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Non-canonical integrin signaling activates EGFR and RAS-MAPK-ERK signaling in small cell lung cancer

Non-canonical integrin signaling activates EGFR and RAS-MAPK-ERK signaling in small cell lung cancer

Karla Rubio1,2,3,4, Addi J. Romero-Olmedo2,5, Pouya Sarvari6, Guruprasadh Swaminathan1, Vikas P. Ranvir7, Diana G. Rogel-Ayala1,2, Julio Cordero8,9, Stefan Günther10,11, Aditi Mehta2,12, Birgit Bassaly13, Peter Braubach14,15, Malgorzata Wygrecka16,17, Stefan Gattenlöhner13, Achim Tresch18,19,20, Thomas Braun11, Gergana Dobreva8,9, Miguel N. Rivera3,21, Indrabahadur Singh7, Johannes Graumann22,23, Guillermo Barreto1,2,4†

Abstract:

Background: Small cell lung cancer (SCLC) is an extremely aggressive cancer type with a patient median survival of 6-12 months. Epidermal growth factor (EGF) signaling plays an important role in triggering SCLC. In addition, growth factor-dependent signals and alpha-, beta-integrin (ITGA, ITGB) heterodimer receptors functionally cooperate and integrate their signaling pathways. However, the precise role of integrins in EGF receptor (EGFR) activation in SCLC remains elusive.

Methods: We analyzed human precision-cut lung slices (hPCLS), retrospectively collected human lung tissue samples and cell lines by classical methods of molecular biology and biochemistry. In addition, we performed RNA-sequencing-based transcriptomic analysis in human lung cancer cells and human lung tissue samples, as well as high-resolution mass spectrometric analysis of the protein cargo from extracellular vesicles (EVs) that were isolated from human lung cancer cells.

Results: Our results demonstrate that non-canonical ITGB2 signaling activates EGFR and RAS/MAPK/ERK signaling in SCLC. Further, we identified a novel SCLC gene expression signature consisting of 93 transcripts that were induced by ITGB2, which may be used for stratification of SCLC patients and prognosis prediction of LC patients. We also found a cell-cell communication mechanism based on EVs containing ITGB2, which were secreted by SCLC cells and induced in control human lung tissue RAS/MAPK/ERK signaling and SCLC markers.

Conclusions: We uncovered a mechanism of ITGB2-mediated EGFR activation in SCLC that explains EGFR-inhibitor resistance independently of EGFR mutations, suggesting the development of therapies targeting ITGB2 for patients with this extremely aggressive lung cancer type.

Keywords: small cell lung cancer, integrin, EGFR, KRAS, extracellular vesicles


 

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Dr. Julián Torres

Obtained his doctoral degree from Instituto de Ciencias Biomedicas at Universidad Autonoma de Colima. His research interests include Cardiovascular Physiopathology and Pharmacology of Diabetes type I and II, oriented to altered mechanisms in lethal arrhythmias and biomarkers using mathematical prognostic and diagnostic models, as well as the identification of novel epigenetic factors involved in metabolic diseases. His other research interest lies on science dissemination and public academic initiatives.

Currently he works as researcher and co-supervisor of the International laboratory EPIGEN-CONCYTEP (Instituto de Ciencias, BUAP).

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BSc. Andrea Zacarías

Bachelor in Environmental Engineering at the Benemerita Universidad Autonoma de Puebla (BUAP). She performed academic internships as fellow in the Soil and Microbiology Laboratory. Her interests include Occupational health and Security. She is currently an intern at the EPIGEN International Laboratory.

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Sara Carrillo

Medical student at Universidad de la Salud del Estado de Puebla (USEP). Bachelor in Nutrition at Universidad Popular Autónoma del Estado de Puebla (UPAEP). Certified in Enteral and Parenteral Feeding in critical care by Instituto Mexicano de Nutriología Clínica A.C. She acts as volunteer at publics hospitals (Hospital para el Niño Poblano and Instituto Mexicano del Seguro Social), into Pediatrics and Nutrition areas.

She has experience managing clinical databases, and is a co-author of book chapters and scientific dissemmination papers focused on Obesity and Pollution. She has presented her work in poster sessions at different regional conferences. She is currently an intern at the EPIGEN International Laboratory.

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Diana Cerón

Medical student at Universidad de la Salud del Estado de Puebla (USEP). Technician in Emergency Medicine at Servicios Integrales de Atención Pre-Hospitalaria SOS, PUEBLA A.C. With extensive experience in databases management, she is co-author of book chapters and scientific dissemmination papers focused on Obesity and Pollution.

She has presented her work in poster sessions at different regional conferences. She is currently an intern at the EPIGEN International Laboratory.

