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Clinical implications of intratumor heterogeneity: challenges and opportunities Ramon y Cajal Agüeras, Santiago Sese Faustino, Marta Capdevila Castillo, Clàudia Aasen, Trond Mattos Arruda, Leticia de Diaz-Cano, Salvador J. Hernandez Losa, Javier Castellví Vives, Josep Institut Català de la Salut [Ramón Y Cajal S] Grup de Patologia molecular translacional, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei de Patologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Barcelona, Spain. Servei de Patologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Sesé M, Aasen T] Grup de Patologia molecular translacional, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Barcelona, Spain. [Capdevila C] Grup de Patologia molecular translacional, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA. [De Mattos-Arruda L] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diaz-Cano SJ] Department of Histopathology, King’s College Hospital and King’s Health Partners, London, UK. [Hernández-Losa J, Castellví J] Grup de Patologia molecular translacional, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei de Patologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Barcelona, Spain Vall d'Hebron Barcelona Hospital Campus Càncer - Tractament Generacions alternants PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Genetic Heterogeneity DISEASES::Neoplasms Other subheadings::Other subheadings::/therapy FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::heterogeneidad genética ENFERMEDADES::neoplasias Otros calificadores::Otros calificadores::/terapia Heterogeneidad intratumoral; Inteligencia artificial; Terapias antitumorales Heterogeneïtat intratumoral; Intel·ligència artificial; Teràpies antitumorals Intratumor heterogeneity; Artificial intelligence; Antitumor therapeutics In this review, we highlight the role of intratumoral heterogeneity, focusing on the clinical and biological ramifications this phenomenon poses. Intratumoral heterogeneity arises through complex genetic, epigenetic, and protein modifications that drive phenotypic selection in response to environmental pressures. Functionally, heterogeneity provides tumors with significant adaptability. This ranges from mutual beneficial cooperation between cells, which nurture features such as growth and metastasis, to the narrow escape and survival of clonal cell populations that have adapted to thrive under specific conditions such as hypoxia or chemotherapy. These dynamic intercellular interplays are guided by a Darwinian selection landscape between clonal tumor cell populations and the tumor microenvironment. Understanding the involved drivers and functional consequences of such tumor heterogeneity is challenging but also promises to provide novel insight needed to confront the problem of therapeutic resistance in tumors. SRYC received support from Fondo de Investigaciones Sanitarias (PI14/01320 and PI17/02247), Redes Temáticas de Investigación Cooperativa en Salud (RD12/0036/0057), CIBERONC (CB16/12/00363), and Generalitat de Catalunya (AGAUR, 2017 SGR 1799 and 2014 SGR 1131). TA received support from Instituto de Salud Carlos III (grants PI16/00772 and CPII16/00042), co-financed by the European Regional Development Fund (ERDF). 2021-10-22T05:54:06Z 2021-10-22T05:54:06Z 2020-02 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Ramón y Cajal S, Sesé M, Capdevila C, Aasen T, De Mattos-Arruda L, Diaz-Cano SJ, et al. Clinical implications of intratumor heterogeneity: challenges and opportunities. J Mol Med (Berl). 2020 Feb;98(2):161–177. 1432-1440 https://hdl.handle.net/11351/6436 10.1007/s00109-020-01874-2 31970428 000508697200001 http://hdl.handle.net/11351/6436 eng Journal of Molecular Medicine;98(2) https://doi.org/10.1007/s00109-020-01874-2 info:eu-repo/grantAgreement/ES/PE2013-2016/PI14%2F01320 info:eu-repo/grantAgreement/ES/PE2013-2016/PI17%2F02247 info:eu-repo/grantAgreement/ES/1PN/2008-2011/RD12%2F0036%2F0057 info:eu-repo/grantAgreement/ES/PE2013-2016/CB16%2F12%2F00363 info:eu-repo/grantAgreement/ES/PERIS2016-2020/2017SGR1799 info:eu-repo/grantAgreement/ES/PE2013-2016/PI16%2F00772 info:eu-repo/grantAgreement/ES/PE2013-2016/CPII16%2F00042 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf Springer Scientia