Intratumoral heterogeneity in dedifferentiated liposarcoma

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Joshua Waterfall, PhD,  Institut Curie (France)
Recipient of the: $50,000 Jay Vernon Jackson Memorial Research Award

Soft tissue sarcomas are a rare entity of very heterogeneous tumors, both epidemiological, histological and molecular. Clinically, sarcomas can occur at any age of life and develop throughout the body. They are associated with a generally unfavorable prognosis, with local relapse and metastatic spread in more than one third of the cases, across subtypes.
Liposarcomas (LPS) are one of the most common soft tissue sarcoma subtypes. The incidence peaks between the ages of 40 and 60. The most common LPS subtype is well-differentiated liposarcoma (WDLPS), in which cancer cells resemble highly differentiated adipose cells. While WDLPS carries a relatively good prognosis, it can transform into dedifferentiated liposarcoma (DDLPS), which is highly aggressive. These tumors are characterized by significant rates of local recurrence and metastasis. At the anatomic-pathological level, DDLPS present major intra-tumoral cellular heterogeneity, with tumour areas more or less differentiated as well as significant amounts of non-malignant microenvironment cells, particularly immune-infiltration.
Very few molecular studies have investigated intra-tumoral heterogeneity of soft tissue sarcomas. Tumor heterogeneity is recognized as a factor in pathogenesis, and is most likely involved in tumor progression and treatment resistance because of the existence of subpopulations of refractory cells. Additionally, DDLPS has shown promising responses to immune checkpoint blockade, with upwards of 30% of patients responding, albeit in small cohorts. The effective clinical application of immunotherapy in DDLPS requires significantly deeper understanding of the immune contexture of these tumors.

The Institut Curie is a major national reference center for clinical and surgical expertise in the care of patients with soft tissue sarcomas of the soft tissue, especially DDLPS. We have initiated a project to perform single-cell sequencing on treatment naïve surgical specimens of DDLPS. From each patient we profile both a well-differentiated component of the tumor as well as a dedifferentiated component. This includes both malignant as well as microenvironment cells in both components. In order to understand the genomic features (somatic mutations as well as copy number changes) associated with the single-cell results, this proposal is to additionally perform whole exome sequencing of both histological components of the tumor as well as germline DNA from each patient.