Increased mRNA translation delays tumour initiation and exposes a therapeutic vulnerability in lung cancer

作者：Luis Pardo, Madeleine Moore, Ruhi Deshmukh, Ian Powley, Joseph Waldron, Björn Kruspig, Lynn McGarry, Lobsang Dolma, América Campos, Colin Wood, Holly Leslie, Mark Hughes, Emanuel Jeldes, June Munro, Louise Mitchell, Leah Officer-Jones, Rachel Baird, Hugo Coquelet, Nigel B. Jamieson, David Sumpton, Douglas Strathdee, John le Quesne, Martin Bushell, Daniel J. Murphy, Jim C. Norman · 发表于：Molecular Cancer · 年份：2026 · DOI：10.1186/s12943-026-02680-z · 研究领域：PI3K/AKT/mTOR signaling in cancer、RNA Research and Splicing、RNA modifications and cancer

Abstract Background Although inhibitors of mRNA translation are being evaluated as anti-cancer agents, the dynamics of protein synthesis throughout tumour progression are still poorly understood. Here we assess how alterations in mRNA translation during early tumorigenesis affect tumour development in KRAS-driven lung adenocarcinoma (LuAd). Methods We deployed autochthonous mouse models of LuAd driven by oncogenic KRAS G12D combined with moderate overexpression of MYC and simultaneously manipulated mRNA translation by deleting the mRNA helicases eIF4A1 and eIF4A2 or by administering pharmacological inhibitors of protein synthesis, such as rapamycin. This permits synchronous assessment of LuAd initiation and progression in vivo and is amenable to parallel ex vivo culture of tumour-derived cells for detailed analysis of protein synthesis (using ribosome footprinting) and metabolic landscapes. These approaches also allowed us to perform multiplex imaging and spatial transcriptomics to characterise tumour formation in altered mRNA translation conditions and to compare results obtained in mice against the Lattice-A cohort of non-small cell lung cancer (NSCLC) patients. Results Deletion of the mRNA-translation repressor, eIF4A2 in KRAS-driven LuAd leads to a dysregulated protein synthesis landscape characterised by a strongly upregulated secretome, enlarged secretory compartments, increased oxidative metabolism and acquisition of senescence-like characteristics. Paradoxically, this...