1. Integrating digital pathology with transcriptomic and epigenomic tools for predicting metastatic uterine tumor aggressiveness
- Author
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Giorgia Sonzini, Sofia Granados-Aparici, Sabina Sanegre, Angel Diaz-Lagares, Juan Diaz-Martin, Carlos de Andrea, Núria Eritja, Aida Bao-Caamano, Nicolás Costa-Fraga, David García-Ros, Carmen Salguero-Aranda, Ben Davidson, Rafael López-López, Ignacio Melero, Samuel Navarro, Santiago Ramon y Cajal, Enrique de Alava, Xavier Matias-Guiu, Rosa Noguera, Instituto de Salud Carlos III, European Commission, Centro de Investigación Biomédica en Red Cáncer (España), Asociación Española Contra el Cáncer, Xunta de Galicia, [Sonzini, Giorgia] Univ Valencia INCLIVA, Med Sch, Dept Pathol, Valencia, Spain, [Granados-Aparici, Sofia] Univ Valencia INCLIVA, Med Sch, Dept Pathol, Valencia, Spain, [Sanegre, Sabina] Univ Valencia INCLIVA, Med Sch, Dept Pathol, Valencia, Spain, [Navarro, Samuel] Univ Valencia INCLIVA, Med Sch, Dept Pathol, Valencia, Spain, [Noguera, Rosa] Univ Valencia INCLIVA, Med Sch, Dept Pathol, Valencia, Spain, [Sanegre, Sabina] Canc CIBER CIBERONC, Madrid, Spain, [Diaz-Lagares, Angel] Canc CIBER CIBERONC, Madrid, Spain, [Diaz-Martin, Juan] Canc CIBER CIBERONC, Madrid, Spain, [de Andrea, Carlos] Canc CIBER CIBERONC, Madrid, Spain, [Eritja, Nuria] Canc CIBER CIBERONC, Madrid, Spain, [Salguero-Aranda, Carmen] Canc CIBER CIBERONC, Madrid, Spain, [Lopez-Lopez, Rafael] Canc CIBER CIBERONC, Madrid, Spain, [Melero, Ignacio] Canc CIBER CIBERONC, Madrid, Spain, [Navarro, Samuel] Canc CIBER CIBERONC, Madrid, Spain, [Ramon y Cajal, Santiago] Canc CIBER CIBERONC, Madrid, Spain, [de Alava, Enrique] Canc CIBER CIBERONC, Madrid, Spain, [Matias-Guiu, Xavier] Canc CIBER CIBERONC, Madrid, Spain, [Noguera, Rosa] Canc CIBER CIBERONC, Madrid, Spain, [Diaz-Lagares, Angel] Univ Clin Hosp Santiago CHUS SERGAS, Hlth Res Inst Santiago IDIS, Epigen Unit, Canc Epigen Translat Med Oncol Grp Oncomet, Santiago De Compostela, Spain, [Bao-Caamano, Aida] Univ Clin Hosp Santiago CHUS SERGAS, Hlth Res Inst Santiago IDIS, Epigen Unit, Canc Epigen Translat Med Oncol Grp Oncomet, Santiago De Compostela, Spain, [Costa-Fraga, Nicolas] Univ Clin Hosp Santiago CHUS SERGAS, Hlth Res Inst Santiago IDIS, Epigen Unit, Canc Epigen Translat Med Oncol Grp Oncomet, Santiago De Compostela, Spain, [Diaz-Martin, Juan] Univ Seville, Virgen Rocio Univ Hosp, Inst BioMed Sevilla, CSIC, Seville, Spain, [Salguero-Aranda, Carmen] Univ Seville, Virgen Rocio Univ Hosp, Inst BioMed Sevilla, CSIC, Seville, Spain, [de Alava, Enrique] Univ Seville, Virgen Rocio Univ Hosp, Inst BioMed Sevilla, CSIC, Seville, Spain, [de Andrea, Carlos] Univ Navarra, Clin Univ Navarra, Pamplona, Spain, [Garcia-Ros, David] Univ Navarra, Clin Univ Navarra, Pamplona, Spain, [Melero, Ignacio] Univ Navarra, Clin Univ Navarra, Pamplona, Spain, [Eritja, Nuria] Univ Barcelona, Univ Lleida, Inst Recerca Biomed LLeida IRBLLEIDA,Dept Pathol, Inst Invest Biomed Bellvitge IDIBELL,Hosp U Arnau, Barcelona, Spain, [Matias-Guiu, Xavier] Univ Barcelona, Univ Lleida, Inst Recerca Biomed LLeida IRBLLEIDA,Dept Pathol, Inst Invest Biomed Bellvitge IDIBELL,Hosp U Arnau, Barcelona, Spain, [Eritja, Nuria] Univ Barcelona, Bellvitge Hosp, Univ Lleida, Barcelona, Spain, [Matias-Guiu, Xavier] Univ Barcelona, Bellvitge Hosp, Univ Lleida, Barcelona, Spain, [Bao-Caamano, Aida] Univ Santiago Compostela USC, Santiago De Compostela, Spain, [Costa-Fraga, Nicolas] Univ Santiago Compostela USC, Santiago De Compostela, Spain, [Davidson, Ben] Univ Oslo, Inst Clin Med, Fac Med, Oslo, Norway, [Davidson, Ben] Univ Oslo, Norwegian Radium Hosp, Dept Pathol, Oslo, Norway, [Lopez-Lopez, Rafael] Hlth Res Inst Santiago IDIS, Translat Med Oncol Grp Oncomet, Roche Chus Joint Unit, Santiago De Compostela, Spain, and [Ramon y Cajal, Santiago] Univ Autonoma Barcelona, Vall Hebron Univ Hosp, Dept Pathol, Barcelona, Spain
