One of the greatest challenges in caring for patients with lymphangioleiomyomatosis (LAM) is to find better ways to track disease progression, either off or on treatment. To date, we mostly rely on pulmonary function tests, which correlate with disease burden but do not necessarily reflect effectiveness of treatment, since rarely does lung function improve – we mostly hope to prevent it from worsening. VEGFD has proven to be a useful biomarker that can be measured from the blood of patients with LAM; however, there are situations where VEGFD is less reflective of disease burden; therefore, discovering alternative blood biomarkers is paramount. Recent research highlights Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) as a potential blood biomarker in LAM, as well as a possible therapeutic target. GPNMB was discovered to be highly expressed in a mouse model for LAM whereby TSC2 was knocked out specifically in the uterus, leading to LAM tumor formation in smooth muscle cells of the uterus. In moving to human LAM, GPNMB was found to be greatly expressed in LAM tumors of the lung and uterus, demonstrating that it could serve as a biomarker for tissue samples from LAM. Interestingly, GPNMB is found on the cell surface of LAM cells, thus distinguishing tumor cells from benign melanocytic cells, where GPNMB is found almost exclusively intracellularly. Moreover, GPNMB has an ectodomain that, when GPNMB is expressed on the cell surface, is released from the cell membrane. This study identified the enzymes that release the GPNMB ectodomain, as well as the target site for these enzymes on the GPNMB protein. Since the GPNM ectodomain is released from the cell surface of LAM cells, the study then went on to determine whether the GPNMB ectodomain could be detected in the blood of patients with LAM. In fact, LAM patients on average have higher levels of GPNMB in their blood relative to control patients, and treatment with sirolimus significantly reduces blood GPNMB levels. This study suggests that GPNMB could serve as a potential biomarker for monitoring LAM progression and response to treatment. Furthermore, the observation that GPNMB is expressed on the cell surface only in tumor cells indicates that it may serve as a tumor-specific target in the treatment of LAM. Overall, this work highlights the importance of pre-clinical models in biological research, as results first discovered in a mouse model for LAM have led to a potentially useful new blood biomarker and therapeutic target.

Read Full Article