While OS cells show a high propensity to disseminate to the lung, only 15% - 20% of newly diagnosed OS are successfully diagnosed with macrometastasis. Genome-wide high-throughput sequencing revealed that metastatic OS exhibited a significantly higher mutational burden including TP53 mutations and genomic instability compared with primary OS.
Establish and characterize new OS GEMM
To address mechanistic insight into OS metastasis, we have generated cell-type specific inducible (tet-on system based) c-Fos gain-of-function and p53 loss-of-function mice. We are investigating the kinetics of primary tumor growth and metastasis with/without c-Fos expression.
Characterize genomic alterations in OS development
To characterize genomic evolution during OS development, we will investigate genome sequence, genome-wide histone modifications and chromatin accessibility by whole genome sequencing, ChIP-seq and ATAC-seq in primary and metastasized OS cells.
Explore functions of Loxl2 in metastasis
We aim to determine Loxl2 functions in OS metastasis. Loxl2 regulates collagen modification but also contributes to transcriptional regulations.
- Unbiased approach: Identify novel Loxl2 substrates by isolating oxidized protein in OS cells
- Hypothesis-based approach: focus on chromatin modifications and transcriptional regulations by c-Fos and Loxl2 in OS metastasis.