Investigating soft tissue sarcoma genomics to uncover driving gene events and elucidate tumor-specific oncogenic pathways
Soft tissue sarcomas are neoplasms of mesenchymal origin, comprising more than 70 histotypes that are defined by heterogenous clinical and genomic features.
While the incidence of sarcomas is lower than more common carcinomas, with approximately 13,000 estimated new cases and 5,000 deaths in the US in 2021, this heterogeneity, rarity, and complexity makes clinical care and molecular research challenging.
Our lab leads sarcoma research through multi-disciplinary approaches conducted by close collaboration of expert teams.
Genomic dissection of soft tissue sarcomas
The lab collects and intensively analyzes surgically resected tumors and applies next-generation sequencing-based approaches to better understand their genomic drivers. Through copy number analysis, transcriptomic profiling, and aberrant epigenetic profiling, our lab can identify genes and oncogenic pathways that drive tumorogenesis. By correlating these genomic analyses with extensive clinical information, we can categorize complex sarcomas into molecular subgroups and discover potential therapeutic targets for them. Development of such targeted therapies will improve overall outcomes for sarcoma patients by providing treatment strategies tailored to each tumor’s molecular features.
Soft tissue sarcoma initiation, clonal evolution, and progression
Most recently, a major focus of the lab is to understand how soft tissue sarcomas initiate and evolve over time. To this end we are analyzing individual patient tumors at single-cell resolution to identify early oncogenic genetic alterations, narrow down the cell of origin, and identify novel molecular drivers of the development and progression of various soft tissue sarcoma subtypes. Comparison of related clones between subtypes on a progression axis from indolent to more aggressive, e.g. well-differentiated to dedifferentiated liposarcoma and myxofibrosarcoma (MFS) to undifferentiated pleomorphic sarcoma (UPS), and between primary tumors and recurrences or metastases, allows us to identify which genetic events underlie progression and may represent prognostic biomarkers or therapeutic targets.
Modeling soft tissue sarcomas for preclinical drug development
Modeling of each patient’s tumor is a key approach to develop precision medicine strategies targeting its specific molecular features. To that end, the lab routinely establishes patient tumor-derived cell lines and patient-derived xenograft models in immunocompromised mice.
Development of novel targeted therapies for aggressive soft tissue sarcomas
An example of our past success in developing novel therapeutics based on genomic information obtained from a large cohort of sarcoma patients is our identification of integrin-α10, a collagen receptor on the cell surface, as a mediator of oncogenic signaling through RAC/PAK and mTORC in aggressive metastatic MFS and UPS (Cancer Discov 2016). These discoveries led us to test specific chemical inhibitors of this pathway in patient-derived models to determine their clinical potential. We are also exploring antibody-based therapeutic and diagnostic strategies for these aggressive sarcomas.
In another strategy, we conduct high-through put screening of chemical and genetic libraries to select tumor-specific differential drugs and targets that could affect cancer cells but spare normal cells. One such screen for agents capable of restoring expression of the tumor suppressor transcription factor CEBPα identified the topoisomerase I inhibitor irinotecan as effective against dedifferentiated liposarcoma (Clin Cancer Res 2021).