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.
Baronio et al. (Fri,) studied this question.