Targeting carcinoma‐associated mesothelial cells with antibody–drug conjugates in ovarian carcinomatosis

Author:

Pascual‐Antón Lucía1ORCID,Sandoval Pilar1ORCID,González‐Mateo Guadalupe T1,Kopytina Valeria1,Tomero‐Sanz Henar1,Arriero‐País Eva María1,Jiménez‐Heffernan José Antonio2,Fabre Myriam3,Egaña Isabel3,Ferrer Cristina3,Simón Laureano3,González‐Cortijo Lucía4,Sainz de la Cuesta Ricardo4,López‐Cabrera Manuel1

Affiliation:

1. Tissue and Organ Homeostasis Program Centro de Biología Molecular Severo Ochoa – Consejo Superior de Investigaciones Científicas – Universidad Autónoma de Madrid (CBMSO‐CSIC‐UAM) Madrid Spain

2. Department of Pathology Hospital Universitario de la Princesa Madrid Spain

3. Oncomatryx Biopharma Vizcaya Spain

4. Hospital Universitario QuirónSalud Madrid Madrid Spain

Abstract

AbstractOvarian carcinomatosis is characterized by the accumulation of carcinoma‐associated mesothelial cells (CAMs) in the peritoneal stroma and mainly originates through a mesothelial‐to‐mesenchymal transition (MMT) process. MMT has been proposed as a therapeutic target for peritoneal metastasis. Most ovarian cancer (OC) patients present at diagnosis with peritoneal seeding, which makes tumor progression control difficult by MMT modulation. An alternative approach is to use antibody–drug conjugates (ADCs) targeted directly to attack CAMs. This strategy could represent the cornerstone of precision‐based medicine for peritoneal carcinomatosis. Here, we performed complete transcriptome analyses of ascitic fluid‐isolated CAMs in advanced OC patients with primary‐, high‐, and low‐grade, serous subtypes and following neoadjuvant chemotherapy. Our findings suggest that both cancer biological aggressiveness and chemotherapy‐induced tumor mass reduction reflect the MMT‐associated changes that take place in the tumor surrounding microenvironment. Accordingly, MMT‐related genes, including fibroblast activation protein (FAP), mannose receptor C type 2 (MRC2), interleukin‐11 receptor alpha (IL11RA), myristoylated alanine‐rich C‐kinase substrate (MARCKS), and sulfatase‐1 (SULF1), were identified as specific actionable targets in CAMs of OC patients, which is a crucial step in the de novo design of ADCs. These cell surface target receptors were also validated in peritoneal CAMs of colorectal cancer peritoneal implants, indicating that ADC‐based treatment could extend to other abdominal tumors that show peritoneal colonization. As proof of concept, a FAP‐targeted ADC reduced tumor growth in an OC xenograft mouse model with peritoneal metastasis‐associated fibroblasts. In summary, we propose MMT as a potential source of ADC‐based therapeutic targets for peritoneal carcinomatosis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Funder

Ministerio de Ciencia e Innovación

Publisher

Wiley

Subject

Pathology and Forensic Medicine

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