Molecular portraits of colorectal cancer morphological regions
Heterogeneity of colorectal carcinoma (CRC) represents a major hurdle towards personalized medicine. Efforts based on whole tumor profiling demonstrated that the CRC molecular subtypes were associated with specific tumor morphological patterns representing tumor subregions. We hypothesize that whole...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-11-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/86655 |
| _version_ | 1797629310199136256 |
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| author | Eva Budinská Martina Hrivňáková Tina Catela Ivkovic Marie Madrzyk Rudolf Nenutil Beatrix Bencsiková Dagmar Al Tukmachi Michaela Ručková Lenka Zdražilová Dubská Ondřej Slabý Josef Feit Mihnea-Paul Dragomir Petra Borilova Linhartova Sabine Tejpar Vlad Popovici |
| author_facet | Eva Budinská Martina Hrivňáková Tina Catela Ivkovic Marie Madrzyk Rudolf Nenutil Beatrix Bencsiková Dagmar Al Tukmachi Michaela Ručková Lenka Zdražilová Dubská Ondřej Slabý Josef Feit Mihnea-Paul Dragomir Petra Borilova Linhartova Sabine Tejpar Vlad Popovici |
| author_sort | Eva Budinská |
| collection | DOAJ |
| description | Heterogeneity of colorectal carcinoma (CRC) represents a major hurdle towards personalized medicine. Efforts based on whole tumor profiling demonstrated that the CRC molecular subtypes were associated with specific tumor morphological patterns representing tumor subregions. We hypothesize that whole-tumor molecular descriptors depend on the morphological heterogeneity with significant impact on current molecular predictors. We investigated intra-tumor heterogeneity by morphology-guided transcriptomics to better understand the links between gene expression and tumor morphology represented by six morphological patterns (morphotypes): complex tubular, desmoplastic, mucinous, papillary, serrated, and solid/trabecular. Whole-transcriptome profiling by microarrays of 202 tumor regions (morphotypes, tumor-adjacent normal tissue, supportive stroma, and matched whole tumors) from 111 stage II-IV CRCs identified morphotype-specific gene expression profiles and molecular programs and differences in their cellular buildup. The proportion of cell types (fibroblasts, epithelial and immune cells) and differentiation of epithelial cells were the main drivers of the observed disparities with activation of EMT and TNF-α signaling in contrast to MYC and E2F targets signaling, defining major gradients of changes at molecular level. Several gene expression-based (including single-cell) classifiers, prognostic and predictive signatures were examined to study their behavior across morphotypes. Most exhibited important morphotype-dependent variability within same tumor sections, with regional predictions often contradicting the whole-tumor classification. The results show that morphotype-based tumor sampling allows the detection of molecular features that would otherwise be distilled in whole tumor profile, while maintaining histopathology context for their interpretation. This represents a practical approach at improving the reproducibility of expression profiling and, by consequence, of gene-based classifiers. |
| first_indexed | 2024-03-11T10:52:35Z |
| format | Article |
| id | doaj.art-df5a7f3756954a51b6a7bf57f1db34a7 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-11T10:52:35Z |
| publishDate | 2023-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-df5a7f3756954a51b6a7bf57f1db34a72023-11-13T17:01:11ZengeLife Sciences Publications LtdeLife2050-084X2023-11-011210.7554/eLife.86655Molecular portraits of colorectal cancer morphological regionsEva Budinská0Martina Hrivňáková1Tina Catela Ivkovic2Marie Madrzyk3Rudolf Nenutil4Beatrix Bencsiková5Dagmar Al Tukmachi6Michaela Ručková7Lenka Zdražilová Dubská8Ondřej Slabý9Josef Feit10Mihnea-Paul Dragomir11Petra Borilova Linhartova12Sabine Tejpar13Vlad Popovici14https://orcid.org/0000-0002-1311-9188RECETOX, Faculty of Science, Masarykova Univerzita, Brno, Czech RepublicRECETOX, Faculty of Science, Masarykova Univerzita, Brno, Czech RepublicCentral European Institute of Technology, Masarykova Univerzita, Brno, Czech RepublicCentral European Institute of Technology, Masarykova