Journal
CLINICAL CANCER RESEARCH
Volume 23, Issue 22, Pages 7097-7107Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-17-0010
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Funding
- Ligue National Contre le Cancer
- Association pour la Recherche Contre le Cancer
- Institut National du Cancer [PAIR 13-002]
- Agence National de la Recherche [ANR10-Labex-0030-INRT]
- Ligue Nationale Contre le Cancer
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Purpose: Understanding tumor heterogeneity is an important challenge in current cancer research. Transcription and epigenetic profiling of cultured melanoma cells have defined at least two distinct cell phenotypes characterized by distinctive gene expression signatures associated with high or low/absent expression of microphthalmia-associated transcription factor (MITF). Nevertheless, heterogeneity of cell populations and gene expression in primary human tumors is much less well characterized. Experimental Design: We performed single-cell gene expression analyses on 472 cells isolated from needle biopsies of 5 primary human melanomas, 4 superficial spreading, and one acral melanoma. The expression of MITF-high and MITF-low signature genes was assessed and compared to investigate intra-and intertumoral heterogeneity and correlated gene expression profiles. Results: Single-cell gene expression analyses revealed varying degrees of intra-and intertumor heterogeneity conferred by the variable expression of distinct sets of genes in different tumors. Expression of MITF partially correlated with that of its known target genes, while SOX10 expression correlated best with PAX3 and ZEB2. Nevertheless, cells simultaneously expressing MITF-high and MITF-low signature genes were observed both by single-cell analyses and RNAscope. Conclusions: Single-cell analyses can be performed on limiting numbers of cells from primary human melanomas revealing their heterogeneity. Although tumors comprised variable proportions of cells with the MITF-high and MITF-low gene expression signatures characteristic of melanoma cultures, primary tumors also comprised cells expressing markers of both signatures defining a novel cell state in tumors in vivo. (C) 2017 AACR.
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