Investigating Intratumoral Heterogeneity and Outcomes in Myxoid/Round Cell Liposarcoma
Myxoid/round cell liposarcoma (MRLS) is a rare subtype of soft tissue sarcoma that typically affects young adults in their 30s to 40s. It most commonly arises within the thigh muscles but can also arise elsewhere. While some patients can be cured with surgery, others have tumors that have metastasized to other parts of the body, which are much more difficult to treat. These patients are typically treated with traditional chemotherapy, but the tumors almost always eventually become chemotherapy-resistant, after which treatment options become very limited. Ultimately, up to 30% of patients with MRLS die of metastases within 10 years of diagnosis.
To develop new treatments for patients with advanced MRLS, we need to better understand the genetic features of these sarcomas. Much of the prior research has assumed that the key genetic changes promoting the growth of a particular MRLS tumor are shared among all cells within the tumor. However, with modern higher-resolution genetic sequencing techniques, we recently found that MRLS tumors in fact contain 2 different subpopulations of tumor cells, in which different genes are active and thus likely play different roles in promoting tumor growth, treatment resistance, and metastasis.
The goal of this project is to test the hypothesis that one MRLS tumor cell subpopulation may be more important in promoting MRLS metastasis than the other. We will: 1. Use genetic sequencing and computational algorithms to calculate the ratio of the 2 tumor cell subpopulations in MRLS tumor samples that we have collected from 110 patients between 2002 and 2022. We will then determine whether there is any association between tumor cell subpopulation ratio and risk of metastasis or death. 2. Perform additional higher-resolution genetic sequencing on a subset of 17 patients for whom we have multiple samples from both primary and metastatic tumors and compare the subpopulation composition of different tumors from the same patient. The results from our project will identify which tumor cell subpopulation is associated with metastasis. This will enable future studies to identify the genes that are active in this subpopulation as potential targets for new treatment strategies to further test in the laboratory and eventually in clinical trials.