Abstract B42: The cell adhesion molecule, L1CAM, is important for the dissemination and metastasis of fallopian tube precursor lesions

One of the hallmarks during the progression of high-grade serous ovarian cancer (HGSOC) is the dissemination and metastasis of cells from fallopian tube precursor lesions, namely serous tubal in situ carcinoma (STIC), to other sites of the fallopian tube, ovary, or peritoneal cavity. We, and others, have previously demonstrated that HGSOC originates from benign-appearing lesions in the fallopian tube, harboring TP53 mutations (P53 signatures), that progress into STIC lesions, and show an increase in DNA damage and proliferation. While studies have analyzed those precursor lesions at the distal end of the fallopian tube, little is known about the mechanism that triggers the dissemination of cells from fallopian tube precursor lesions to other sites. The L1 cell adhesion molecule (L1CAM, CD171) has been shown to play an important role in many types of cancer, including ovarian carcinoma. In vitro studies have shown that L1CAM enhances proliferation, cell migration, epithelial-to-mesenchymal transition (EMT), and chemoresistance in ovarian carcinoma cells. In HGSOC, high expression of L1CAM is associated with poor overall survival and confers chemoresistance in this setting. It was further shown that L1CAM expression and the presence of its soluble form in ovarian carcinoma patient ascites correlates with shorter patient survival. Current knowledge is limited on the role of L1CAM during the initiation or the early stages of HGSOC. Therefore, we investigated precursor STIC lesions for L1CAM expression. We found expression of L1CAM in most of the analyzed STIC lesions, but also in scattered normal fallopian epithelial cells. Interestingly, the expression in STIC lesions was not homogenous but showed a gradient with its lowest expression in cells attached to the basement membrane and its highest expression in pseudo-stratified cells that appear to be in the process of detaching. To investigate whether L1CAM contributes to detachment, we used the CRISPR/CAS9 system to knock down L1CAM in the ovarian cancer cell line OVCAR8. Importantly, the knockdown of L1CAM decreased the ability of cells to grow and survive under anchorage-independent culture conditions and to build 3-dimensional spheres. Conversely, overexpression of L1CAM in primary fallopian tube cells led to a strong increase in their ability to form spheres. We found that the expression of L1CAM in ovarian cancer and primary fallopian tube cell lines led to an increase in integrin alpha-5 and integrin beta-1 expression. This ultimately leads to an increased recruitment and organization of fibronectin and assembly of a basement membrane under anchorage-independent culture conditions. These data indicate that in precursor lesions L1CAM expression may be necessary for the tumor to disseminate and metastasize to other sites of the fallopian tube, ovary, or peritoneal cavity. Finally, we found a strong link between the noncanonical WNT pathway and L1CAM expression, which might explain the high L1CAM expression at the apical side of the STIC lesions. However, further studies must be performed to analyze which factors regulate the expression gradient of L1CAM and whether the inhibition of those factors or L1CAM itself delay the onset of the malignant disease. Citation Format: Kai Doberstein, Marcin Iwanicki, Mina Fogel, Peter Altevogt, Ronny Drapkin. The cell adhesion molecule, L1CAM, is important for the dissemination and metastasis of fallopian tube precursor lesions. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B42.