Intratumor heterogeneity and cell secretome promote chemotherapy resistance and progression of colorectal cancer
Abstract The major underlying cause for the high mortality rate in colorectal cancer (CRC) relies on its drug resistance, to which intratumor heterogeneity (ITH) contributes substantially. CRC tumors have been reported to comprise heterogeneous populations of cancer cells that can be grouped into 4...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-05-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05806-z |
| _version_ | 1797831920914006016 |
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| author | Julia Källberg Alexandra Harrison Valerie March Santa Bērziņa Ivan Nemazanyy Oliver Kepp Guido Kroemer Sophie Mouillet-Richard Pierre Laurent-Puig Valérie Taly Wenjin Xiao |
| author_facet | Julia Källberg Alexandra Harrison Valerie March Santa Bērziņa Ivan Nemazanyy Oliver Kepp Guido Kroemer Sophie Mouillet-Richard Pierre Laurent-Puig Valérie Taly Wenjin Xiao |
| author_sort | Julia Källberg |
| collection | DOAJ |
| description | Abstract The major underlying cause for the high mortality rate in colorectal cancer (CRC) relies on its drug resistance, to which intratumor heterogeneity (ITH) contributes substantially. CRC tumors have been reported to comprise heterogeneous populations of cancer cells that can be grouped into 4 consensus molecular subtypes (CMS). However, the impact of inter-cellular interaction between these cellular states on the emergence of drug resistance and CRC progression remains elusive. Here, we explored the interaction between cell lines belonging to the CMS1 (HCT116 and LoVo) and the CMS4 (SW620 and MDST8) in a 3D coculture model, mimicking the ITH of CRC. The spatial distribution of each cell population showed that CMS1 cells had a preference to grow in the center of cocultured spheroids, while CMS4 cells localized at the periphery, in line with observations in tumors from CRC patients. Cocultures of CMS1 and CMS4 cells did not alter cell growth, but significantly sustained the survival of both CMS1 and CMS4 cells in response to the front-line chemotherapeutic agent 5-fluorouracil (5-FU). Mechanistically, the secretome of CMS1 cells exhibited a remarkable protective effect for CMS4 cells against 5-FU treatment, while promoting cellular invasion. Secreted metabolites may be responsible for these effects, as demonstrated by the existence of 5-FU induced metabolomic shifts, as well as by the experimental transfer of the metabolome between CMS1 and CMS4 cells. Overall, our results suggest that the interplay between CMS1 and CMS4 cells stimulates CRC progression and reduces the efficacy of chemotherapy. |
| first_indexed | 2024-04-09T13:59:28Z |
| format | Article |
| id | doaj.art-f3c2f693a1da46e99b45f5f98c739dd7 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-09T13:59:28Z |
| publishDate | 2023-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-f3c2f693a1da46e99b45f5f98c739dd72023-05-07T11:25:41ZengNature Publishing GroupCell Death and Disease2041-48892023-05-0114511210.1038/s41419-023-05806-zIntratumor heterogeneity and cell secretome promote chemotherapy resistance and progression of colorectal cancerJulia Källberg0Alexandra Harrison1Valerie March2Santa Bērziņa3Ivan Nemazanyy4Oliver Kepp5Guido Kroemer6Sophie Mouillet-Richard7Pierre Laurent-Puig8Valérie Taly9Wenjin Xiao10Centre de Recherche des Cordeliers, INSERM, CNRS, Université Paris Cité, Sorbonne Université, USPC, Equipe labellisée Ligue Nationale contre le cancerCentre de Recherche des Cordeliers, INSERM, CNRS, Université Paris Cité, Sorbonne Université, USPC, Equipe labellisée Ligue Nationale contre le cancerCentre de Recherche des Cordeliers, INSERM, CNRS, Université Paris Cité, Sorbonne Université, USPC, Equipe labellisée Ligue Nationale contre le cancerCentre de Recherche des Cordeliers, INSERM, CNRS, Université Paris Cité, Sorbonne