Genetic Screen in a Preclinical Model of Sarcoma Development Defines Drivers and Therapeutic Vulnerabilities

Area of Science:

• Oncology
• Cancer Genomics
• Sarcoma Research

Background:

• High-grade complex karyotype sarcomas are aggressive and difficult to treat.
• Identifying clinically relevant genetic drivers in these heterogeneous tumors remains a challenge.

Purpose of the Study:

• To identify key genetic drivers and modifiers of sarcoma development.
• To validate these drivers in vivo and investigate sarcoma subtype heterogeneity.
• To discover potential therapeutic vulnerabilities in aggressive sarcomas.

Main Methods:

• Utilized a pooled genetic screening approach informed by The Cancer Genome Atlas (TCGA) data.
• Validated identified drivers (YAP1, KRAS, CDK4, PIK3CA) in vivo by transforming human mesenchymal stem cells.
• Performed differential gene expression analysis comparing TCGA samples to model tumors.
• Treated soft tissue sarcoma cell lines with a combination of YAP1 and oxidative phosphorylation inhibitors.

Main Results:

• YAP1 and wild-type KRAS were validated as drivers, generating undifferentiated pleomorphic sarcoma and myxofibrosarcoma models.
• CDK4 and PIK3CA drove leiomyosarcoma and osteosarcoma models, demonstrating approach plasticity.
• Generated tumors showed histological resemblance to human sarcomas with increased aneuploidy.
• YAP1-driven tumors exhibited increased oxidative phosphorylation signaling.
• Combined YAP1 and oxidative phosphorylation inhibition significantly reduced sarcoma cell viability.

Conclusions:

• YAP1 and KRAS drive distinct sarcoma subtypes, suggesting they lie on a disease spectrum.
• This approach aids in understanding sarcoma development, heterogeneity, and therapeutic targets.
• Transcriptional co-analysis provides guidance for refining sarcoma subtyping.
• Identified a potential therapeutic strategy combining YAP1 and oxidative phosphorylation inhibition for aggressive sarcomas.