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

Jack Freeland ¹, Maria Muñoz ², Edmond O'Donnell ³

¹Department of Molecular and Medical Pharmacology, Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, California.
²Division of Hematology/Oncology, Department of Internal Medicine, University of California, Davis, Sacramento, California.
³Department of Orthopaedic Surgery, University of California, Davis, Sacramento, California.
⁴Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, California.
⁵Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, California.
⁶Biochemistry, Molecular, Cellular, and Developmental Biology Graduate Group, University of California, Los Angeles, Davis, California.
⁷Division of Surgical Oncology, Department of Surgery, University of California, Davis, Sacramento, California.
⁸Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, California.
⁹Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California.
¹⁰Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California.
¹¹Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, California.
¹²Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California.
¹³Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California.

⁰Department of Molecular and Medical Pharmacology, Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, California.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research +

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August 23, 2024

View abstract on PubMed

Summary

Researchers identified YAP1 and KRAS as key drivers in high-grade sarcomas, transforming stem cells into distinct subtypes. Targeting YAP1 and oxidative phosphorylation shows promise for treating these aggressive cancers.

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.

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