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- Title
Triple negative-breast cancer translation rewiring shapes invasiveness and niche composition.
- Authors
Falletta, Paola; Chauhan, Jagat; Salemme, Vincenzo; Licari, Eugenia; Sarcinella, Alessandro; Gaviraghi, Marco; Loffreda, Alessia; Daniele, Tiziana; Defilippi, Paola; Tacchetti, Carlo
- Abstract
Breast cancer (BC) is the deadliest cancer for women worldwide. Despite great progresses in breast cancer treatment, a targeted therapy for Triple Negative Breast Cancer (TNBC), the most aggressive and metastatic subtype, is still an unmet therapeutic need1. We previously demonstrated that cancer cells with metastatic potential are capable to survive microenvironmental stress and initiate the transition towards a migratory phenotype by triggering the evolutionarily conserved Integrated Stress Response (ISR)2. ISR encom-passes several interconnected signalling pathways, converging on the eIF2a/ATF4 axis and eliciting translation and metabolic rewiring3. The mechanism by which the metastatic cells hijack eIF2a/ATF4 pathway and the downstream effect on the cancer niche are yet to be unravelled and may provide promising therapeutic targets for TNBC treatment. Our aim is to provide a mechanistic understanding of stress-induced translation and metabolic reprogramming in TNBC, elucidating how these stress-induced mechanisms are involved in driving the metastatic phenotype and modulate the immune niche composition. Here we show that TNBC bears high levels of ISR, which correlates to high metastatic potential, EGFR tyrosine kinase receptor expression levels and macrophagic infiltration, shedding light on a stress-driven and EGFR-enhanced cross-talk between the cancer cell and its immune niche. Our studies point towards proposing, as an innovative therapeutic approach, that the targeting of the translation machinery in combination to the EGFR inhibitors already available would be an effective therapy by limiting the capacity of cells to survive stresses in the intratumour microenvironment or during metastatic dissemination.
- Subjects
TRIPLE-negative breast cancer; PROTEIN-tyrosine kinases
- Publication
Italian Journal of Anatomy & Embryology / Archivio Italiano di Anatomia Ed Embriologia, 2021, Vol 125, p64
- ISSN
1122-6714
- Publication type
Article