State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences , Shanghai, China.
University of Chinese Academy of Sciences , Beijing, China.
J Exp Med. 2024 Mar 4;221(3). doi: 10.1084/jem.20232028. Epub 2024 Jan 29.
Human lung adenosquamous cell carcinoma (LUAS), containing both adenomatous and squamous pathologies, exhibits strong cancer plasticity. We find that ALK rearrangement is detectable in 5.1-7.5% of human LUAS, and transgenic expression of EML4-ALK drives lung adenocarcinoma (LUAD) formation initially and squamous transition at late stage. We identify club cells as the main cell-of-origin for squamous transition. Through recapitulating lineage transition in organoid system, we identify JAK-STAT signaling, activated by EML4-ALK phase separation, significantly promotes squamous transition. Integrative study with scRNA-seq and immunostaining identify a plastic cell subpopulation in ALK-rearranged human LUAD showing squamous biomarker expression. Moreover, those relapsed ALK-rearranged LUAD show notable upregulation of squamous biomarkers. Consistently, mouse squamous tumors or LUAD with squamous signature display certain resistance to ALK inhibitor, which can be overcome by combined JAK1/2 inhibitor treatment. This study uncovers strong plasticity of ALK-rearranged tumors in orchestrating phenotypic transition and drug resistance and proposes a potentially effective therapeutic strategy.
人类肺腺鳞癌（LUAS），包含腺性和鳞状两种病变，表现出很强的癌症可塑性。我们发现 ALK 重排可在 5.1-7.5%的人类 LUAS 中检测到，并且 EML4-ALK 的转基因表达最初驱动肺腺癌（LUAD）的形成，后期则驱动鳞状转化。我们确定 club 细胞是鳞状转化的主要起始细胞。通过在类器官系统中重现谱系转换，我们发现 EML4-ALK 相分离激活的 JAK-STAT 信号显著促进了鳞状转化。与 scRNA-seq 和免疫染色的综合研究确定了在具有 ALK 重排的人类 LUAD 中具有鳞状生物标志物表达的可塑性细胞亚群。此外，那些复发的具有 ALK 重排的 LUAD 显示出明显的鳞状生物标志物上调。一致地，具有鳞状特征的小鼠鳞状肿瘤或 LUAD 对 ALK 抑制剂表现出一定的耐药性，联合 JAK1/2 抑制剂治疗可以克服这种耐药性。这项研究揭示了 ALK 重排肿瘤在协调表型转化和耐药性方面的强大可塑性，并提出了一种潜在有效的治疗策略。
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