Unravelling the role of Integrated Stress Response signalling in metastatic Breast Cancer bioenergetics

The Integrated Stress Response (ISR) is an evolutionarily conserved adaptive pathway that mediates translation reprogramming in response to microenvironmental stress, often hijacked by cancer cells to promote metastasis. To reveal novel targetable vulnerabilities in Triple-negative Breast Cancer (TNBC), the most aggressive breast cancer subtype, characterized by high metastatic propensity and limited therapeutic options, here we elucidate the mechanisms by which ISR accommodates the energy de...

Unraveling the role of the alarmin HMGB1 in the ageing process

High Mobility Group Box 1 (HMGB1) is a nuclear protein that, in physiological conditions, is predominantly localized in the nucleus. Upon cellular stress, it can translocate to the cytosol and can be released extracellularly, where it regulates tissue regeneration and inflammatory responses in a redox-state-dependent manner. HMGB1 bioactivities has been associated with several hallmarks of aging, and HMGB1 has been recently proposed as a biomarker of frailty. Here we hypothesized that aging p...

Proliferative stress and DNA damage response pathways in hematopoietic stem cell gene therapy and clonal hematopoiesis

Gene editing (GE) of hematopoietic stem and progenitor cells (HSPCs) holds significant therapeutic promise but remains constrained by genotoxic risks associated with DNA double-strand breaks, donor template delivery, and proliferation-induced stress during ex vivo manipulation. Ex vivo culture is indispensable to achieve efficient homology-directed repair (HDR), yet comes at the cost of inducing cellular stress and compromising HSPC fitness. Here, we identify p38 MAPK signaling as a central r...

Cross-Correction in HSC Gene Therapy for Metachromatic Leukodystrophy