Tumor Microenvironment Landscapes Supporting EGFR-mutant NSCLC Are Modulated at the Single-cell Interaction Level by Unesbulin Treatment.

Autor:	Maroni G; Cancer Science Institute of Singapore, National University of Singapore, Singapore.; Harvard Medical School, Boston, Massachusetts.; Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy., Krishnan I; Harvard Medical School, Boston, Massachusetts., Alfieri R; Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy., Maymi VA; Beth Israel Deaconess Medical Center, Boston, Massachusetts.; Preclinical Murine Pharmacogenetics Core, Beth Israel Deaconess Cancer Center, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts., Pandell N; Beth Israel Deaconess Medical Center, Boston, Massachusetts.; Preclinical Murine Pharmacogenetics Core, Beth Israel Deaconess Cancer Center, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts., Csizmadia E; Beth Israel Deaconess Medical Center, Boston, Massachusetts., Zhang J; Beth Israel Deaconess Medical Center, Boston, Massachusetts., Weetall M; PTC Therapeutics, South Plainfield, New Jersey., Branstrom A; PTC Therapeutics, South Plainfield, New Jersey., Braccini G; Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy., Cabrera San Millán E; Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy., Storti B; NEST, Scuola Normale Superiore and Istituto Nanoscienze-CNR, Pisa, Italy., Bizzarri R; NEST, Scuola Normale Superiore and Istituto Nanoscienze-CNR, Pisa, Italy.; Department of Surgical, Medical and Molecular Pathology, and Critical Care Medicine, University of Pisa, Pisa, Italy., Kocher O; Harvard Medical School, Boston, Massachusetts.; Beth Israel Deaconess Medical Center, Boston, Massachusetts., Daniela Sanchez Bassères DS; Biochemistry Department, Chemistry Institute, University of Sao Paulo, Sao Paulo, Brazil., Welner RS; Department of Medicine, Hemathology/Oncology, University of Alabama at Birmingham, Birmingham, Alabama., Magli MC; Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy., Merelli I; Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy., Clohessy JG; Harvard Medical School, Boston, Massachusetts.; Beth Israel Deaconess Medical Center, Boston, Massachusetts.; Preclinical Murine Pharmacogenetics Core, Beth Israel Deaconess Cancer Center, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts., Ali A; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Tenen DG; Cancer Science Institute of Singapore, National University of Singapore, Singapore.; Harvard Medical School, Boston, Massachusetts.; Harvard Stem Cell Institute, Cambridge, Massachusetts., Levantini E; Harvard Medical School, Boston, Massachusetts.; Institute of Biomedical Technologies, National Research Council (CNR), Pisa, Italy.; Harvard Stem Cell Institute, Cambridge, Massachusetts.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2024 Mar 26; Vol. 4 (3), pp. 919-937.
DOI:	10.1158/2767-9764.CRC-23-0161
Abstrakt:	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. Significance: 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. (© 2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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