ABSTRACT
Recurrences frequently occur following surgical removal of primary tumors. In many cancers, adjuvant therapies have limited efficacy. Surgery provides access to the tumor microenvironment, creating an opportunity for local therapy, in particular immunotherapy, which can induce local and systemic anti-cancer effects. Here, we develop a surgically optimized biodegradable hyaluronic acid-based hydrogel for sustained intraoperative delivery of Toll-like receptor 3 agonist poly(I:C) and demonstrate that it significantly reduces tumor recurrence after surgery in multiple mouse models. Mechanistically, poly(I:C) induces a transient interferon alpha (IFNα) response, reshaping the tumor/wound microenvironment by attracting inflammatory monocytes and depleting regulatory T cells. We demonstrate that a pre-existing IFN signature predicts response to the poly(I:C) hydrogel, which sensitizes tumors to immune checkpoint therapy. The safety, immunogenicity, and surgical feasibility are confirmed in a veterinary trial in canine soft tissue tumors. The surgically optimized poly(I:C)-loaded hydrogel provides a safe and effective approach to prevent cancer recurrence.
Subject(s)
Hydrogels , Neoplasm Recurrence, Local , Mice , Animals , Dogs , Hydrogels/therapeutic use , Neoplasm Recurrence, Local/prevention & control , Immunotherapy , Disease Models, Animal , Tumor MicroenvironmentABSTRACT
The FEBS-IUBMB-ENABLE 1st International Molecular Biosciences PhD and Postdoc Conference was held in Seville, Spain, from the 16-18th of November 2022. Nearly 300 participants from all over the globe were welcomed by the host institution, the Institute of Biomedicine of Seville (IBiS). Following the theme "The perfect tandem: How technology expands the frontiers of biomedicine", the Scientific Symposium of the conference hosted eight world-renowned keynote speakers who presented their work in one of the four sessions: Innovation, Basic Research, Translational and Clinical Research, and Computational Biology and Artificial Intelligence. Participants had the chance to present their research to their peers: more than 200 posters were presented during the dedicated poster sessions and 19 selected PhD students and postdocs presented their work as short talks. The Career Day featured a wide range of workshops fully devoted to trainees' professional development, as well as a job fair and career chats with professionals to discuss future perspectives. Besides, several outreach activities were organised before and during the conference to engage with the general public and bring science closer to society. The success of this conference will be followed by the next FEBS-IUBMB-ENABLE conferences in Cologne, Germany, in 2023 and Singapore in 2024.
Subject(s)
Artificial Intelligence , Computational Biology , Humans , Research PersonnelABSTRACT
Resistance to asparaginase, an antileukemic enzyme that depletes asparagine, is a common clinical problem. Using a genome-wide CRISPR/Cas9 screen, we found a synthetic lethal interaction between Wnt pathway activation and asparaginase in acute leukemias resistant to this enzyme. Wnt pathway activation induced asparaginase sensitivity in distinct treatment-resistant subtypes of acute leukemia, but not in normal hematopoietic progenitors. Sensitization to asparaginase was mediated by Wnt-dependent stabilization of proteins (Wnt/STOP), which inhibits glycogen synthase kinase 3 (GSK3)-dependent protein ubiquitination and proteasomal degradation, a catabolic source of asparagine. Inhibiting the alpha isoform of GSK3 phenocopied this effect, and pharmacologic GSK3α inhibition profoundly sensitized drug-resistant leukemias to asparaginase. Our findings provide a molecular rationale for activation of Wnt/STOP signaling to improve the therapeutic index of asparaginase.
Subject(s)
Antineoplastic Agents/pharmacology , Asparaginase/pharmacology , Drug Resistance, Neoplasm , Leukemia/drug therapy , Polyethylene Glycols/pharmacology , Synthetic Lethal Mutations , Wnt Signaling Pathway/genetics , Wnt3A Protein/genetics , Animals , Cell Death/drug effects , Dose-Response Relationship, Drug , Glycogen Synthase Kinase 3 beta/antagonists & inhibitors , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Jurkat Cells , Leukemia/genetics , Leukemia/metabolism , Leukemia/pathology , Male , Mice, Inbred NOD , Mice, Transgenic , Proteasome Endopeptidase Complex/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Stability , Proteolysis , THP-1 Cells , Ubiquitination , Wnt3A Protein/metabolism , Xenograft Model Antitumor AssaysABSTRACT
The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondrial apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (EZH2, EED, or SUZ12) were associated with mitochondrial apoptosis resistance. In T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action. PRC2 loss induced apoptosis resistance via transcriptional up-regulation of the LIM domain transcription factor CRIP2 and downstream up-regulation of the mitochondrial chaperone TRAP1 These findings demonstrate the importance of mitochondrial apoptotic priming as a prognostic factor in T-ALL and implicate mitochondrial chaperone function as a molecular determinant of chemotherapy response.
