Targeting tumor-associated macrophage-induced IGF1/PI3K/Zic1 axis triggers SHH medulloblastoma regression and chemosensitization

Abstract

Background: Tumor-associated macrophages (TAMs) are key contributors to the brain tumor microenvironment. However, their role in medulloblastoma (MB) progression and chemoresistance remains elusive.

Methods: We utilized the CD11b-diphtheria toxin receptor (DTR)/Ptch1-deficient MB model to genetically delete TAMs. NeuroD2-SmoA1 MB mice were treated with CSF1R inhibitor PLX3397, PI3K inhibitor buparlisib, and a combination of PLX3397 with chemotherapy to examine the functional significance of TAMs in MB. Tumor tissues and cell co-culture system were analyzed using RNA sequencing (RNA-seq), Western blotting, flow cytometry, immunohistochemistry, quantitative polymerase chain reaction, and EdU assay to delineate mechanistic interactions.

Results: Myeloid-derived TAMs were abundant in MB tissues and primarily exhibited M2-like polarization. We demonstrated that TAM depletion, achieved either genetically via diphtheria toxin or pharmacologically via PLX3397-mediated preferential targeting of M2-like TAMs, markedly downregulates Zic1 expression and impedes MB growth. Mechanistically, M2-like TAMs secreted high levels of IGF1 to activate the PI3K/mTOR/Zic1 axis in MB cells, whereas the PI3K inhibitor buparlisib effectively reduced the population of Zic1-expressing cells and restricted MB growth. Notably, the PI3K/mTOR/Zic1 axis was demonstrated to confer chemoresistance. While chemotherapy exacerbates M2-like TAM accumulation within MB, combining PLX3397 with chemotherapy abrogates this infiltration and attenuates IGF1/PI3K/Zic1 signaling axis. This combination strategy synergistically inhibits tumor growth and extends survival in mice.

Conclusion: Our findings demonstrate that inhibiting the TAM-induced IGF1/PI3K/Zic1 signaling axis results in MB regression and chemosensitization. These results underscore the therapeutic potential of combining a clinical CSF1R inhibitor with standard chemotherapy as an effective treatment strategy for SHH-MB.

Keywords: IGF1; PI3K; Zic1; medulloblastoma; tumor-associated macrophages.