MPNST (malignant peripheral nerve sheath tumors) are highly aggressive soft tissue sarcomas of Schwann cell (SC) origin, representing a major cause of mortality in neurofibromatosis (NF) patients, which affects 1 in 3500 individuals worldwide. The prognosis of MPNST patients is dismal due to invasive tumor growth, metastatic proclivity and resistance to radiation and conventional chemotherapy, posing an urgent need for improved effective therapeutic modalities for this challenging disease.
MPNST are heterogeneous tumors with a distinct microenvironment that contributes to the establishment of a tumor niche. Cancer behaviors including progression, metastasis and drug resistance cannot be fully defined by genetic mutations alone, but are critically dependent on intercellular communication between tumor cells and the microenvironment. Targeting stromal cells within the tumor microenvironment has been shown to reduce risk of therapeutic resistance in cancers. However, currently, a comprehensive understanding of tumor cell lineage evolution and cell-cell communication network in MPNST is lacking. Studying single cells provides unique insights into tumor cell state evolution and cell diversity within a tumor. I hypothesize that a comprehensive profiling of tumor cellular heterogeneity at a single-cell level will open new opportunities for identifying molecular and cellular determinants underlying malignant transformation and drug resistance in MPNST. Our study will integrate regulatory chromatin landscape and DNA methylation profiling in NF and MPNST using ATAC-seq and bisulfite sequencing at single-cell resolution and will identify novel enhancers and transcription regulators that drive NF-to-MPNST transformation. We will propose the following specific aims:
Specific Aim 1 is to define cellular heterogeneity during SC malignant transformation using MPNST animal models at different stages of tumorigenesis.
Specific Aim 2 is to identify transcriptional and epigenetic regulatory networks governing human NF-to-MPNST transition and drug resistance by single-cell and multi-omics approaches.
Our aggressive murine MPNST model provides a unique opportunity for dissecting mechanisms of SC malignant transformation. 1) We will determine cellular diversity and microenvironment changes by single-cell transcriptomics in mouse models of NF and MPNST. 2) We will define cellular heterogeneity and characterize epigenetic variability and the core transcriptional circuitry governing a) human NF-to-MPNST transition and b) drug resistance, by multi-omics approaches (e.g. single-cell RNA-seq, ATAC-seq and single-cell bisulfite-seq).
Our goal is to define dynamic gene regulatory networks and microenvironment niche for driving malignant transformation of NF and identify therapeutic targets of MPNST using pre-clinical animal models and patient samples. The outcome of studies should establish a proof-of-principle for therapeutic interventions for NF1-associated MPNST.