Biology subjects

Cannata, C.

Publications and source records attributed to Cannata, C..

4 recordsLinked to original sources

bioRxiv2025

Reconfiguration of tumor cells with LCOR transcription factor mRNA nanotherapy to enhance immunotherapy efficacy

Transcription factors (TFs) are generally deemed undruggable due to their structural complexity. mRNA technologies have paved the way to overcome this therapeutic limitation by enabling the development of mRNA protein replacement therapies. Here we explore the newly described TF activity of LCOR (Ligand-dependent corepressor), which suppresses tumor growth by inducing the antigen presentation machinery (APM) of the tumor cells and constrains cellular plasticity. These LCOR effects facilitate recognition of the tumor by the immune system and immune-mediated tumor cell death. To deliver Lcor mRNA into tumor cells, we have used poly {beta}-(amino esters) (pBAE) nanoparticles (NPs) for local delivery of Lcor mRNA in breast cancer primary tumor models. We have engineered pBAE-NPs with high potential for efficiently encapsulate mRNA and facilitate cellular uptake. Our results show optimal endosomal escape, which results in high transfection efficiency in vitro and in vivo, restoring LCOR function in tumor cells and engaging their APM. In preclinical triple-negative breast cancer (TNBC) models, the intratumoral delivery of Lcor mRNA led to a reduction in tumor growth. Importantly, the combination of Lcor mRNA-loaded NPs with anti-PDL1 or anti-CTLA4 immunotherapies eradicated most of the tumors in our preclinical TNBC model. Overall, our nanotherapeutic strategy emerges as an innovative TF-replacement therapy, leveraging the immunogenic effects of LCOR to eradicate breast cancer tumors when combined with immunotherapy. Gaphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/646434v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1814de3org.highwire.dtl.DTLVardef@207a08org.highwire.dtl.DTLVardef@2bddc1org.highwire.dtl.DTLVardef@1ebc3a2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Adaptation to ARF6-depletion in KRAS-driven PDAC is abolished by targeting TLR2

Metastasis is responsible for nearly 90% of all cancer-related deaths. Despite global efforts to prevent aggressive tumours, cancers such as pancreatic ductal adenocarcinoma (PDAC) are poorly diagnosed in the primary stage, resulting in lethal metastatic disease. RAS mutations are known to promote tumour spread, with mutant KRAS present in up to 90% of cases. Until recently, mutant KRAS remained untargeted and, despite the recent development of inhibitors, results show that tumour cells develop resistance. Another strategy for targeting mutant KRAS-dependent PDAC proliferation and metastasis may come from targeting the downstream effectors of KRAS. One such axis, which controls tumour proliferation, invasiveness and immune evasion, is represented by ARF6-ASAP1. Here we show that targeting ARF6 results in adaptive rewiring that can restore proliferation and invasion potential over time. Using time-series RNA and ATAC sequencing approaches, we identified TLR-dependent NF{kappa}B, TNF and hypoxia signalling as key drivers of adaptation in ARF6-depleted KRAS-dependent PDAC. Using in vitro and in vivo assays, we show that knocking down TLR2 with ARF6 significantly reduces proliferation, migration and invasion. Taken together, our data shed light on a novel co-targeting strategy with the therapeutic potential to counteract PDAC proliferation and metastasis. GRAPHICAL SUMMARY O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/569405v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@192ac2org.highwire.dtl.DTLVardef@4659e5org.highwire.dtl.DTLVardef@b7e225org.highwire.dtl.DTLVardef@6019aa_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Defining the data gap: what do we know about environmental exposure, hazards and risks of pharmaceuticals in the European aquatic environment?

Active pharmaceutical ingredients (APIs) and their transformation products inevitably enter waterways where they might cause adverse effects to aquatic organisms. Identifying the potential risks of APIs in the environment is therefore a goal and current strategic direction of environmental management described in the EU Strategic Approach to Pharmaceuticals in the Environment and the Green Deal. This is challenged by a paucity of monitoring and ecotoxicity data to adequately describe risks. In this study we analyze measured environmental concentrations (MECs) of APIs from 5933 sites in 25 European countries as documented in the EMPODAT database or collected by the German Environment Agency for the time period between 1997 to 2020. These data were compared with empirical data on the ecotoxicity of APIs from the U.S. EPA ECOTOX database. Although 1763 uniquely identifiable APIs are registered with the European Medicines Agency (EMA) for sale in the European Economic Area (EEA), only 312 (17.7%) of these are included in publicly available monitoring data, and only 36 (1.8%) compounds have sufficient ecotoxicological data to perform an EMA-compliant ERA. Among the 27 compounds with sufficient exposure and hazard data to conduct a single substance risk assessment according to EMA guidelines, four compounds (14.8%) had a median risk quotient (RQ) > 1. Endocrine disruptors had the highest median RQ, with 7.0 and 5.6 for 17-ethinyl-estradiol and 17{beta}-estradiol respectively. A comparison of in-silico and empirical data for 72 APIs demonstrated the high protectiveness of the current EMA guidelines, with predicted environmental concentrations (PECs) exceeding median MECs in 98.6% of cases, with a 100-fold median increase. This study describes the data shortfalls hindering an accurate assessment of the risk posed to European waterways by APIs, and identifies 68 APIs for prioritized inclusion in monitoring programs, and 66 APIs requiring ecotoxicity testing to fill current data gaps. HighlightsO_LI1763 medicines are EMA-approved for sale in the EEA C_LIO_LIThe data gap is 1201 APIs (68%) that have no ecotoxicity or public monitoring data C_LIO_LIOnly 27 APIs (1.5%) have sufficient empirical data for risk assessment. C_LIO_LIERA using 23 years of EU monitoring data shows four compounds with a median RQ > 1 C_LIO_LIData gap APIs prioritized for monitoring programs (68) and ecotoxicity testing (66) C_LI

pharmacology and toxicology↗

bioRxiv2022

The BRD4S-LOXL2-MED1 interaction at the forefront of cell cycle transcriptional control in triple-negative breast cancer

Triple-negative breast cancer often develops resistance to single-agent treatments, which can be circumvented with targeted combinatorial approaches. Here, we demonstrate that the simultaneous inhibition of LOXL2 and BRD4 cooperate to reduce triple-negative breast cancer proliferation in vitro and in vivo. Mechanistically, we reveal that LOXL2 interacts in the nucleus with the short isoform of BRD4 and MED1 to control cell cycle progression at the gene expression level via sustaining the formation of BRD4-MED1 nuclear transcriptional foci. Indeed, the pharmacological or transcriptional repression of LOXL2 provokes downregulation of cell cycle gene expression, G1-S cell cycle arrest, and loss of BRD4-MED1 foci. Our results indicate that the BRD4S-LOXL2-MED1 interaction is fundamental for the proliferation of triple-negative breast cancer. Therefore, targeting such interaction holds potential for the development of novel triple-negative breast cancer therapies.

cancer biology↗