bims-myxlip 2021-08-15 papers

Issue of 2021–08–15
three papers selected by
Laura Mannarino, Humanitas Research

Hum Cell. 2021 Aug 12.

Establishment and characterization of NCC-MFS4-C1: a novel patient-derived cell line of myxofibrosarcoma.

Yuki Yoshimatsu, Rei Noguchi, Ryuto Tsuchiya, Yooksil Sin, Takuya Ono, Jun Sugaya, Shintaro Iwata, Akihiko Yoshida, Akira Kawai, Tadashi Kondo.

Myxofibrosarcoma (MFS) is an aggressive sarcoma with a highly complex karyotype. Complete resection is the only curative treatment for MFS because it is refractory to chemotherapy. To improve clinical outcomes, it is critical to develop novel treatments for MFS. Although patient-derived cell lines play a key role in cancer research, only 12 MFS cell lines have been reported to date, and considering the diversity of the disease, more cell lines need to be established. Hence, in the present study, we established a novel MFS cell line, NCC-MFS4-C1, using a surgically resected tumor tissue from a patient with MFS. NCC-MFS4-C1 cells exhibited copy number alterations similar to those of the original tumors and showed constant proliferation, spheroid formation, and aggressive invasion. By screening a drug library, we found that actinomycin D, bortezomib, docetaxel, eribulin, and romidepsin significantly reduced the proliferation of NCC-MFS4-C1 cells. Therefore, the NCC-MFS4-C1 cell line may be a useful resource for researching MFS.

Keywords: Drug screening; Myxofibrosarcoma; Patient-derived cancer model; Patient-derived cell line; Sarcoma

DOI: https://doi.org/10.1007/s13577-021-00589-x

Cancer Res. 2021 Aug 12. pii: canres.1497.2020. [Epub ahead of print]

Radiation-induced phosphorylation of a prion-like domain regulates transformation by FUS-CHOP.

Mark Chen, Joseph P Foster, Ian C Lock, Nathan H Leisenring, Andrea R Daniel, Warren Floyd, Eric Xu, Ian J Davis, David G Kirsch.

Chromosomal translocations generate oncogenic fusion proteins in approximately one-third of sarcomas, but how these proteins promote tumorigenesis is not well understood. Interestingly, some translocation-driven cancers exhibit dramatic clinical responses to therapy, such as radiotherapy, though the precise mechanism has not been elucidated. Here we reveal a molecular mechanism by which the fusion oncoprotein FUS-CHOP promotes tumor maintenance that also explains the remarkable sensitivity of myxoid liposarcomas to radiation therapy. FUS-CHOP interacted with chromatin remodeling complexes to regulate sarcoma cell proliferation. One of these chromatin remodelers, SNF2H, co-localized with FUS-CHOP genome-wide at active enhancers. Following ionizing radiation, DNA damage response kinases phosphorylated the prion-like domain of FUS-CHOP to impede these protein-protein interactions, which are required for transformation. Therefore, the DNA damage response after irradiation disrupted oncogenic targeting of chromatin remodelers required for FUS-CHOP-driven sarcomagenesis. This mechanism of disruption links phosphorylation of the prion-like domain of an oncogenic fusion protein to DNA damage after ionizing radiation and reveals that a dependence on oncogenic chromatin remodeling underlies sensitivity to radiation therapy in myxoid liposarcoma.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-1497

Biochim Biophys Acta Rev Cancer. 2021 Aug 06. pii: S0304-419X(21)00103-7. [Epub ahead of print] 188606

Targeted and immuno-based therapies in sarcoma: mechanisms and advances in clinical trials.

Fan Tang, Yan Tie, Yu-Quan Wei, Chong-Qi Tu, Xia-Wei Wei.

Sarcomas represent a distinct group of rare malignant tumors with high heterogeneity. Limited options with clinical efficacy for the metastatic or local advanced sarcoma existed despite standard therapy. Recently, targeted therapy according to the molecular and genetic phenotype of individual sarcoma is a promising option. Among these drugs, anti-angiogenesis therapy achieved favorable efficacy in sarcomas. Inhibitors targeting cyclin-dependent kinase 4/6, poly-ADP-ribose polymerase, insulin-like growth factor-1 receptor, mTOR, NTRK, metabolisms, and epigenetic drugs are under clinical evaluation for sarcomas bearing the corresponding signals. Immunotherapy represents a promising and favorable method in advanced solid tumors. However, most sarcomas are immune "cold" tumors, with only alveolar soft part sarcoma and undifferentiated pleomorphic sarcoma respond to immune checkpoint inhibitors. Cellular therapies with TCR-engineered T cells, chimeric antigen receptor T cells, tumor infiltrating lymphocytes, and nature killer cells transfer show therapeutic potential. Identifying tumor-specific antigens and exploring immune modulation factors arguing the efficacy of these immunotherapies are the current challenges. This review focuses on the mechanisms, advances, and potential strategies of targeted and immune-based therapies in sarcomas.

Keywords: Adoptive cell transfer; Immunotherapy; Sarcoma; Targeted therapy

DOI: https://doi.org/10.1016/j.bbcan.2021.188606