Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy
Open accessAbstract
A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased. We determine that CT accumulation in CAFs intensifies TGF-beta activity, leading to the production of multiple factors enhancing cancer aggressiveness. We establish periostin as a stromal marker of chemotherapeutic activity intrinsically upregulated in consensus molecular subtype 4 (CMS4) tumors and highly expressed before and/or after treatment in patients unresponsive to therapy. Collectively, our study underscores the ability of CT-retaining CAFs to support cancer progression and resistance to treatment.
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CAFs form reservoirs for oxaliplatin in the colorectal cancer tumour microenvironment, which increases tumour aggressiveness and therapy resistance.
“For example, CAFs form reservoirs for oxaliplatin in the CRC TME which increases tumour aggressiveness and therapy resistance144”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [144]
Stromal contribution to resistance in CMS4 colorectal cancer occurs through drug retention, as demonstrated for oxaliplatin.
“or even drug retention, as demonstrated in the case of oxaliplatin (72)”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [72]
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References 78 · Cited by 109
- Authors
- Linares, J., Sallent-Aragay, A., Badia-Ramentol, J., Recort-Bascuas, A., Méndez, A., Manero-Rupérez, N., Re, D. L., Rivas, E. I., Guiu, M., Zwick, M., Iglesias, M., Martinez-Ciarpaglini, C., Tarazona, N., Varese, M., Hernando-Momblona, X., Cañellas-Socias, A., Orrillo, M., Garrido, M., Saoudi, N., Elez, E., Navarro, P., Tabernero, J., Gomis, R. R., Batlle, E., Pisonero, J., Cervantes, A., Montagut, C., & Calon, A.
- Affiliations
- Institut Català d'Oncologia (ES)
- Hospital Del Mar (ES)
- Institute for Research in Biomedicine (ES)
- Universitat de València (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Universidad de Oviedo (ES)
- Corresponding author
- Calon, Alexandre
- ORCID
- Linares, Jenniffer
- Badia-Ramentol, Jordi
- Recort-Bascuas, Alba
- Re, Daniele Lo
- Rivas, Elisa I.
- Guiu, Marc
- Zwick, Melissa
- Iglesias, Mar
- Tarazona, Noelia
- Cañellas-Socias, Adrià
- Garrido, Marta
- Elez, Elena
- Navarro, Pilar
- Tabernero, Josep
- Gomis, Roger R.
- Batlle, Eduard
- Pisonero, Jorge
- Cervantes, Andres
- Montagut, Clara
- Calon, Alexandre
- Venue
- Nature Communications
- Published
- 2023-02-10
- Volume
- 14
- Issue
- 1
- Pages
- 746-746
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC9918738
- OpenAlex
- W4319925940
- Cited by
- 109
- References
- 78
- Citations by year
- 2026: 30 · 2025: 38 · 2024: 32 · 2023: 9
- FWCI
- 13.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Fundación Científica Asociación Española Contra el Cáncer (6884, GCAEC20030CERV)
- Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (PI20/00625, PI17/00211, PI20/00011, CP16/00151, CPII21/00012, MS16/00151)
- Ministerio de Economía y Competitividad (PID2019-104948RB-I00)
- "la Caixa" Foundation (LCF/PR/HR19/52160018)
- Ministerio de Ciencia e Innovación MICINN
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- platinum-based chemotherapy, oxaliplatin, cancer-associated fibroblasts, drug accumulation, colorectal cancer, chemoresistance, TGF-beta signaling, tumor microenvironment, periostin, residual tumor, elemental imaging
- MeSH terms
- Cancer-Associated Fibroblasts, Oxaliplatin, Antineoplastic Agents, Fibroblasts, Humans, Tissue Distribution, Colorectal Neoplasms, Cell Line, Tumor, Tumor Microenvironment
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