Université, USPC, Equipe labellisée Ligue Nationale contre le cancerPlatform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633Equipe labellisée par La Ligue contre le cancer, Université Paris Cité, Sorbonne Université, INSERM UMR1138, Centre de Recherche des CordeliersEquipe labellisée par La Ligue contre le cancer, Université Paris Cité, Sorbonne Université, INSERM UMR1138, Centre de Recherche des CordeliersCentre de Recherche des Cordeliers, INSERM, CNRS, Université Paris Cité, Sorbonne Université, USPC, Equipe labellisée Ligue Nationale contre le cancerCentre de Recherche des Cordeliers, INSERM, CNRS, Université Paris Cité, Sorbonne Université, USPC, Equipe labellisée Ligue Nationale contre le cancerCentre de Recherche des Cordeliers, INSERM, CNRS, Université Paris Cité, Sorbonne Université, USPC, Equipe labellisée Ligue Nationale contre le cancerCentre de Recherche des Cordeliers, INSERM, CNRS, Université Paris Cité, Sorbonne Université, USPC, Equipe labellisée Ligue Nationale contre le cancerAbstract The major underlying cause for the high mortality rate in colorectal cancer (CRC) relies on its drug resistance, to which intratumor heterogeneity (ITH) contributes substantially. CRC tumors have been reported to comprise heterogeneous populations of cancer cells that can be grouped into 4 consensus molecular subtypes (CMS). However, the impact of inter-cellular interaction between these cellular states on the emergence of drug resistance and CRC progression remains elusive. Here, we explored the interaction between cell lines belonging to the CMS1 (HCT116 and LoVo) and the CMS4 (SW620 and MDST8) in a 3D coculture model, mimicking the ITH of CRC. The spatial distribution of each cell population showed that CMS1 cells had a preference to grow in the center of cocultured spheroids, while CMS4 cells localized at the periphery, in line with observations in tumors from CRC patients. Cocultures of CMS1 and CMS4 cells did not alter cell growth, but significantly sustained the survival of both CMS1 and CMS4 cells in response to the front-line chemotherapeutic agent 5-fluorouracil (5-FU). Mechanistically, the secretome of CMS1 cells exhibited a remarkable protective effect for CMS4 cells against 5-FU treatment, while promoting cellular invasion. Secreted metabolites may be responsible for these effects, as demonstrated by the existence of 5-FU induced metabolomic shifts, as well as by the experimental transfer of the metabolome between CMS1 and CMS4 cells. Overall, our results suggest that the interplay between CMS1 and CMS4 cells stimulates CRC progression and reduces the efficacy of chemotherapy.https://doi.org/10.1038/s41419-023-05806-z |
| spellingShingle | Julia Källberg Alexandra Harrison Valerie March Santa Bērziņa Ivan Nemazanyy Oliver Kepp Guido Kroemer Sophie Mouillet-Richard Pierre Laurent-Puig Valérie Taly Wenjin Xiao Intratumor heterogeneity and cell secretome promote chemotherapy resistance and progression of colorectal cancer Cell Death and Disease |
| title | Intratumor heterogeneity and cell secretome promote chemotherapy resistance and progression of colorectal cancer |
| title_full | Intratumor heterogeneity and cell secretome promote chemotherapy resistance and progression of colorectal cancer |
| title_fullStr | Intratumor heterogeneity and cell secretome promote chemotherapy resistance and progression of colorectal cancer |
| title_full_unstemmed | Intratumor heterogeneity and cell secretome promote chemotherapy resistance and progression of colorectal cancer |
| title_short | Intratumor heterogeneity and cell secretome promote chemotherapy resistance and progression of colorectal cancer |
| title_sort | intratumor heterogeneity and cell secretome promote chemotherapy resistance and progression of colorectal cancer |
| url | https://doi.org/10.1038/s41419-023-05806-z |
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