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Med. Miguel Coral

Bachelor in Medicine by Benemerita Universidad Autonoma de Puebla (BUAP). Undergraduate Medicine Internship at the General Hospital of Puebla. National Program of Social Service in Health Research of the Interinstitutional Commission for the Training of Health Human Resources (CIFRHS). He is autor of scientific and dissemination articles in indexed journals, as well as book chapters. He is certified in biomedical research, teching, scientific communication and statistics.

He is currently Masters student at the International Laboratory EPIGEN-CONCYTEP (BUAP) and the Medical Sciences Program at Universidad Popular Autónoma de Puebla (UPAEP).

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Masters in Chemical Sciences in the area of Biochemistry and Molecular Biology and Bachelor in Biomedicine by Benemerita Universidad Autonoma de Puebla (BUAP). She has been awarded with fellowships from Consejo Nacional de Ciencia y Tecnología (CONACYT) and Instituto Mexicano del Seguro Social (IMSS) working at the Molecular Biology Laboratory of Centro de Investigacion Biomedica de Oriente del IMSS (CIBIOR-IMSS).

She is autor of scientific and dissemination articles in indexed journals, as well as book chapters. Additionally, she is certified in Data Analysis and Research Design by the College of Data Scientist (COCID), obtaining a badge issued by BEDU-SANTANDER. She is currently PhD student at the International Laboratory EPIGEN-CONCYTEP (BUAP) and the Biotechnology Program at Universidad Popular Autónoma de Puebla (UPAEP) with a national graduate scholarship by CONACYT. Her line of research focuses on epigenetic mechanisms of tumorigenesis induced by environmental toxicants.

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MSc. Ivonne Ramírez

Masters in Chemical Sciences in the area of Biochemistry and Molecular Biology and Bachelor in Biomedicine by Benemerita Universidad Autonoma de Puebla (BUAP). She has been awarded with fellowships from Consejo Nacional de Ciencia y Tecnología (CONACYT) and Instituto Mexicano del Seguro Social (IMSS) working at the Molecular Biology Laboratory of Centro de Investigacion Biomedica de Oriente del IMSS (CIBIOR-IMSS).

She is autor of scientific and dissemination articles in indexed journals, as well as book chapters. Additionally, she is certified in Data Analysis and Research Design by the College of Data Scientist (COCID), obtaining a badge issued by BEDU-SANTANDER. She is currently PhD student at the International Laboratory EPIGEN-CONCYTEP (BUAP) and the Biotechnology Program at Universidad Popular Autónoma de Puebla (UPAEP) with a national graduate scholarship by CONACYT. Her line of research focuses on epigenetic mechanisms of tumorigenesis induced by environmental toxicants.

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MSc. Andrea Pérez

Masters in Chemical Sciences (Biochemistry and Molecular Biology) by Benemerita Universidad Autonoma de Puebla (BUAP) and Bachelor in Biotechnology Engeenering by Universidad Autonoma Popular del Estado de Puebla (UPAEP).  She has been awarded with fellowships from Consejo Nacional de Ciencia y Tecnologia (CONCYTEP) and Instituto Mexicano del Seguro Social (IMSS) as student of the Cellular Biology Laboratory at Centro de Investigacion Biomedica de Oriente (CIBIOR-IMSS); and from the Mexican Academy of Sciences (AMC) as intern at Centro de Investigaciones Biologicas del Noroeste (CIBNOR).

She has worked as Technological Consultant in Biotechnology, Nanotechnology and Biomaterials in collaboration with UPAEP and companies in the health sector. In addition, she is coauthor of book chapters and scientific articles in indexed journals. Currently, she works as laboratory technician at the International Laboratory EPIGEN-CONCYTEP with a focus on pollution-related diseases

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Dra. Karla Rubio

Head of the iniciative EPIGEN International Laboratory, CONCYTEP, BUAP, in Puebla, Mexico. Postdoctoral Researcher at the IMoPA Institute, University of Lorraine, in Nancy, France. Doctor in Sciences (Dr. rer. nat.) by the Max Planck Institute for Heart and Lung Research (Prof. Barreto) in Bad Nauheim, and the Justus-Liebig University in Giessen, Germany. Masters in Physiological Sciences and Bachelor in Biomedicine at the Benemérita Universidad Autónoma de Puebla (BUAP, Prof. Vindrola and Prof. Padros). Her line of research covers the mechanisms of epigenetic regulation in lung, neurodegenerative diseases and those associated with environmental pollution, such as cancer, fibrosis and metabolic syndrome. She established in vitro, in vivo and ex vivo experimental models integrated with next generation sequencing (NGS) techniques for Translational Medicine and Epigenetic Therapy. She has been awarded with the international prices from the von Behring-Röntgen Foundation, the Medizinische Gesellschaft Giessen, and the German Society for Pulmonology and Respiratory Medicine. She is the author of numerous articles indexed in high-profile journals, book chapters and science dissemmination articles. In addition, she is a professor of postgraduate courses in France, Germany and Mexico and belongs to the CONACYT National System of Researchers.