therapeutic Target for Melanoma

Denitsa M Hristova,Zhi Wei,Mizuho Fukunaga-Kalabis,Chihiro Takemori,Chaoran Cheng,Xia Hua,Ling Li,Jie Zhang,Meenhard Herlyn,Rajasekharan Somasundaram,Marilda Beqiri,Joshua X Wang,Anastasia Samarkina,Haruki Jimbo,Le Gao,Adina Vultur,Yusra Gimie,Andrea Watters,Takeshi Fukumoto,Chikako Nishigori,Vito W Rebecca

doi:10.1016/j.jid.2021.11.027

Abstract

The upregulation of the adaptor protein NUMB triggers melanocytic differentiation from multipotent skin stem cells, which share many properties with aggressive melanoma cells. Although NUMB acts as a tumor suppressor in various human cancer types, little is known about its role in melanoma. In this study, we investigated the role of NUMB in melanoma progression and its regulatory mechanism. Analysis of The Cancer Genome Atlas melanoma datasets revealed that high NUMB expression in melanoma tissues correlates with improved patient survival. Moreover, NUMB expression is downregulated in metastatic melanoma cells. NUMB knockdown significantly increased the invasion potential of melanoma cells in a three-dimensional collagen matrix invitro and in the lungs of a mouse model invivo; it also significantly upregulated the expression of the NOTCH target gene CCNE. Previous studies suggested that Wnt signaling increases NUMB expression. By mimicking Wnt stimulation through glycogen synthase kinase-3 inhibition, we increased NUMB expression in melanoma cells. Furthermore, a glycogen synthase kinase-3 inhibitor reduced the invasion of melanoma cells in a NUMB-dependent manner. Together, our results suggest that NUMB suppresses invasion and metastasis in melanoma, potentially through its regulation of the NOTCH‒CCNE axis and that the inhibitors that upregulate NUMB can exert therapeutic effects in melanoma.

Highlights

Melanoma is a cancer that develops in melanocytes and the phenotype of advanced stage melanoma often resembles neural crest precursors, which are the cellular origin of melanocytes in the skin (Li et al, 2010)
NUMB expression correlates with melanoma survival and is downregulated in metastatic melanoma cells First, to investigate the potential involvement of NUMB in melanoma progression, we analyzed melanoma RNA-seq data from The Cancer Genome Atlas together with the patients’ clinical information (Cancer Genome Atlas, 2015)
Recent evidence showed the pivotal role of long non-coding RNAs in uveal melanoma by regulating proliferation, invasion and metastasis (Cheng et al, 2016, Milan-Rois et al, 2021)

Summary

Introduction

Melanoma is a cancer that develops in melanocytes and the phenotype of advanced stage melanoma often resembles neural crest precursors, which are the cellular origin of melanocytes in the skin (Li et al, 2010). Journal Pre-proof can migrate throughout tissues in a manner similar to neural crest cells during vertebrate embryonic development. The molecular signaling pathways critical for normal embryonic development and stem cell maintenance are often reactivated in melanoma cells (Liu et al, 2014). We previously demonstrated that NOTCH plays a role in the self-renewal of multipotent, neural crest-like skin precursors, which is a potential reservoir for skin melanocytes (Fukunaga-Kalabis et al, 2015). The initial step of this differentiation is triggered by upregulated NUMB, which inhibits NOTCH signaling in skin precursors (Fukunaga-Kalabis et al, 2015)

Methods

Results

Conclusion