Funding
Beth Israel Deaconess Medical Center (BIDMC)
National University of Singapore (NUS)
Regione Toscana (Tuscany Region)
Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR)
PTC Therapeutics (PTC)
Fondazione AIRC per la ricerca sul cancro ETS (AIRC)
Ministero dell'Economia e delle Finanze (MEF)
National Research Foundation Singapore (NRF)
Ministry of Health -Singapore (MOH)
HHS | National Institutes of Health (NIH)
NUS | Cancer Science Institute of Singapore, National University of Singapore (CSI)
FAPESP | Centros de Pesquisa, Inovação e Difusão, Fundação Amazônia Paraense de Amparo à Pesquisa (RIDC)
University of Alabama at Birmingham (UAB)
ARTICLE ABSTRACT
Lung cancer is the leading cause of cancer deaths. Lethal pulmonary adenocarcinomas (ADC) present with frequent mutations in the EGFR. Genetically engineered murine models of lung cancer expedited comprehension of the molecular mechanisms driving tumorigenesis and drug response. Here, we systematically analyzed the evolution of tumor heterogeneity in the context of dynamic interactions occurring with the intermingled tumor microenvironment (TME) by high-resolution transcriptomics. Our effort identified vulnerable tumor-specific epithelial cells, as well as their cross-talk with niche components (endothelial cells, fibroblasts, and tumor-infiltrating immune cells), whose symbiotic interface shapes tumor aggressiveness and is almost completely abolished by treatment with Unesbulin, a tubulin binding agent that reduces B cell–specific Moloney murine leukemia virus integration site 1 (BMI-1) activity. Simultaneous magnetic resonance imaging (MRI) analysis demonstrated decreased tumor growth, setting the stage for future investigations into the potential of novel therapeutic strategies for EGFR-mutant ADCs.
Targeting the TME is an attractive strategy for treatment of solid tumors. Here we revealed how EGFR-mutant landscapes are affected at the single-cell resolution level during Unesbulin treatment. This novel drug, by targeting cancer cells and their interactions with crucial TME components, could be envisioned for future therapeutic advancements.
