A Targeted Nanotoxin Inhibits Colorectal Cancer Growth Through Local Tumor Pyroptosis and Eosinophil Infiltration and Degranulation

Luis Miguel Carrasco-Díaz,1– 3 Alberto Gallardo,4 Eric Voltà-Durán,3,5,6 Anna C Virgili,1,7 David Páez,7,8 Antonio Villaverde,3,5,6 Esther Vazquez,3,5,6 Patricia Álamo,1– 3 Ugutz Unzueta,1– 3,6 Isolda Casanova,1– 3 Ramon Mangues,1– 3,* Lorena Alba-Castellon1– 3,* 1Onco-Hematological Diseases Department, Institut de Recerca SANT Pau (IR Sant Pau), Barcelona, Spain; 2Myeloid Neoplasms Program, Josep Carreras Leukaemia Research Institute (IJC Sant Pau), Barcelona, Spain; 3CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain; 4Department of Pathology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain; 5Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain; 6Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Spain; 7Department of Medical Oncology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain; 8CIBER de Enfermedades Raras (CIBERER), Madrid, Spain*These authors contributed equally to this workCorrespondence: Ramon Mangues, Lorena Alba-Castellon, Institut de Recerca Sant Pau (IR SANT PAU), Sant Quintí 77-79, Barcelona, 08041, Spain, Email [email protected]; [email protected]: Colorectal cancer (CRC) has traditionally been treated with genotoxic chemotherapy to activate pro-apoptotic proteins to induce anticancer effects. However, cancer cells develop resistance to apoptosis, which leads to recurrence and poor prognosis. Moreover, this kind of therapy has been shown to be highly toxic to healthy tissues and, therefore, to patients. To overcome this issue, we developed a self-assembly tumor-targeted nanoparticle, T22-DITOX-H6, that incorporates the T22 peptide (a CXCR4 ligand) to selectively target cells overexpressing CXCR4, fused to the catalytic domain of diphtheria toxin, that exhibits a potent cytotoxic effect on these CXCR4+ cancer cells that exhibits potent cytotoxic effects on CXCR4-overexpressing cancer cells through the activation of pyroptosis, an immunogenic type of cell death.Methods: Colorectal CXCR4-expressing tumor cells (CT26-CXCR4+) were implanted subcutaneously into immunocompetent mice to study the effects of T22-DITOX-H6 treatment on tumor growth, cell death and innate immune cell recruitment to the tumor.Results: Here, we demonstrated that the T22-DITOX-H6 nanoparticle selectively activated pyroptosis, an immunogenic cell death that differs from apoptosis, leading to cell death in CXCR4-expressing cells, without affecting the viability of CXCR4-lacking cells. In addition, the nanoparticle administered to tumor-bearing mice induced a local antitumor effect due to the selective activation of pyroptosis in CXCR4+ targeted cancer cells. Biochemical analysis of plasma and histological analysis of non-tumor tissues revealed no differences between the groups. Remarkably, pyroptosis activation stimulates eosinophil infiltration into the tumor microenvironment, an effect recently reported to have an anti-tumorigenic function.Conclusion: These results highlight the dual role of CXCR4-targeted cytotoxic nanoparticle in eliminating cancer cells and boosting the self-immune response without compromising healthy organs. Keywords: solid tumor, targeted therapy, innate immune response, protein-only nanoparticl

