Lucile Guilbert

Antinuclear antibodies (ANAs) are a hallmark of connective tissue diseases (CTDs) and serve as robust diagnostic biomarkers. Because their cognate antigens are intracellular, ANAs have long been considered non-pathogenic in CTDs. Here, using systemic sclerosis (SSc) associated anti-topoisomerase I antibodies (ATAs) as a model, we provide data challenging this view. We show that ANAs enter living cells, accumulate in nuclei, and engage their intracellular antigen. Nuclear ATAs inhibit topoisomerase I enzymatic activity, induces DNA damage, fibrosis, and, through the STING pathway, activates type I interferon production. We further identify neonatal Fc receptor (FcRn)-dependent intracellular trafficking as a key determinant of ANAs nuclear access and demonstrate that pharmacological FcRn blockade impairs ATAs functionality. These findings reveal a previously unrecognized intracellular effector function of ANAs and establish a mechanistic framework by which ANAs may directly contribute to tissue injury in CTDs.

Purpose: High throughput technologies have identified molecular patterns in colorectal cancer (CRC) cells, aiding in modeling responses to anti‐cancer treatments. The different responses observed depend on the type of cancer, the tumour grade and the functional programme of the cancer cells. Recent studies suggest that the unfolded protein response (UPR), autophagy and apoptosis could be involved in treatment resistance mechanisms by interacting with the tumour microenvironment (TME).Experimental Design: We analysed by LC‐MS/MS the proteome of two representative colon adenocarcinoma epithelial cell lines from different tumour grades (CCL‐233 and CCL‐221) at the basal state or after the UPR induction.Results: Cell lines expressed a different proteome on about 10% of their total proteins identified, especially on UPR, autophagy and apoptosis pathways proteins at basal state. After UPR induction, the proteome of the cells was modified with a greater adaptive response to cellular stress in CCL‐221 cells where the UPR was strongly activated at the basal state.Conclusions and Clinical Relevance: CRC cell lines at different tumour grades expressed different functional programmes at the proteomic level and were characterised by different responses to the UPR induction. This study suggests that baseline cancer cell stress status could have an impact on the efficiency of cancer therapies.