Univerzita, Brno, Czech RepublicMasaryk Memorial Cancer Institute, Brno, Czech RepublicMasaryk Memorial Cancer Institute, Brno, Czech RepublicCentral European Institute of Technology, Masarykova Univerzita, Brno, Czech RepublicCentral European Institute of Technology, Masarykova Univerzita, Brno, Czech RepublicFaculty of Medicine, Masarykova Univerzita, Brno, Czech RepublicCentral European Institute of Technology, Department of Biology, Faculty of Medicine, Masarykova Univerzita, Brno, Czech RepublicDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Masarykova Univerzita, Brno, Czech RepublicInstitute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany; Berlin Institute of Health, Berlin, Germany; German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, GermanyRECETOX, Faculty of Science, Masarykova Univerzita, Brno, Czech RepublicFaculty of Medicine, Digestive Oncology Unit, Katholieke Universiteit Leuven, Leuven, BelgiumRECETOX, Faculty of Science, Masarykova Univerzita, Brno, Czech RepublicHeterogeneity of colorectal carcinoma (CRC) represents a major hurdle towards personalized medicine. Efforts based on whole tumor profiling demonstrated that the CRC molecular subtypes were associated with specific tumor morphological patterns representing tumor subregions. We hypothesize that whole-tumor molecular descriptors depend on the morphological heterogeneity with significant impact on current molecular predictors. We investigated intra-tumor heterogeneity by morphology-guided transcriptomics to better understand the links between gene expression and tumor morphology represented by six morphological patterns (morphotypes): complex tubular, desmoplastic, mucinous, papillary, serrated, and solid/trabecular. Whole-transcriptome profiling by microarrays of 202 tumor regions (morphotypes, tumor-adjacent normal tissue, supportive stroma, and matched whole tumors) from 111 stage II-IV CRCs identified morphotype-specific gene expression profiles and molecular programs and differences in their cellular buildup. The proportion of cell types (fibroblasts, epithelial and immune cells) and differentiation of epithelial cells were the main drivers of the observed disparities with activation of EMT and TNF-α signaling in contrast to MYC and E2F targets signaling, defining major gradients of changes at molecular level. Several gene expression-based (including single-cell) classifiers, prognostic and predictive signatures were examined to study their behavior across morphotypes. Most exhibited important morphotype-dependent variability within same tumor sections, with regional predictions often contradicting the whole-tumor classification. The results show that morphotype-based tumor sampling allows the detection of molecular features that would otherwise be distilled in whole tumor profile, while maintaining histopathology context for their interpretation. This represents a practical approach at improving the reproducibility of expression profiling and, by consequence, of gene-based classifiers.https://elifesciences.org/articles/86655intra-tumor heterogeneitycolorectal cancermorphologytranscriptomics |
| spellingShingle | Eva Budinská Martina Hrivňáková Tina Catela Ivkovic Marie Madrzyk Rudolf Nenutil Beatrix Bencsiková Dagmar Al Tukmachi Michaela Ručková Lenka Zdražilová Dubská Ondřej Slabý Josef Feit Mihnea-Paul Dragomir Petra Borilova Linhartova Sabine Tejpar Vlad Popovici Molecular portraits of colorectal cancer morphological regions eLife intra-tumor heterogeneity colorectal cancer morphology transcriptomics |
| title | Molecular portraits of colorectal cancer morphological regions |
| title_full | Molecular portraits of colorectal cancer morphological regions |
| title_fullStr | Molecular portraits of colorectal cancer morphological regions |
| title_full_unstemmed | Molecular portraits of colorectal cancer morphological regions |
| title_short | Molecular portraits of colorectal cancer morphological regions |
| title_sort | molecular portraits of colorectal cancer morphological regions |
| topic | intra-tumor heterogeneity colorectal cancer morphology transcriptomics |
| url | https://elifesciences.org/articles/86655 |
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