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Genetic and microenvironmental intra-tumor heterogeneity impacts colorectal cancer evolution and metastatic development

2022Journal article Open access
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dc.contributor.authorSobral, Daniel
dc.contributor.authorMartins, Marta
dc.contributor.authorKaplan, Shannon
dc.contributor.authorGolkaram, Mahdi
dc.contributor.authorSalmans, Michael
dc.contributor.authorKhan, Nafeesa
dc.contributor.authorVijayaraghavan, Raakhee
dc.contributor.authorCasimiro, Sandra
dc.contributor.authorFernandes, Afonso
dc.contributor.authorBorralho, Paula
dc.contributor.authorFerreira, Cristina
dc.contributor.authorPinto, Rui
dc.contributor.authorMarques, Catarina
dc.contributor.authorCosta, Ana Lúcia
dc.contributor.authorZhang, Shile
dc.contributor.authorPawlowski, Traci
dc.contributor.authorGodsey, Jim
dc.contributor.authorMansinho, André
dc.contributor.authorMacedo, Daniela
dc.contributor.authorLobo-Martins, Soraia
dc.contributor.authorFilipe, Pedro
dc.contributor.authorEsteves, Rui
dc.contributor.authorCoutinho, Joao
dc.contributor.authorCosta, Paulo M.
dc.contributor.authorRamires, Afonso
dc.contributor.authorAldeia, Fernando
dc.contributor.authorQuintela, António
dc.contributor.authorSo, Alex
dc.contributor.authorLiu, Li
dc.contributor.authorGrosso, Ana Rita
dc.contributor.authorCosta, Luis
dc.date.accessioned2022-09-13T11:18:47Z
dc.date.available2022-09-13T11:18:47Z
dc.date.issued2022
dc.description© The Author(s) 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.pt_PT
dc.description.abstractColorectal cancer (CRC) is a highly diverse disease, where different genomic instability pathways shape genetic clonal diversity and tumor microenvironment. Although intra-tumor heterogeneity has been characterized in primary tumors, its origin and consequences in CRC outcome is not fully understood. Therefore, we assessed intra- and inter-tumor heterogeneity of a prospective cohort of 136 CRC samples. We demonstrate that CRC diversity is forged by asynchronous forms of molecular alterations, where mutational and chromosomal instability collectively boost CRC genetic and microenvironment intra-tumor heterogeneity. We were able to depict predictor signatures of cancer-related genes that can foresee heterogeneity levels across the different tumor consensus molecular subtypes (CMS) and primary tumor location. Finally, we show that high genetic and microenvironment heterogeneity are associated with lower metastatic potential, whereas late-emerging copy number variations favor metastasis development and polyclonal seeding. This study provides an exhaustive portrait of the interplay between genetic and microenvironment intra-tumor heterogeneity across CMS subtypes, depicting molecular events with predictive value of CRC progression and metastasis development.pt_PT
dc.description.sponsorshipThis work was financed by national funds from FCT - Fundação para a Ciência e a Tecnologia, I.P., in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences - UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy - i4HB. This research was also funded by: PTDC/MED-ONC/28660/2017 from Fundação para a Ciência e Tecnologia (FCT) to A.R.G. A.R.G is recipient of Researcher Grant CEECIND/02699/2017 from FCT. The biobanking of CRC samples from Hospital Santa Maria, Lisbon, Portugal was supported by FCT research grant PIC/IC/82821/2007. This work was produced with the support of INCD funded by FCT and FEDER under the project 22153-01/SAICT/2016.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCommun Biol. 2022 Sep 9;5(1):937pt_PT
dc.identifier.doi10.1038/s42003-022-03884-xpt_PT
dc.identifier.eissn2399-3642
dc.identifier.urihttp://hdl.handle.net/10451/54445
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relation22153-01/SAICT/2016pt_PT
dc.relationApplied Molecular Biosciences Unit
dc.relationApplied Molecular Biosciences Unit
dc.relationNot Available
dc.relation.publisherversionhttps://www.nature.com/commsbio/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleGenetic and microenvironmental intra-tumor heterogeneity impacts colorectal cancer evolution and metastatic developmentpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleApplied Molecular Biosciences Unit
oaire.awardTitleApplied Molecular Biosciences Unit
oaire.awardTitleNot Available
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04378%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04378%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMED-ONC%2F28660%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/CEEC IND 2017/CEECIND%2F02699%2F2017%2FCP1462%2FCT0018/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5646-ICCMS/PIC%2FIC%2F82821%2F2007/PT
oaire.citation.issue1pt_PT
oaire.citation.titleCommunications Biologypt_PT
oaire.citation.volume5pt_PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream3599-PPCDT
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person.familyNameMartins
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project.funder.nameFundação para a Ciência e a Tecnologia
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