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.
Department of Pathology, Hospital Universitario de la Princesa, Madrid, Spain.
J Pathol. 2023 Oct;261(2):238-251. doi: 10.1002/path.6170. Epub 2023 Aug 9.
Ovarian 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.
卵巢癌转移的特征是癌细胞相关间皮细胞（CAMs）在腹膜基质中的积累，主要通过间皮向间质转化（MMT）过程发生。MMT 已被提议作为腹膜转移的治疗靶点。大多数卵巢癌（OC）患者在诊断时就已经出现腹膜播种，这使得通过 MMT 调节来控制肿瘤进展变得困难。另一种方法是使用直接靶向攻击 CAMs 的抗体药物偶联物（ADC）。这种策略可能代表腹膜癌转移精准医学的基石。在这里，我们对患有原发性、高级别和低级别、浆液性亚型的晚期 OC 患者的腹水分离的 CAMs 进行了完整的转录组分析，并进行了新辅助化疗。我们的研究结果表明，癌症生物学侵袭性和化疗诱导的肿瘤质量减少都反映了肿瘤周围微环境中发生的 MMT 相关变化。因此，MMT 相关基因，包括成纤维细胞激活蛋白（FAP）、甘露糖受体 C 型 2（MRC2）、白细胞介素 11 受体α（IL11RA）、豆蔻酰化丙氨酸丰富的 C 激酶底物（MARCKS）和硫酸酯酶 1（SULF1），被鉴定为 OC 患者 CAMs 中的特定可操作靶点，这是 ADC 从头设计的关键步骤。这些细胞表面靶受体也在结直肠癌腹膜种植的腹膜 CAMs 中得到验证，表明基于 ADC 的治疗方法可以扩展到其他表现出腹膜定植的腹部肿瘤。作为概念验证，一种针对 FAP 的 ADC 减少了具有腹膜转移相关成纤维细胞的 OC 异种移植小鼠模型中的肿瘤生长。总之，我们提出 MMT 作为腹膜癌转移基于 ADC 的治疗靶点的潜在来源。