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Cell Biology ,Epigenètica ,Defines ,Multiplex immunofluorescence ,Metastasis ,Methylomics ,Lung metastasis ,Càncer d'úter ,Invasive tumor front ,Metàstasi ,Uterine adenocarcinoma ,Uterine leiomyosarcoma ,Uterine cancer ,Digital pathology ,Epigenetics ,Collagen ,Transcriptomics ,Developmental Biology ,Cancer - Abstract
The incidence of new cancer cases is expected to increase significantly in the future, posing a worldwide problem. In this regard, precision oncology and its diagnostic tools are essential for developing personalized cancer treatments. Digital pathology (DP) is a particularly key strategy to study the interactions of tumor cells and the tumor microenvironment (TME), which play a crucial role in tumor initiation, progression and metastasis. The purpose of this study was to integrate data on the digital patterns of reticulin fiber scaffolding and the immune cell infiltrate, transcriptomic and epigenetic profiles in aggressive uterine adenocarcinoma (uADC), uterine leiomyosarcoma (uLMS) and their respective lung metastases, with the aim of obtaining key TME biomarkers that can help improve metastatic prediction and shed light on potential therapeutic targets. Automatized algorithms were used to analyze reticulin fiber architecture and immune infiltration in colocalized regions of interest (ROIs) of 133 invasive tumor front (ITF), 89 tumor niches and 70 target tissues in a total of six paired samples of uADC and nine of uLMS. Microdissected tissue from the ITF was employed for transcriptomic and epigenetic studies in primary and metastatic tumors. Reticulin fiber scaffolding was characterized by a large and loose reticular fiber network in uADC, while dense bundles were found in uLMS. Notably, more similarities between reticulin fibers were observed in paired uLMS then paired uADCs. Transcriptomic and multiplex immunofluorescence-based immune profiling showed a higher abundance of T and B cells in primary tumor and in metastatic uADC than uLMS. Moreover, the epigenetic signature of paired samples in uADCs showed more differences than paired samples in uLMS. Some epigenetic variation was also found between the ITF of metastatic uADC and uLMS. Altogether, our data suggest a correlation between morphological and molecular changes at the ITF and the degree of aggressiveness. The use of DP tools for characterizing reticulin scaffolding and immune cell infiltration at the ITF in paired samples together with information provided by omics analyses in a large cohort will hopefully help validate novel biomarkers of tumor aggressiveness, develop new drugs and improve patient quality of life in a much more efficient way., This research was supported by grants from the ISCIII and ERDF (PI17/01558), by the CIBERONC (contracts CB16/12/00484, CB16/12/0328, CB16/12/00363, CB16/12/00364, CB16/12/00481, and CB16/12/00231) and Grupos Coordinados Estables from the Asociación Española Contra el Cáncer (AECC). AB-C was funded by a predoctoral contract PFIS from ISCIII (FI19/00240) co-funded by “Fondo Social Europeo” (FSE). NC-F was funded by a predoctoral contract from “Xunta de Galicia” (IN606A-2020/004). AD-L was funded by a “Juan Rodés” contract from the ISCIII (JR17/00016).
- Published
- 2022