PO.BCS01.16 · 生物信息与计算
单核多组学分析揭示EGFR和ALK突变型肺腺癌中保守的适应性状态
Single-nuclei multiomic profiling reveals conserved adaptive states in EGFR- and ALK-mutant lung adenocarcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：肺腺癌（LUAD）对EGFR和ALK酪氨酸激酶抑制剂（TKI）的耐药仍是一项重大临床挑战。肿瘤持存和复发源于动态的谱系转变和适应性信号重连，然而定义微小残留病（MRD）的分子特征仍未被充分了解。
方法：我们从纵向患者肿瘤活检中生成了单核RNA和ATAC测序数据集，涵盖基线、微小残留病（MRD）和复发阶段。我们总共分析了38例患者样本（18例基线、10例MRD、10例复发，包括6例匹配样本），横跨RNA-seq和ATAC-seq。此外，我们生成了六个携带EGFR和/或ALK突变的患者来源异种移植（PDX）模型，在基线和MRD期间采样（每个模型2例基线样本和3-6例MRD样本）。
结果：转录组学分析揭示了与分化、粘附和应激适应相关的调控程序的一致重塑。在各PDX模型中，出现了一个保守的持存细胞（persister）特征，富集于与纤毛发生、神经元信号传导、脂质代谢和衰老相关的通路。在患者样本中，MRD和复发以从肺泡状态向纤毛状态和神经内分泌样状态的转录转变为标志，反映了同样在PDX中观察到的谱系连续体，这一转变得到基线与MRD之间127个显著改变的基因（34个下调和93个上调）的支持，量化了与耐药耐受持存细胞出现相关的转录重编程程度。
结论：总之，这些结果指向了跨临床前和临床背景的共享适应性轨迹，捕获了从耐药耐受持存到确立耐药的连续过程。这些发现定义了EGFR和ALK驱动的LUAD中一个保守的适应性图景，并为识别根除残留病、预防TKI治疗肺癌复发的治疗策略奠定了基础。
查看英文原文 English abstract
Background: Resistance to EGFR and ALK tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma (LUAD) remains a major clinical challenge. Tumor persistence and relapse arise from dynamic lineage transitions and adaptive signaling rewiring, yet the molecular features defining minimal residual disease (MRD) remain incompletely understood.
Methods: We generated single-nucleus RNA and ATAC sequencing datasets from the longitudinal patient tumor biopsies at baseline, minimal residual disease (MRD), and relapse. In total, we analyzed 38 patient samples (18 baseline, 10 MRD, 10 relapse, including 6 matched samples) across both RNA-seq and ATAC-seq. Moreover, we generated six patient-derived xenograft (PDX) models harboring EGFR or/and ALK mutations, sampled at baseline and during MRD (2 baseline samples and 3-6 MRD samples per model).
Results: Transcriptomic analyses revealed consistent remodeling of regulatory programs associated with differentiation, adhesion, and stress adaptation. Across PDX models, a conserved persister signature emerged, enriched in pathways related to ciliogenesis, neuronal signaling, lipid metabolism, and senescence. In patient samples, MRD and relapse were marked by transcriptional transitions from alveolar to ciliated and neuroendocrine-like states, reflecting a lineage continuum also observed in PDXs, and this shift was supported by 127 significantly altered genes between baseline and MRD (34 downregulated and 93 upregulated), quantifying the extent of transcriptional reprogramming associated with the emergence of drug tolerant persister cells.
Conclusion: Together, these results point to shared adaptive trajectories across preclinical and clinical contexts, capturing the continuum from drug-tolerant persistence to established resistance. These findings define a conserved adaptive landscape across EGFR- and ALK-driven LUAD and lay the groundwork for identifying therapeutic strategies to eradicate residual disease and prevent relapse in TKI-treated lung cancer.
利益披露 Disclosure
N. K. Mfonfu,
Sanofi Employment.
F. Brayé, None.
G. Boldina,
Sanofi Employment.
M. Cesaroni,
Sanofi Employment.
L. Friboulet,
Sanofi ).
S. Nikolaev, None..
A. Yurchenko, None.