Mechanisms of myeloid cell- tumor cell interactions in senescence induction and progression of pediatric low-grade glioma

• Applicants: Professor Dr. Kornelius Kerl; Professor Dr. Till Milde
• Subject Area: Pediatric and Adolescent Medicine ; Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549021161

Pediatric low-grade gliomas (pLGGs) are the most common pediatric brain tumors. Despite a generally favorable overall survival, patients often suffer from high tumor- and therapy-related morbidity and multiple recurrences. Hence, there is a critical need for a better understanding of the biological characteristics of pLGG, coupled with the development of new therapies. pLGGs are a single pathway-driven disease activating the mitogen-activated protein kinase (MAPK) pathway, which is associated with an integral biological feature of pLGG, the oncogene-induced senescence. These molecular hallmarks contribute to the typically slow-growing nature of these tumors, resulting in a limited responsiveness to chemotherapy. In contrast to these shared general features, distinct parameters impact the clinical behavior of these tumors, including histopathological and molecular subgroups, age of the patients, location of the tumor and molecular alterations. A variety of targeted agents inhibiting MAPK signaling showed principle efficacy, but only 30-50% of patients responded partially or better. The biological background of the differential responses to MAPK inhibition and to chemotherapy in genetically identical pLGGs is not understood. We have recently described gene expression signatures indicating sensitivity to MAPK inhibition. Unexpectedly, our data support a role of the tumor microenvironment (TME), specifically of microglia, in the response of pLGGs to MAPKi, emphasizing the critical role of MAPK activity in microglia. Therefore this project first aims at a deeper understanding of mechanisms how pLGG tumor cells interact and influence myeloid cells and vice versa. This knowledge will potentially result in innovative target directed treatments by manipulating tumor-TME interactions. The second main objective is to unravel the influence of cellular heterogeneity and cellular interactions on clinically important aspects of pLGG, such as: i.) progression, ii.) therapy response and iii.) tumor behavior after treatment. These insights will guide to better selection of different therapeutic options for distinct pLGG patients. More specifically we will address the following scientific questions by: 1) unravel mechanisms how tumor cells influence the infiltrating myeloid cell diversity and vice versa by analyzing a large and well molecularly and clinically annotated pLGG cohort (LOGGIC core cohort) by using single cell RNA sequencing and spatial transcriptomics; 2) functionally analyze tumor-immune cell interactions in vitro, using a) co-cultures of pLGG cell lines and microglia in 2D, b) organoid pLGG tissue co-culture; 3) describe targetable mechanisms of tumor cell-immune cell interaction impacting tumor cell growth and survival in preclinical model systems; 4) provide preclinical data sufficient for the design of future clinical trials targeting these mechanisms of tumor cell-immune cell interaction.

• DFG Programme: Research Grants