Intratumor heterogeneity and cell secretome promote chemotherapy resistance and progression of colorectal cancer.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
05 05 2023
05 05 2023
Historique:
received:
11
10
2022
accepted:
11
04
2023
revised:
03
04
2023
medline:
8
5
2023
pubmed:
5
5
2023
entrez:
4
5
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37142595
doi: 10.1038/s41419-023-05806-z
pii: 10.1038/s41419-023-05806-z
pmc: PMC10160076
doi:
Substances chimiques
Fluorouracil
U3P01618RT
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
306Informations de copyright
© 2023. The Author(s).
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