Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy
Jenniffer Linares, Anna Sallent-Aragay, Jordi Badia-Ramentol, Alba Recort-Bascuas, Ana Méndez-Vicente, Noemí Manero‐Rupérez, Daniele Lo Re, Elisa Rivas, Marc Guiu, Melissa Zwick, Mar Iglesias, Carolina Martínez‐Ciarpaglini, Noelia Tarazona, Mónica Varese, Xavier Hernando‐Momblona, Adrià Cañellas‐Socias, Mayra Orrillo, Marta Garrido, N. Saoudi Gonzalez, Elena Élez, Pilar Navarro, Josep Tabernero, Roger R. Gomis, Eduard Batlle, Jorge Pisonero, Andrés Cervantes, Clara Montagut, Alexandre Calon
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.