Targeting the Cancer Stem Cells in Malignant Peripheral Nerve Sheath Tumor

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Project Summary Malignant peripheral nerve sheath tumor (MPNST) is a type of soft tissue sarcomas deeply associated with nerves. The clinical observation and mouse model studies indicate the vital role of the nerve microenvironment in MPNST tumorigenesis, but the mechanism is still not clear. Our recent data showed a stem-like tumor cell population in both primary human MPNST and MPNST mouse models. The cancer stem cell (CSC) population in mouse MPNSTs can be labeled by a transgene that was also expressed in the neural crest stem cell, the cell-of-origin of NF1-associated tumors. The CSCs demonstrated significantly high potentials to generate new tumors in sciatic nerve transplantation and the metastases by intracardiac injection. The nerve-enriched tumor microenvironment and the consistent high ERBB3 expression between neural crest stem cells and CSCs strongly suggest the neuregulin1 (NRG1)-ERBB3 signaling, which regulates early Schwann cell lineage development, can contribute to the tumor initiation. CD44 facilitates the ERBB2 and ERBB3 heterodimer formation and promotes the downstream focal adhesion kinase, boosting the metastatic phenotype. Interestingly, the CD44 can be upregulated through loss of function of TP53 and activated ERK signaling that are also the two critical determinants for MPNST malignant progression. Therefore, we will test the central hypothesis that targeting the NRG1-ERBB3-CD44 positive feedback loop can inhibit tumor initiation and CSC- related metastasis. Using a novel transgenic mouse model and humanized MPNST models, we will pursue three aims 1) To test the hypothesis that disruption of the NRG1-ERBB3-CD44 loop blocks MPNST growth and progression. 2) To test whether hyaluronan-CD44-PAK2 signaling is critical for MPNST CSC-initiated metastatic seeding and growth. 3) To evaluate the therapeutic potential of targeting the ERBB3-CD44 axis combined with ERK inhibition on humanized MPNST models. We expect the 1) ERBB3-targeted treatment will inhibit the tumor growth, 2) CD44-targeted treatment can attenuate the CSC-induced metastasis, and 3) we can prove the principle of therapeutic effects on MPNST xenograft models and through combination with MEK inhibitor to suppress the single-drug induced resistance. These discoveries may fill the gap in MPNST tumorigenesis and metastasis and pave the path for innovative translational study and clinical application.