Nanog maintains stemness of Lkb1-deficient lung adenocarcinoma and prevents gastric differentiation

ABSTRACT: Growing evidence supports that LKB1-deficient KRAS-driven lung tumor represents a unique therapeutic challenge, displaying strong cancer plasticity which promotes lineage conversion and drug resistance. Here we find that murine lung tumors from KrasLSL-G12D/+; Lkb1flox/flox (KL) model show strong plasticity which links to up-regulation of stem cell pluripotency genes such as Nanog. Deletion of Nanog in KL model initiates gastric differentiation program and promotes mucinous lung tumor growth. We find that NANOG is not expressed at a meaningful level in human lung adenocarcinoma (ADC) as well as human lung invasive mucinous adenocarcinoma (IMA). The gastric differentiation involves the activation of Notch signaling and perturbation of Notch pathway by the ?-secretase inhibitor LY-411575 remarkably impairs mucinous tumor formation. In contrast to non-mucinous tumors, these mucinous tumors are resistant to phenformin treatment. Such therapeutic resistance could be overcome through combined treatments with LY-411575 and phenformin. Overall, we uncover a previously unappreciated plasticity of LKB1-deficient tumors and identify the Nanog-Notch axis in regulating gastric differentiation, which holds important therapeutic implication against mucinous lung cancer.

SUBMITTER: xinyuan tong 

PROVIDER: S-SCDT-EMM-2020-12627 | biostudies-other |

REPOSITORIES: biostudies-other