Controversies around epithelial–mesenchymal plasticity in cancer metastasis

Experimental evidence accumulated over decades has implicated epithelial–mesenchymal plasticity (EMP), which collectively encompasses epithelial–mesenchymal transition and the reverse process of mesenchymal–epithelial transition, in tumour metastasis, cancer stem cell generation and maintenance, and therapeutic resistance. However, the dynamic nature of EMP processes, the apparent need to reverse mesenchymal changes for the development of macrometastases and the likelihood that only minor cancer cell subpopulations exhibit EMP at any one time have made such evidence difficult to accrue in the clinical setting. In this Perspectives article, we outline the existing preclinical and clinical evidence for EMP and reflect on recent controversies, including the failure of initial lineage-tracing experiments to confirm a major role for EMP in dissemination, and discuss accumulating data suggesting that epithelial features and/or a hybrid epithelial–mesenchymal phenotype are important in metastasis. We also highlight strategies to address the complexities of therapeutically targeting the EMP process that give consideration to its spatially and temporally divergent roles in metastasis, with the view that this will yield a potent and broad class of therapeutic agents.See 'additional link' for access to a free to read version of the article.</p

Observation of inverse Compton emission from a long gamma-ray burst

Long-duration γ-ray bursts (GRBs) originate from ultra-relativistic jets launched from the collapsing cores of dying massive stars. They are characterized by an initial phase of bright and highly variable radiation in the kiloelectronvolt-to-megaelectronvolt band, which is probably produced within the jet and lasts from milliseconds to minutes, known as the prompt emission1,2. Subsequently, the interaction of the jet with the surrounding medium generates shock waves that are responsible for the afterglow emission, which lasts from days to months and occurs over a broad energy range from the radio to the gigaelectronvolt bands1–6. The afterglow emission is generally well explained as synchrotron radiation emitted by electrons accelerated by the external shock7–9. Recently, intense long-lasting emission between 0.2 and 1 teraelectronvolts was observed from GRB 190114C10,11. Here we report multi-frequency observations of GRB 190114C, and study the evolution in time of the GRB emission across 17 orders of magnitude in energy, from 5 × 10−6 to 1012 electronvolts. We find that the broadband spectral energy distribution is double-peaked, with the teraelectronvolt emission constituting a distinct spectral component with power comparable to the synchrotron component. This component is associated with the afterglow and is satisfactorily explained by inverse Compton up-scattering of synchrotron photons by high-energy electrons. We find that the conditions required to account for the observed teraelectronvolt component are typical for GRBs, supporting the possibility that inverse Compton emission is commonly produced in GRBs

New landscape of science, technology and innovation

La Ingeniería Química Colombiana está inmersa en nuevos panoramas de Ciencia, Tecnología e Innovación que traen consigo grandes retos para la industria, la academia y el Estado. Las investigaciones multidisciplinarias en energía, materiales, ingeniería de procesos y bioprocesos han llevado a estrategias de emprendimiento e innovación que prometen ser base de desarrollo en el país. En los siguientes capítulos se presentan los resultados más relevantes de las investigaciones realizadas por 19 instituciones colombianas en cooperación con 7 universidades internacionales, así como las contribuciones científicas de numerosas empresas colombianas. Este libro compila 236 resúmenes de investigaciones clasificadas en las siguientes líneas temáticas:1. Bioprocesos - 2. Economía circular - 3. Educación en Ingeniería Química - 4. Emprendimiento e innovación en Ingeniería Química - 5. Energías alternativas - 6. Oil & Gas - 7. Procesos y ciencia - 8. Tecnología en Ingeniería Química y simulación - 9. Tópicos ambientales - 10. MaterialesColombian Chemical Engineering is immersed in new scenarios of Science, Technology and Innovation that bring great challenges for industry, academia and the State. Multidisciplinary research in energy, materials, process engineering and bioprocesses have led to entrepreneurship and innovation strategies that promise to be the basis for development in the country. The following chapters present the most relevant results of the research carried out by 19 Colombian institutions in cooperation with 7 international universities, as well as the scientific contributions of numerous Colombian companies. This book compiles 236 research summaries classified in the following thematic lines: 1. Bioprocesses - 2. Circular economy - 3. Education in Chemical Engineering - 4. Entrepreneurship and innovation in Chemical Engineering - 5. Alternative energies - 6. Oil & Gas - 7. Processes and science - 8. Technology in Chemical Engineering and simulation - 9 Environmental topics - 10. MaterialsUniversidad EA