OCRA-Funded Study Reveals Role of L1CAM in Development and Spread of HGSOC
A recent study, funded in part by OCRA, has shed new light on how the most common subtype of ovarian cancer develops and metastasizes, by identifying a key molecule that allows malignancies in the fallopian tube to migrate to the ovaries and continue to grow.
High-grade serous ovarian carcinoma (HGSOC) is the most common subtype of ovarian cancer, and it is now widely accepted that in a majority of cases, HGSOC initially develops from serous tubal intraepithelial carcinoma (STIC) – cancerous lesions in the fallopian tubes – before seeding in the ovaries. Earlier studies have shown that it takes approximately 6.5 years for fallopian tube lesions to invade the ovaries, but it is not yet known what causes the cancer cells to migrate from the fallopian tube.
In this study, led by OCRA grantee Dr. Ronny Drapkin of University of Pennsylvania, along with OCRA grantees Dr. Gordon Mills and Dr. Jagmohan Hooda, researchers sought to understand the mechanisms that enable fallopian tube malignancies to develop into ovarian cancer, by focusing on L1CAM, a molecule that is found in high amounts in HGSOC tumor cells.
L1CAM, short for L1 cell adhesion molecule, is found in excess in several cancers in addition to HGSOC, and has been linked in other cancers to chemotherapy resistance, rapid metastatic progression, and poor prognosis. Though researchers have known L1CAM is found in high quantity in HGSOC, it has been unclear at what stage the cellular alterations that lead to L1CAM’s overproduction begin to occur, and what role it may play in development of the disease.
Researchers in the study analyzed data from The Cancer Genome Atlas (TCGA), comparing HGSOC with other types of solid tumors, and found that HGSOC displays some of the highest levels of L1CAM. Their analysis revealed that higher L1CAM expression is associated with shorter overall survival, and that expression gradually increases from Stage II and Stage IV, with a period of more rapidly increased expression between Stage IIIA and Stage IIIC. L1CAM expression was also found to be notably higher in patients with progressive disease.
To better understand if L1CAM is produced in the early development of HGSC, the research team examined specimens of fallopian tube lesions. They found some of the highest L1CAM expression in cells that were detached from the main lesions, suggesting a link between L1CAM and cell dissemination.
The team also tested three cancer cell lines of the ovaries and fallopian tube, to determine whether deactivation of L1CAM would alter cell migration. They found that migration decreased significantly after L1CAM deactivation, and increased with over-expression, supporting the hypothesis that L1CAM plays a functional role in HGSOC progression from the fallopian tube to the ovaries.
Further segments of the study explored L1CAM’s role in cell adhesion, finding that the molecule plays a functional role in forming cancer cell clusters. Additional tests showed that cells expressing L1CAM bind to each other; that L1CAM expression promotes survival of abnormal cells; and that overexpression activates the critical ERK and AKT pathways in fallopian tube cells, supporting colonization of cancer cells to the ovaries.
Results from the study demonstrate that L1CAM plays an important role in the early development and spread of HGSOC, and may be a promising target for future methods of ovarian cancer prevention.
Read the full study, “L1CAM is required for early dissemination of fallopian tube carcinoma precursors to the ovary,” in Nature.
Dr. Hooda’s Mentored Investigator Grant was supported in part by a generous donation from Teal There’s a Cure (Syracuse, NY).
Dr. Mills’ Collaborative Research Development Grant was supported in part by a generous donation from Turn the Towns Teal.