Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Nat Commun. 2022 Feb 28;13(1):1090. doi: 10.1038/s41467-022-28619-8.
LKB1 is among the most frequently altered tumor suppressors in lung adenocarcinoma. Inactivation of Lkb1 accelerates the growth and progression of oncogenic KRAS-driven lung tumors in mouse models. However, the molecular mechanisms by which LKB1 constrains lung tumorigenesis and whether the cancer state that stems from Lkb1 deficiency can be reverted remains unknown. To identify the processes governed by LKB1 in vivo, we generated an allele which enables Lkb1 inactivation at tumor initiation and subsequent Lkb1 restoration in established tumors. Restoration of Lkb1 in oncogenic KRAS-driven lung tumors suppressed proliferation and led to tumor stasis. Lkb1 restoration activated targets of C/EBP transcription factors and drove neoplastic cells from a progenitor-like state to a less proliferative alveolar type II cell-like state. We show that C/EBP transcription factors govern a subset of genes that are induced by LKB1 and depend upon NKX2-1. We also demonstrate that a defining factor of the alveolar type II lineage, C/EBPα, constrains oncogenic KRAS-driven lung tumor growth in vivo. Thus, this key tumor suppressor regulates lineage-specific transcription factors, thereby constraining lung tumor development through enforced differentiation.
LKB1 是肺腺癌中最常发生改变的肿瘤抑制因子之一。Lkb1 的失活会加速致癌 KRAS 驱动的肺肿瘤在小鼠模型中的生长和进展。然而，LKB1 限制肺肿瘤发生的分子机制以及是否可以逆转源自 LKB1 缺失的癌症状态仍然未知。为了鉴定 LKB1 在体内控制的过程，我们生成了一个等位基因，该等位基因可在肿瘤起始时使 Lkb1 失活，并随后在已建立的肿瘤中恢复 Lkb1。在致癌 KRAS 驱动的肺肿瘤中恢复 Lkb1 会抑制增殖，并导致肿瘤停滞。Lkb1 的恢复会激活 C/EBP 转录因子的靶标，并使肿瘤细胞从祖细胞样状态转变为增殖性较低的肺泡 II 型细胞样状态。我们表明，C/EBP 转录因子控制一组由 LKB1 诱导且依赖 NKX2-1 的基因。我们还证明了肺泡 II 型谱系的一个定义因素，C/EBPα，在体内限制了致癌 KRAS 驱动的肺肿瘤生长。因此，这个关键的肿瘤抑制因子调节谱系特异性转录因子，从而通过强制分化来限制肺肿瘤的发展。
