Three new cell lines derived from ocular adnexal sebaceous carcinoma (SebCA) have been introduced to serve as models for drug development and understanding the disease’s pathobiology. Though rare, these tumors most often present in the meibomian glands and present significant treatment challenges, including recurrence, metastases, and difficulty completing resection.
SebCA is “one of the most clinically problematic periocular tumors, often requiring aggressive surgical resection,” the researchers wrote in their article, recently published in the International Journal of Molecular Sciences. Despite the nature of these tumors, their pathobiology is not well-understood, and drug testing is limited by the availability of suitable models. Previous research found possible connections with high-risk human papillomavirus, while other studies found associations with malignancies from Muir-Torre Syndrome. The researchers previously “demonstrated an increased copy number at the MYC locus as well as high MYC protein levels in a subset of ocular adnexal SebCA,” and focused particularly on the role of MYC in this study.
The three cell lines — JHH-SebCA01, JHH-SebCA02 and JHH-SebCA03 — were derived from primary SebCA surgical specimens. These lines represent the diversity of SebCA presentations, including cases of recurrent tumors and metastasis. Conditional reprogramming techniques allowed for consistent growth and differentiation, and helped to overcome the challenges associated with cultivating SebCA cells.
The cell lines exhibited hallmark features of SebCA, including high expression of adipophilin, a marker of sebaceous differentiation. Molecular profiling revealed several genetic alterations, including mutations in tumor-related genes such as BRCA2, ERBB4, and POLD1, aligning with previous studies on SebCA.
Chemotherapeutic agents mitomycin-C (MMC) and 5-fluorouracil (5-FU) demonstrated dose-dependent growth inhibition across all three cell lines. The glutamine analog 6-Diazo-5-oxo-L-norleucine (DON) effectively inhibited cell growth, suggesting that targeting MYC-related pathways may benefit SebCA patients.
MYC overexpression in these tumors offered a promising avenue for targeted therapies, particularly for aggressive and recurrent cases. These cell lines have the potential to be used for testing therapies, developing biomarkers, and further exploring the molecular drivers of SebCA. Additionally, integrating these cell lines into larger-scale studies could reduce the reliance on invasive procedures such as orbital exenteration.
“Current therapies for ocular adnexal SebCA that can minimize the need for exenteration, including cryotherapy, radiation, and topical chemotherapy, such as MMC and interferon-alpha, show only limited efficacy,” the researchers explained. “Other stem cell markers including ALDH1A1, CD44, and CD133 could be examined in the future, along with other signaling pathways such as WNT which have been reported to affect sebaceous gland growth and differentiation.”
However, the complexity of tumor heterogeneity remains a challenge. The study noted some genetic discrepancies between the original tumors and the derived cell lines. Further research is required to explore these differences and evaluate the in vivo relevance of the researchers' findings.