Therapeutic progress in well differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS) is hampered by lack of relevant experimental models, thereby limiting comprehensive molecularly-based investigations. Our goal is to bridge this experimental gap by establishing and characterizing an in vitro/in vivo model useful for examining WDLPS/DDLPS molecular pathogenesis and also therapeutic screening and testing. WDLPS/DDLPS cells were isolated from freshly resected human surgical specimens and phenotypically and molecularly characterized. MDM2 amplification was determined via FISH analysis. Adipogenic differentiation was evaluated using Oil Red O staining and western blotting (WB). Tyrosine kinase receptors' (TKRs) expression in pre-adipocytes, adipocytes, WDLPS, and DDLPS cells was determined via western blot analysis. SCID mouse xenograft growth was assessed after subcutaneous and/or intraperitoneal tumor cell injection. There was enhanced proliferation, migration, invasion, survival and pro-angiogenic capacity in DDLPS cells versus WDLPS cells. DDLPS cells formed tumors in SCID mice whereas WDLPS did not. WDLPS/DDLPS cells, especially those that exhibited baseline PPARγ expression, partially retained terminal adipogenic differentiation capacity. MDM2 amplification was found in all WDLPS/DDLPS cell strains, CDK4 over-expression was observed in LPS cells as compared to normal adipocytes, and enhanced JUN expression and phosphorylation was seen in DDLPS cells as compared to WDLPS cells. The TKRs: MET, AXL, KIT, and IGF-1R were overexpressed in LPS cells versus normal adipocytes and pre-adipocytes. In conclusion: these newly established cellular and xenograft models can facilitate investigation of liposarcomagenesis, dedifferentiation, and tumor progression. Further studies of the molecular deregulations so identified may lead to improved therapeutic strategies for patients afflicted by these unfavorable malignancies.
Cancer immunotherapies with monoclonal antibodies (mAb) against exhaustion-associated surface molecules, known as immune-checkpoints, reactivate T cells cytotoxic for cancers, and significantly improve survival of patients with various types of cancer. These immunecheckpoint inhibitors are directed against cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1), and disruption of their interactions improves the intermediate-term prognosis even in patients with advanced stage IV melanoma. As the immune system is able to kill tumor cells, it is not astonishing that cancer cell killing has also been demonstrated during immune checkpoint inhibitor therapies. Preclinical data, however, has shown that anti-cancer immunity is not limited to killing cancer cells, and other mechanisms, such as permanent growth arrest or cellular senescence may play an important role as well. Here, we first show that treatment of humans with immune-checkpoint inhibitors induced, besides killing, interferon-dominated type I immunity and senescence in regressing melanoma metastases. To investigate the underlying mechanisms in more detail, we analyzed immune checkpoint inhibitors in advanced solid cancers of RIP1-Tag2 mice, expressing large T antigen (Tag) under the insulin promoter. Besides partial killing of tumor cells, therapy with immune-checkpoint inhibitors induced type I immunity, a p16 INK4a+ /Ki67senescent phenotype in the remaining cancer cells, and restored long-term survival. In clear contrast, cancers of RIP1-Tag2xSTAT1-/mice, deficient in interferon-gsignaling, were resistant to interferon-induced senescence, both in vitro and in vivo. As a consequence, therapy of STAT1-deficient cancers with immune-checkpoint inhibitors in RIP1-Tag2xSTAT1-/mice completely failed. Thus, cancer control by immunotherapy with immune-checkpoint inhibitors strictly requires Stat1-dependent cancer cell senescence.
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