Craniopharyngiomas are types of brain tumors that adversely affect the hormonal functions of the adjacent pituitary gland. Their positioning often makes surgical removal challenging. Effective pharmaceutical treatment necessitates comprehensive knowledge of the tumor’s molecular features. To fill this knowledge gap, a team of researchers from Japan examined gene expression at the single-cell level within these tumors. Their findings outline the molecular traits and interactions of tumor and immune cells related to two specific subtypes of craniopharyngiomas, paving the way for the discovery of future targeted treatments.
Craniopharyngioma (CP) is an uncommon brain tumor found near the hypothalamus and pituitary gland. These tumors can lead to complications such as vision problems, neurological issues, diabetes, and developmental challenges. There are two main CP subtypes: adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP), which are differentiated based on their unique genetic characteristics. ACP commonly exhibits mutations in the CTNNB1 gene, whereas PCP is primarily linked to mutations in the BRAF gene.
Typically, surgery is the first-line treatment for CP. However, the tumor’s invasive nature and its proximity to vital structures create significant difficulties for surgical procedures. As the tumor grows, it spreads into surrounding tissues, leading to serious neurological deficits. Consequently, surgery alone is often inadequate for addressing the complex issues posed by CPs. A complete understanding of the tumor’s biological features and molecular evolution is crucial to ensure effective tumor removal without damaging nearby healthy tissue.
In response to this challenge, Professor Tomoaki Tanaka joined forces with Professors Yoshinori Higuchi and Dr. Takashi Kono from Chiba University’s Graduate School of Medicine, conducting research that delves into the biological mechanisms at play in these tumors. Their study was made publicly available online on September 30, 2024, and subsequently published in the journal iScience’s November 15, 2024, issue (Volume 27, Issue 11). They employed single-cell RNA sequencing, a method that highlights differences in gene expression among individual cells, to analyze 10 CP cases.
During an interview, Prof. Tanaka, the lead author, shared the study’s purpose, stating, “Even though these tumors are benign in terms of histology, they pose a significant threat to crucial brain structures.” He added, “We aim to develop more targeted, less invasive therapy options that could greatly enhance patients’ outcomes and quality of life.”
The single-cell analysis uncovered a wide variety of cell types in the tumor microenvironment (TME), including tumor cells, immune cells, and fibroblasts, with varying distributions across different cases. Tumor cells were categorized into two primary types: Type 1, prevalent in ACP, and Type 2, dominant in PCP. By clustering single-cell gene expression data, the researchers identified distinct cell types within the tumors corresponding to the development of epithelial cells and the immune response, with a notable presence of cell types associated with tumor calcification in ACP and cell cycle-related genes in PCP.
Moreover, the research team found a significant variation in macrophage types between the two subtypes. The pro-inflammatory M1 macrophages and related inflammatory markers were found in higher amounts in ACP, while the anti-inflammatory M2 macrophages were more prominent in PCP. This suggests that a greater balance of M1 and M2 macrophages is linked to the development of conditions like diabetes and pituitary dysfunction.
The study also identified an important interaction between cell surface proteins CD44 and secreted phosphoprotein 1 (SPP1). This SPP1-CD44 signaling pathway originating from classical M2 macrophages inhibited the prolonged growth of T cells.
Overall, this research offers a detailed profile of the different cell types present in CP tumors and highlights a significant connection between immune cells and clinical symptoms.
Prof. Tanaka pointed out the clinical relevance of their findings, stating, “Our research opens the door to personalized treatment strategies for CP patients tailored to their specific tumor subtype and immune cell makeup. Recognizing these differences will also aid clinicians in anticipating which patients may face a higher risk for complications like diabetes insipidus.”
Looking ahead, these findings may facilitate the development of new targeted therapies designed to specifically modulate the tumor microenvironment and interactions with immune cells, ultimately resulting in more effective treatments with fewer side effects.
