肺腺鳞癌（ASC）的基因组起源和发展尚不确定。本研究通过全外显子测序、Stereo-seq和患者来源的异种移植物，推导了ASC的潜在进化轨迹。我们发现EGFR和MET活化突变是ASC的主要驱动因素。在系统发育上，这些驱动因素和在两个组分中发现的乘客突变都是主干克隆事件，证实了单克隆起源。多个病灶的比较还揭示了淋巴结转移灶与具有相同表型的ASC组分之间更接近的基因组距离。然而，由于EGFR阳性肺鳞癌（LUSCs）的突变标志性与EGFR阳性ASC相比较而言更接近野生型LUSCs，我们推测这些LUSCs可能有不同的起源，其中ASC可能是驱动基因阳性LUSCs的中间状态。空间转录组谱学分析推测了从腺癌向鳞状细胞癌的转化，并在体内组织学上得到了捕获。综上所述，我们的研究结果解释了ASC的发展并为未来的临床决策提供了洞见。©2023 Nature Publishing Group UK.

The genomic origin and development of the biphasic lung adenosquamous carcinoma (ASC) remain inconclusive. Here, we derived potential evolutionary trajectory of ASC through whole-exome sequencing, Stereo-seq, and patient-derived xenografts. We showed that EGFR and MET activating mutations were the main drivers in ASCs. Phylogenetically, these drivers and passenger mutations found in both components were trunk clonal events, confirming monoclonal origination. Comparison of multiple lesions also revealed closer genomic distance between lymph node metastases and the ASC component with the same phenotype. However, as mutational signatures of EGFR-positive lung squamous carcinomas (LUSCs) were more comparable to EGFR-positive ASCs than to wild-type LUSCs, we postulated different origination of these LUSCs, with ASC being the potential intermediate state of driver-positive LUSCs. Spatial transcriptomic profiling inferred transformation from adenocarcinoma to squamous cell carcinoma, which was then histologically captured in vivo. Together, our results explained the development of ASC and provided insights into future clinical decisions.© 2023. Nature Publishing Group UK.