Optimal Factors That Influence the Establishment of Successful Primary Human Soft-Tissue Sarcoma Cell Lines.

Abstract

The development of improved therapies is complicated by the limited availability of well-characterized human models, especially in rare tumors such as soft-tissue sarcoma (STS). We report the optimization of conditions and clinical factors that correlate with the successful establishment of primary STS cell lines. We focus on leiomyosarcoma, myxofibrosarcoma, and undifferentiated pleomorphic sarcoma, which are adult STS with complex genomics and poor survival rates. We initiated cell lines from 165 fresh STS specimens. Cultures were classified as (i) no/little in vitro growth or (ii) persistent growth. Tumor and clinical characteristics were analyzed to determine their correlation with cell line growth. To determine whether cell lines shared tumor-specific variations (TSV) and mutational signatures with bulk specimens, comparative and Catalogue of Somatic Mutations in Cancer mutational signature analyses were performed on a subset of cases with cell line, tumor, and blood DNAs available. Cell lines were established from 46 specimens (28%). Myxofibrosarcoma specimens yielded more successful cell lines (P < 0.05) than leiomyosarcoma specimens. Primary specimens from treatment-naïve patients and those who presented with metastases demonstrated higher success rates (P < 0.05) compared with treated specimens and those who had only local disease, respectively. Cell line growth was not associated with patient outcomes or specimen grade. Six of the eight cases retained TSVs, including in ATRX or TP53, whereas two did not retain TSVs. Paired samples shared clock-like mutational signatures. Xenograft mouse models were created with a subset of the cell lines. The development and characterization of preclinical STS models will advance our understanding of STS biology.