Abstract A074: Crosstalk between tumor vasculature and ovarian cancer stem cells: the angiocrine role of L1CAM

Abstract Ovarian cancer (OC) dissemination, relapse and chemoresistance are thought to be driven by the subpopulation of ovarian cancer stem cells (OCSC). The tumor microenvironment (TME) acts as a niche for OCSC, preserving stem cells properties and sustaining tumor recurrence. Therefore, the crosstalk between TME and OCSC offers a source of viable targets and vulnerabilities to overcome the limitations of current treatments. We identified L1 cell adhesion molecule (L1CAM) as a novel effector in the interaction between the vascular TME (vTME) and OCSC. Notably, tumor-associated endothelial cells express a new isoform of L1CAM (L1-DTM), that is released as a soluble factor and acts as an angiocrine factor which in turn modulates OCSC pathophysiology. In fact, the secretome of L1-DTM-expressing endothelial cells promotes several stem-related features, an effect that is recapitulated by purified, recombinant L1-DTM. Of note, in vivo assays showed that vascular L1-DTM increases the frequency of tumor-initiating cells among OC cells and enhances their tumorigenic potential. To better investigate the role of L1-DTM in the perivascular niche, we setup microfluidics chips that entailed the co-culture of endothelial cells with OCSC. This “niche-on-a-chip” model confirmed the capability of L1-expressing vessels to foster OCSC proliferation and spreading. Mechanistically, we found that L1-DTM drives OC stemness via the activation of the IL6/JAK2/STAT3 signaling pathway, thus implying a paracrine axis that links endothelial L1-DTM to STAT3 function in OCSC. Furthermore, L1-DTM-treated OCSC exhibited a massive transcriptional response which included not only stem-related and EMT genes, but also a proinflammatory phenotype. The latter is under investigation for its possible link to OCSC-driven immune escape, with potential implications for OC response to immunotherapy. We also obtained evidence that L1-DTM reduces the responsiveness of OCSC to chemotherapy, thus emerging as a possible target to overcome chemoresistance. Our approach highlights L1-DTM as a druggable target in the crosstalk between vTME and OCSC. Indeed, our findings could provide the rationale for exploring novel L1CAM-based therapeutic approaches aimed at the eradication of OC through the elimination of its stem cell compartment. Citation Format: Micol Baronio, Mattia Ballerini, Marta Rosa. Sallese, Pietro Lo Riso, Giuseppe Testa, Luigi Nezi, Ugo Cavallaro. Crosstalk between tumor vasculature and ovarian cancer stem cells: the angiocrine role of L1CAM abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl): Abstract nr A074.