Biology subjects

Baietti, M. F.

Publications and source records attributed to Baietti, M. F..

3 recordsLinked to original sources

bioRxiv2023

The cancer-specific lncRNA LISR customizes ribosomes to suppress anti-tumour immunity

Although immune checkpoint blockade (ICB) has revolutionized cancer treatment, resistance mechanisms limit its clinical benefit. Here we characterise LISRR, a cancer-specific lncRNA highly expressed in melanoma patients refractory to ICB. In cells undergoing (therapeutic) stress, LISRR recruits DAZAP1 (Deleted in AZoospermia Associated Protein 1) to polysomes and drives the assembly of a subset of ribosomes at the endoplasmic reticulum, directing the synthesis of an immunosuppressive translatome. This includes the immune checkpoint PD-L1 and the enzymes necessary for building the glycocalyx, the sugar coat surrounding the cells. Notably, proper glycocalyx assembly is required for spermatozoa immune evasion during fertilization. Accordingly, targeting LISRR activates immune responses and re-sensitizes to ICB in co-culture models, ex vivo in patient explants, and in vivo in humanized patient-derived models. Our study reveals the contribution of lncRNAs to the generation of cancer-specific ribosomes and identifies an RNA-based cancer-specific strategy to overcome intrinsic resistance to ICB.

cancer biology↗

bioRxiv2022

Expanding the HDAC druggable landscape beyond enzymatic inhibition

Enzymatic pockets such as those of histone deacetylases (HDACs) are among the most favored targets for drug development. However, enzymatic inhibitors often exhibit low selectivity and high toxicity due to targeting multiple enzyme paralogs, which are often involved in distinct multisubunit complexes. Here, we report the discovery and characterization of a non-enzymatic small molecule inhibitor of HDAC transcriptional repression functions with comparable anti-tumor activity to the enzymatic HDAC inhibitor Vorinostat, and anti-psychedelic activity of an HDAC2 knockout in vivo. We highlight that these phenotypes are achieved while modulating the expression of 20- and 80-fold fewer genes than enzymatic and genetic inhibition in the respective models. Thus, by achieving the same biological outcomes as established therapeutics while impacting a dramatically smaller number of genes, inhibitors of protein-protein interactions can offer important advantages in improving the selectivity of epigenetic modulators. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/519454v2_ufig1.gif" ALT="Figure 1"> View larger version (96K): org.highwire.dtl.DTLVardef@3a4e68org.highwire.dtl.DTLVardef@1f1be2corg.highwire.dtl.DTLVardef@1fc5e94org.highwire.dtl.DTLVardef@1a54790_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2021

Wnt/β-catenin inhibition disrupts drug-tolerance in isogenic carboplatin-resistant models of Triple-Negative Breast Cancer.

Triple-Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype, characterized by both limited treatment options and higher relapse rates than hormone-receptor-positive breast cancers. Chemotherapy remains the mainstay treatment for TNBC, and platinum salts have been explored as a therapeutic alternative in neo-adjuvant and metastatic settings. However, primary and acquired resistance to chemotherapy in general and platinum-based regimens specifically strongly hampers TNBC management. In this study, we used carboplatin-resistant in vivo patient-derived xenograft and isogenic TNBC cell-line models and detected enhanced Wnt/{beta}-catenin activity correlating with an induced expression of stem cell markers in both resistant models. In accordance, the activation of canonical Wnt signaling in parental TNBC cell lines increases stem cell markers expression, formation of tumorspheres, and promotes carboplatin resistance. Finally, we prove that Wnt signaling inhibition resensitizes resistant models to carboplatin both in vitro and in vivo, suggesting the synergistic use of Wnt inhibitors and carboplatin as a therapeutic option in TNBC. Here we provide evidence for a prominent role of Wnt signaling in mediating resistance to carboplatin, and we establish that combinatorial targeting of Wnt signaling overcomes carboplatin resistance enhancing chemotherapeutic drug efficacy.

cancer biology↗