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Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy
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Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy
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Journal Article
Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy
2023
Overview
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.
Standard platinum-based chemotherapy is the basis of treatment of many cancers, however a proportion of patients do not derive benefit. Here the authors show that the platinum-based drug oxaliplatin accumulates in cancer-associated fibroblasts, activating pathways associated with cancer progression and resistance to therapy.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/51
/ 38
/ 38/88
/ 96/63
/ Antineoplastic Agents - pharmacology
/ Antineoplastic Agents - therapeutic use
/ Cancer
/ Cancer-Associated Fibroblasts - pathology
/ Colorectal Neoplasms - drug therapy
/ Colorectal Neoplasms - genetics
/ Colorectal Neoplasms - pathology
/ Humanities and Social Sciences
/ Humans
/ Platinum
/ Science
/ Tumors
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