Saturday, April 26, 2025
4/26/2025
DISSECTING THE ROLES OF FAT1 AND NEAT1 IN SOFT TISSUE SARCOMA DEVELOPMENT AND METASTASIS USING NOVEL IN VIVO SARCOMA MODELS - Soft tissue sarcomas (STSs) are rare heterogeneous mesenchymal tumors that have more than 75 subtypes. STSs are understudied tumors for which there are few established research models and a lack of funding sources. Over decades, there has been little improvement in the therapeutic strategies for STSs, which are often resistant to current therapies and can be frequently fatal as 50% of patients develop metastasis in distant organs. To solve this unmet clinical problem, in vivo models that accurately recapitulate this spectrum of cancers provide a unique and effective platform for studying sarcoma biology and preclinical trials before novel therapeutic strategies translate to limited population of sarcoma patients. However, there are very few in vivo sarcoma models available because the tumor suppressor and oncogenic drivers for sarcoma development and metastasis remain unknown. Therefore, I performed genome-wide in vitro genetic screens and direct in vivo CRISPR/Cas9 knockout screens in wild type mice to identify driver genes whose mutation is required for sarcoma initiation. From these screens, I generate a novel in vivo sarcoma model driven by the mutation of Fat1 which is frequently mutated in human STSs. This is a de novo in vivo model that recapitulates a subset of human STSs and, to our knowledge, the first determination that Fat1 is a potent tumor suppressor in human STSs. Furthermore, using in vivo sarcoma models and high throughput RNA sequencing, I also identified the long non-coding RNA (lncRNA) Neat1 as an oncogenic driver for sarcoma metastasis. This K22 award will allow me to build my own research platform to further characterize the critical signaling pathways and target genes in sarcoma development and metastasis using these unique in vivo sarcoma models. In Specific Aim 1, we will dissect the mechanism by which the Hippo pathways and their effectors Yap1/Taz drive sarcomas through the mutation of Fat1. In addition, we will use my novel in vivo sarcoma models to test and optimize the best combination treatment strategies that suppress sarcoma tumor growth. In Specific Aim 2, we will determine the mechanisms by which lncRNA Neat1 drives sarcoma metastasis. My preliminary results suggest that RNA splicing regulating genes, such as Khsrp, interact with Neat1 and promote sarcoma metastasis. We will use my unique in vivo sarcoma models to dissect the mechanisms governing sarcoma metastasis and the implications of these genes for targeted therapies in treating metastatic sarcoma patients. In conclusion, completion of this proposal will determine the functional consequences of expression of the coding gene Fat1 and the non-coding gene Neat1 in sarcoma development and metastasis and provide novel candidate pathways and genes for designing effective targeted therapies to improve outcomes for sarcoma patients.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).