P2.16-33 Adenosquamous Carcinoma of the Lung: Comparison of Surgical Outcomes with Squamous Cell and Adenocarcinoma

Melek, Hüseyin; Çetinkaya, G.; Bayram, Ahmet Sami; Akyıldız, Elif Ülker; Yentürk, Eylem; Özer, Enver; Sevinç, Tolga Evrim; Gebitekin, Cengiz

doi:10.1016/j.jtho.2018.08.1508

Cited by 1 publication

(1 citation statement)

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“…[1][2][3][4][5][6][7] Perturbation of those lineage-specific TFs may result in the destabilization and loss of the corresponding cellular identity. 6,8,9 Interestingly, the existence of mixed adenosquamous (AdSCC) histology in clinic 10,11 and the largely shared genetic alterations between these two histological portions [12][13][14] indicate potential phenotypic transition, which is known as the adeno-tosquamous transdifferentiation (AST). [15][16][17] Squamous transformation is recently observed in relapsed EGFR-mutant lung ADC patients after initially successful tyrosine kinase inhibitor (TKI) treatments.…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress-triggered Wnt signaling perturbation characterizes the tipping point of lung adeno-to-squamous transdifferentiation

Fang

Han

Chen

et al. 2023

Sig Transduct Target Ther

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Lkb1 deficiency confers the Kras-mutant lung cancer with strong plasticity and the potential for adeno-to-squamous transdifferentiation (AST). However, it remains largely unknown how Lkb1 deficiency dynamically regulates AST. Using the classical AST mouse model (KrasLSL-G12D/+;Lkb1flox/flox, KL), we here comprehensively analyze the temporal transcriptomic dynamics of lung tumors at different stages by dynamic network biomarker (DNB) and identify the tipping point at which the Wnt signaling is abruptly suppressed by the excessive accumulation of reactive oxygen species (ROS) through its downstream effector FOXO3A. Bidirectional genetic perturbation of the Wnt pathway using two different Ctnnb1 conditional knockout mouse strains confirms its essential role in the negative regulation of AST. Importantly, pharmacological activation of the Wnt pathway before but not after the tipping point inhibits squamous transdifferentiation, highlighting the irreversibility of AST after crossing the tipping point. Through comparative transcriptomic analyses of mouse and human tumors, we find that the lineage-specific transcription factors (TFs) of adenocarcinoma and squamous cell carcinoma form a “Yin-Yang” counteracting network. Interestingly, inactivation of the Wnt pathway preferentially suppresses the adenomatous lineage TF network and thus disrupts the “Yin-Yang” homeostasis to lean towards the squamous lineage, whereas ectopic expression of NKX2-1, an adenomatous lineage TF, significantly dampens such phenotypic transition accelerated by the Wnt pathway inactivation. The negative correlation between the Wnt pathway and AST is further observed in a large cohort of human lung adenosquamous carcinoma. Collectively, our study identifies the tipping point of AST and highlights an essential role of the ROS-Wnt axis in dynamically orchestrating the homeostasis between adeno- and squamous-specific TF networks at the AST tipping point.

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