1. Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy.
- Author
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Linares J, Sallent-Aragay A, Badia-Ramentol J, Recort-Bascuas A, Méndez A, Manero-Rupérez N, Re DL, Rivas EI, 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 RR, Batlle E, Pisonero J, Cervantes A, Montagut C, and Calon A
- Subjects
- Humans, Oxaliplatin pharmacology, Tissue Distribution, Tumor Microenvironment, Fibroblasts pathology, Cell Line, Tumor, Cancer-Associated Fibroblasts pathology, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology
- Abstract
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., (© 2023. The Author(s).)
- Published
- 2023
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