Authors: Jenniffer Linares, Anna Sallent-Aragay, Jordi Badia-Ramentol, Alba Recort-Bascuas, Ana Méndez, Noemí Manero-Rupérez, Daniele Lo Re, Elisa I. Rivas, Marc Guiu, Melissa Zwick, Mar Iglesias, Carolina Martinez-Ciarpaglini, Noelia Tarazona, Monica Varese, Xavier Hernando-Momblona, Adrià Cañellas-Socias, Mayra Orrillo, Marta Garrido, Nadia Saoudi, Elena Elez, Pilar Navarro, Josep Tabernero, Roger R. Gomis, Eduard Batlle, Jorge Pisonero, Andres Cervantes, Clara Montagut, Alexandre Calon
Published: 2023-02-10
DOI: 10.1038/s41467-023-36334-1
Source: Full article
AbstractA 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.