Epigenomic Profiling Discovers Trans-lineage SOX2 Partnerships Driving Tumor Heterogeneity in Lung Squamous Cell Carcinoma

Takashi Sato, Seungyeul Yoo, Ranran Kong, Abhilasha Sinha, Prashanth Chandramani-Shivalingappa, Ayushi Patel, Maya Fridrikh, Osamu Nagano, Takashi Masuko, Mary Beth Beasley, Charles A. Powell, Jun Zhu, Hideo Watanabe

研究成果: Article査読

13 被引用数 (Scopus)

抄録

Molecular characterization of lung squamous cell carcinoma (LUSC), one of the major subtypes of lung cancer, has not sufficiently improved its nonstratified treatment strategies over decades. Accumulating evidence suggests that lineage-specific transcriptional regulators control differentiation states during cancer evolution and underlie their distinct biological behaviors. In this study, by investigating the super-enhancer landscape of LUSC, we identified a previously undescribed "neural" subtype defined by Sox2 and a neural lineage factor Brn2, as well as the classical LUSC subtype defined by Sox2 and its classical squamous partner p63. Robust protein–protein interaction and genomic cooccupancy of Sox2 and Brn2, in place for p63 in the classical LUSC, indicated their transcriptional cooperation imparting this unique lineage state in the "neural" LUSC. Forced expression of p63 downregulated Brn2 in the "neural" LUSC cells and invoked the classical LUSC lineage with more squamous/ epithelial features, which were accompanied by increased activities of ErbB/Akt and MAPK–ERK pathways, suggesting differential dependency. Collectively, our data demonstrate heterogeneous cell lineage states of LUSC featured by Sox2 cooperation with Brn2 or p63, for which distinct therapeutic approaches may be warranted. Significance: Epigenomic profiling reveals a novel subtype of lung squamous cell carcinoma with neural differentiation.

本文言語English
ページ(範囲)6084-6100
ページ数17
ジャーナルCancer Research
79
24
DOI
出版ステータスPublished - 2019 12 15

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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