Investigate Extracellular Matrix Proteins Local and Systemic Role in Promoting Soft Tissue Sarcoma
Abstract
Sarcoma is one of the Peer Reviewed Cancer Research Program (PRCRP) Topic Areas for the fiscal year 2022 (FY22). Our proposed research addresses this critical topic by developing new and more effective therapies for different subtypes of soft tissue sarcomas (STS) with a high risk of recurrence and death. Surgical resection and chemotherapy are the mainstay treatments for STS; however, many sarcomas relapse after the treatment and often metastasize to the lungs. When this happens, the 5-year survival rate is below 20%. Thus, a major clinical challenge is understanding how to treat the primary lesions better and eradicate all the tumor cells to prevent their later relapse and metastasis. In the past decade, our understanding of sarcoma biology has advanced. However, previous studies have failed to dissect the sarcoma composition at the single-cell scale necessary to provide a detailed portrait of the lesion. That is, previous approaches analyzed the properties of the entire bulk of the tumor mass without distinguishing between the different cells that compose it. In so doing, many details have been lost. For example, these methods could not distinguish between tumor cells and the non-malignant ones that infiltrate the tumor lesion, such as different types of immune cells. To overcome this limitation, our laboratory has employed cutting-edge technologies that allow the characterization of sarcoma mass at the single-cell level, such as single-cell RNA- sequencing. These new technologies enable novel studies of the tumor s immune microenvironment, and will foster the discovery of new mechanisms used by the tumor cells to suppress their immune neighbors, which have been neglected in previous studies. Additionally, the lack of adequate mouse models for preclinical testing has hindered the advancement of sarcoma therapies, in particular novel approaches of immunotherapy. Most of the sarcoma mouse models used in previous investigations could not recapitulate critical traits of the disease, such as the presence of immune cells in the tumor mass, which are known to play critical roles in tumor progression. Accordingly, these mouse models cannot be used to develop or evaluate novel immunotherapies, which aim to target the immune cells or the interaction mechanisms between tumor and immune cells instead of directly targeting tumor cells. Our laboratory has recently developed immunocompetent mouse models of soft tissue sarcoma to tackle this problem. Using these models, we have discovered new potential therapeutic targets, Periostin and Osteopontin, secreted by the sarcoma cells to dampen antitumor immune responses. Our proposal intends to study the molecular involvement of the identified targets in sarcoma progression and, in parallel, test their blockade. Discoveries in this vein should bolster conventional treatments such as chemotherapy or enable the application of immunotherapies that have been previously unsuccessful. The proposed investigations have the potential to generate preclinical data that may directly impact future clinical trials of soft tissue sarcoma. This proposal will address two of the FY22 PRCRP Overarching Challenges: (1) Transform cancer treatment through the identification of new targets, especially for advanced disease and metastasis. (2) Advance immunotherapy across the different PRCRP Areas. The proposed investigation will increase the number of military personnel who undergo curative resection of soft tissue sarcoma to facilitate their return to duty. Veterans, who have been exposed in the past years to herbicides, will also benefit from this study. Achieving a cure for soft tissue sarcoma will profoundly impact the health and well-being of Service Members, their families, Veterans, and the general American population.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310775
Entities
People
- Jlenia Guarnerio
Organizations
- Cedars-Sinai Medical Center
- United States Army