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posted on 2024-03-26, 14:20 authored by Giorgia Maroni, Indira Krishnan, Roberta Alfieri, Valerie A. Maymi, Nicole Pandell, Eva Csizmadia, Junyan Zhang, Marla Weetall, Art Branstrom, Giulia Braccini, Eva Cabrera San Millán, Barbara Storti, Ranieri Bizzarri, Olivier Kocher, Daniela S. Daniela Sanchez Bassères, Robert S. Welner, Maria Cristina Magli, Ivan Merelli, John G. Clohessy, Azhar Ali, Daniel G. Tenen, Elena Levantini Deconvolution of healthy and diseased macrophage clusters demonstrates presence of interstitial and alveolar subpopulations and identifies tumor-specific cross-talks occurring in the malignant stem epithelial compartment. A, UMAP cluster distribution of macrophages from healthy lungs (n = 3, dark blue), Vehicle- (n = 10, red), and Unesbulin-treated tumors (n = 3, light blue), up to 30 days. B, Split UMAP distribution of the nine macrophage transcriptional clusters (C0–C8) identified in healthy lungs (left), Vehicle- (middle), and Unesbulin-treated tumors (right). Each color represents a defined transcriptional cluster. C, Histograms representing macrophage cluster percentage distribution per sample (healthy lungs in blue, Vehicle- and Unesbulin-treated tumors in red and light blue, respectively). D, Histograms representing the percentages contribution of macrophage clusters per sample (healthy lungs, Vehicle- and Unesbulin-treated tumors). E, KEGG analysis of identified signaling pathways differentially enriched in selected macrophage clusters (C0 and C2). F, Heat map showing AM and IM expressed genes in healthy macrophage clusters. UMAP plot representing the expression of the representative category-specific signature in AM (G) and IM (H). I and J, Heat maps showing the predicted interactions between AM clusters and START in Vehicle- (red) and Unesbulin-treated tumors (light blue). K, Sankey plot of the protumorigenic phenotypes promoted on START by alveolar C0 macrophage-secreted ligands (left) and on macrophages by START secreted ligands (right). L and M, Heat maps showing the predicted interactions between IM clusters and START in Vehicle- (red) and Unesbulin-treated tumors (light blue). N, Sankey plot of the protumorigenic phenotypes promoted on START by C2 IM-secreted ligands (left) and on macrophages by START secreted ligands (right).
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)
History
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.
