Deciphering and targeting the metabolic control of lung cancer de-differentiation.
Final Report Abstract
The most lethal features of lung cancers (LC) are chemo-resistance and metastatic dissemination. In many cases, both can be attributed to the presence of cells driven by de-differentiation processes like the epithelial-to-mesenchymal transition (EMT) program, which can foster a clinical relapse. However, to date there are no approved drugs reducing or preventing the occurrence of EMT in LC. Our lab had previously showed that some metabolic pathways can exert a powerful regulatory role on cancer de-differentiation and promote LC aggressiveness driving EMT. This led us to speculate the existence of a broader network of metabolic genes with a similar activity, which we proposed here to identify, investigate and target. During the funded period, we conducted a large-scale transcriptomics/metabolomics analysis from lung cancer datasets, and we found that EMT can be inhibited by metabolites belonging to the class of short chain fatty acids, like propionate. These are non-toxic small metabolites produced by commensal microbiota potentially very interesting for therapeutic use. Treatment of lung cancer cell lines with sodium propionate (SP) 1) reduced EMT as evaluated by markers and in vitro migration, 2) reduced their metastatic ability once injected in immune-deficient mice, and 3) sensitized the cells towards cisplatin, backbone for cytotoxic chemotherapy in advanced-stage patients. RNA-sequencing, ChIP-sequencing and histones modification profiling on SP-treated cells indicated chromatin remodeling via histone acetylation as the mechanism behind EMT attenuation. Additional work to understand the role of lung microbiota on the EMT status of lung cancer cells is planned for the future. The findings of the present work therefore provide the rationale for novel metabolism-based therapeutic strategies to suppress the devastating effects of aggressive LC.
Publications
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Targeting EMT in Cancer with Repurposed Metabolic Inhibitors. Trends in Cancer, 6(11), 942-950.
Ramesh, Vignesh; Brabletz, Thomas & Ceppi, Paolo
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Propionate reinforces epithelial identity and reduces aggressiveness of lung carcinoma. EMBO Molecular Medicine, 15(12).
Ramesh, Vignesh; Gollavilli, Paradesi Naidu; Pinna, Luisa; Siddiqui, Mohammad Aarif; Turtos, Adriana Martinez; Napoli, Francesca; Antonelli, Yasmin; Leal‐Egaña, Aldo; Havelund, Jesper Foged; Jakobsen, Simon Toftholm; Boiteux, Elisa Le; Volante, Marco; Færgeman, Nils Joakim; Jensen, Ole N.; Siersbæk, Rasmus; Somyajit, Kumar & Ceppi, Paolo
