A protein overexpressed in several solid tumors, known as BACE2, regulates fat uptake by cancer cells. Inhibiting this protein could represent a new strategy against skin cancer, pancreatic cancer, and other lipid-dependent cancers, according to research from the IFOM, the Institute of Molecular Oncology of the AIRC Foundation in Milan.
The findings, published in January , shed light on the metabolic vulnerabilities of cancer cells and position BACE2 as a potential therapeutic target. Cancer cells often exhibit increased lipid uptake, synthesis, and storage, but the underlying mechanisms driving this metabolic reprogramming have remained largely unclear.
Researchers employed a multi-omics approach – encompassing proteomics, lipidomics, and N-terminomics – combined with advanced imaging and functional assays to dissect BACE2’s role in lipid regulation. They discovered that BACE2 regulates lipid uptake through the shedding of lipid transporters. This shedding process impacts how cancer cells acquire and utilize fats, ultimately influencing their proliferation.
Analysis of patient tumor biopsies and cancer cell lines revealed a strong positive correlation between BACE2 expression, lipid metabolism, and the accumulation of lipid droplets (LDs). Interestingly, the availability of lipids outside the cell modulates BACE2 protein levels, suggesting a feedback loop between lipid metabolism and BACE2 activity.
The study builds upon growing evidence of BACE2’s broader role in cancer. Previous research has indicated that BACE2 is upregulated in various human cancers and contributes to tumor growth, and progression. A publication in the Journal of Experimental & Clinical Cancer Research noted that BACE2 may promote cancer growth either by modulating the surrounding microenvironment or through a cell-autonomous mechanism.
More recently, research has highlighted BACE2’s influence on the tumor immune microenvironment. A study published by Research Square demonstrated that BACE2 plays a critical role in modulating immune-related gene expression and promoting immune cell infiltration within tumors. Specifically, the research showed that knocking down BACE2 inhibited M2 macrophage polarization – a process often associated with tumor progression – and suppressed lung tumor growth.
The Research Square study also found that inhibiting BACE2 enhanced the efficacy of both Sorafenib, a targeted therapy, and PD-L1 inhibitors, a type of immunotherapy, in lung cancer models. This suggests that targeting BACE2 could potentially improve the effectiveness of existing cancer treatments.
the Research Square study identified BACE2 as a prognostic biomarker, meaning its expression levels can help predict patient outcomes. Higher BACE2 expression was associated with poorer outcomes in multiple cancers.
The findings from IFOM and other research groups suggest that BACE2’s role extends beyond its previously known function in Alzheimer’s disease. BACE2 is a beta-secretase, an enzyme involved in the processing of amyloid precursor protein, which is implicated in the development of Alzheimer’s. However, this research demonstrates that BACE2 has distinct and significant functions in cancer metabolism.
Researchers are now exploring potential therapeutic strategies to target BACE2. Further analysis of the BACE2 cleavage site on the low-density lipoprotein receptor (LDLR) and clinical drugs already designed to target BACE2 for Alzheimer’s disease treatment could provide avenues for developing new cancer therapies, particularly for tumors that exhibit high ENO1 expression.
While these findings are promising, it’s important to note that research is ongoing. Further studies are needed to fully understand the complex role of BACE2 in different types of cancer and to develop safe and effective BACE2-targeted therapies. The potential for enhancing existing treatments by inhibiting BACE2 represents a significant step forward in cancer research, offering hope for improved patient outcomes.
