Lucía Pascual‐Antón

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

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.

Mesothelial-to-Mesenchymal Transition and Exosomes in Peritoneal Metastasis of Ovarian Cancer

Most patients with ovarian cancer (OvCA) present peritoneal disseminated disease at the time of diagnosis. During peritoneal metastasis, cancer cells detach from the primary tumor and disseminate through the intraperitoneal fluid. The peritoneal mesothelial cell (PMC) monolayer that lines the abdominal cavity is the first barrier encountered by OvCA cells. Subsequent progression of tumors through the peritoneum leads to the accumulation into the peritoneal stroma of a sizeable population of carcinoma-associated fibroblasts (CAFs), which is mainly originated from a mesothelial-to-mesenchymal transition (MMT) process. A common characteristic of OvCA patients is the intraperitoneal accumulation of ascitic fluid, which is composed of cytokines, chemokines, growth factors, miRNAs, and proteins contained in exosomes, as well as tumor and mesothelial suspended cells, among other components that vary in proportion between patients. Exosomes are small extracellular vesicles that have been shown to mediate peritoneal metastasis by educating a pre-metastatic niche, promoting the accumulation of CAFs via MMT, and inducing tumor growth and chemoresistance. This review summarizes and discusses the pivotal role of exosomes and MMT as mediators of OvCA peritoneal colonization and as emerging diagnostic and therapeutic targets.