Neuro-oncology · 2026
Targeting tumor-associated macrophage-induced IGF1/PI3K/Zic1 axis triggers SHH medulloblastoma regression and chemosensitization.
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Pang Yan-Chun, Wang Chi, Qiu Jun-Feng, Chen Hai-Xin, Deng Kaiwen, Feng Zhaoyang, Nie Menglin, Wang Yanan, Tian Yu, Su Yu, Peng Dong-Ling, Wang Han-Chen, Wu Changfeng, Chen Xuan, Yin Zhinan, Gonzalez Ricardo Daniel, Gonzalez-Salinas Fernando, Daniels Craig, Koh Hyun Yong, Santa-Maria Lopez Vicente, Zhang Jiao, Taylor Michael D, Jiang Tao, Li Peng, Liu Hailong, Liu Yong-Qiang
Аннотация
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.
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.