侵袭特性的获得是肿瘤进展和转移的先决条件。 KRAS 驱动的肺癌的分子亚型表现出不同的侵袭模式，从而导致独特的生长特性和治疗敏感性。尽管如此，仍缺乏旨在利用入侵背景下的生长的临床前策略。为了解决这个问题，我们设计了一个实验系统来筛选与 KRAS 驱动的肺腺癌 (LUAD) 不同分子亚型中活跃的早期 3D 侵袭表型相关的靶向信号通路。 3D 侵袭矩阵中人支气管上皮细胞的活细胞成像和转录组分析相结合，确定了 BMP6 的突变型 LKB1 特异性上调。 LKB1 缺失增加了 BMP6 信号传导，从而诱导经典铁调节激素铁调素的产生。完整的 LKB1 对于维持 BMP6 信号稳态和限制 ALK2/BMP6 驱动的生长是必要的。 Kras/Lkb1 突变同基因小鼠模型和异种移植模型的临床前研究表明，目前正在进行临床试验的单药抑制剂可通过抑制 ALK2/BMP6 信号轴来有效抑制生长。最后，LKB1 突变的早期肺癌患者肿瘤中 BMP6 表达升高。这些结果与 LKB1 作为铁调节生长的“制动器”的模型一致，表明 ALK2 抑制可用于 LKB1 突变肿瘤患者。

The acquisition of invasive properties is a prerequisite for tumor progression and metastasis. Molecular subtypes of KRAS-driven lung cancer exhibit distinct modes of invasion that contribute to unique growth properties and therapeutic susceptibilities. Despite this, pre-clinical strategies designed to exploit growth within the context of invasion are lacking. To address this, we designed an experimental system to screen for targetable signaling pathways linked to active early 3D invasion phenotypes in different molecular subtypes of KRAS-driven lung adenocarcinoma (LUAD). Combined live-cell imaging of human bronchial epithelial cells in a 3D invasion matrix and transcriptomic profiling identified mutant LKB1-specific upregulation of BMP6. LKB1 loss increased BMP6 signaling, which induced the canonical iron regulatory hormone hepcidin. Intact LKB1 was necessary to maintain BMP6 signaling homeostasis and restrict ALK2/BMP6-fueled growth. Pre-clinical studies in a Kras/Lkb1-mutant syngeneic mouse model and in a xenograft model showed potent growth suppression by inhibiting the ALK2/BMP6 signaling axis with single agent inhibitors that are currently in clinical trials. Lastly, BMP6 expression was elevated in LKB1-mutant early-stage lung cancer patient tumors. These results are consistent with a model where LKB1 acts as a 'brake' to iron regulated growth and suggest that ALK2 inhibition can be used for patients with LKB1-mutant tumors.