bims-myxlip 2022-02-06 papers

Issue of 2022–02–06
four papers selected by
Laura Mannarino, Humanitas Research

Hum Cell. 2022 Feb 03.

Establishment and characterization of NCC-UPS4-C1: a novel cell line of undifferentiated pleomorphic sarcoma from a patient with Li-Fraumeni syndrome.

Takuya Ono, Yuki Yoshimatsu, Rei Noguchi, Yooksil Sin, Ryuto Tsuchiya, Taro Akiyama, Jun Sugaya, Suguru Fukushima, Naoki Kojima, Akihiko Yoshida, Akira Kawai, Tadashi Kondo.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by a germline mutation of the TP53. The lifetime risk of cancer in individuals with LFS is ≥ 70% for men and ≥ 90% for women. Undifferentiated pleomorphic sarcoma (UPS) is one of the core cancers associated with LFS. UPS is a subtype of undifferentiated soft tissue sarcoma that shows no identifiable line of differentiation. The standard curative treatment for UPS is complete surgical resection. However, local recurrence and distant metastasis to the lung can usually be found after resection of the UPS. Therefore, a novel treatment strategy for patients with UPS is required. Although well characterized, patient-derived tumor cell lines facilitate the high-throughput screening of a large number of drugs, and no sarcoma cell lines derived from a patient with LFS have been registered in public cell banks. Thus, this study aimed to establish a novel, well-characterized UPS cell line from a patient with LFS. From surgically resected UPS tumor tissues, we established the first UPS cell line from a patient with LFS and named it NCC-UPS4-C1. NCC-UPS4-C1 harbored copy number alterations and had the TP53 tumor suppressor gene mutation. The cells exhibited constant cell growth and invasive ability. This well-characterized NCC-UPS4-C1 cell line was then utilized for high-throughput screening of 214 anti-cancer drugs, and two effective drugs were identified. One of the two drugs, romidepsin, was commonly effective for the NCC-UPS1-C1, NCC-UPS2-C1, and NCC-UPS3-C1 cell lines that we previously reported; a potential drug for the treatment of UPS was suggested using well-characterized UPS cell lines. These data indicate that NCC-UPS4-C1, which is the first sarcoma cell line established from a patient with LFS, enables researchers to conduct vigorous preclinical research on UPS.

Keywords: Anti-cancer drug screening; Li–Fraumeni syndrome; Patient-derived cell line; Soft tissue sarcoma; Undifferentiated pleomorphic sarcoma

DOI: https://doi.org/10.1007/s13577-022-00671-y

JCO Precis Oncol. 2022 Feb;6 e2100211

Clinical Utility of CDK4/6 Inhibitors in Sarcoma: Successes and Future Challenges.

Jocelyn Y Hsu, Nathan D Seligson, John L Hays, Wayne O Miles, James L Chen.

PURPOSE: Soft tissue and bone sarcomas are rare malignancies that exhibit significant pathologic and molecular heterogeneity. Deregulation of the CDKN2A-CCND-CDK4/6-retinoblastoma 1 (Rb) pathway is frequently observed in about 25% of unselected sarcomas and is pathognomonic for specific sarcoma subtypes. This genomic specificity has fueled the clinical evaluation of selective CDK4/6 inhibitors in sarcomas. Here, we highlight successes, opportunities, and future challenges for using CDK4/6 inhibitors to treat sarcoma.
MATERIALS AND METHODS: This review summarizes the current evidence for the use of CDK4/6 inhibitors in sarcoma while identifying molecular rationale and predictive biomarkers that provide the foundation for targeting the CDK4/6 pathway in sarcoma. A systematic review was performed of articles indexed in the PubMed database and the National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov). For each sarcoma subtype, we discuss the preclinical rationale, case reports, and available clinical trials data.
RESULTS: Despite promising clinical outcomes in a subset of sarcomas, resistance to CDK4/6 inhibitors results in highly heterogeneous clinical outcomes. Current clinical data support the use of CDK4/6 inhibitors in subsets of sarcoma primarily driven by CDK4/6 deregulation. When dysregulation of the Rb pathway is a secondary driver of sarcoma, combination therapy with CDK4/6 inhibition may be an option. Developing strategies to identify responders and the mechanisms that drive resistance is important to maximize the clinical utility of these drugs in patients with sarcoma. Potential biomarkers that indicate CDK4/6 inhibitor sensitivity in sarcoma include CDK4, CCND, CCNE, RB1, E2F1, and CDKN2A.
CONCLUSION: CDK4/6 inhibitors represent a major breakthrough for targeted cancer treatment. CDK4/6 inhibitor use in sarcoma has led to limited, but significant, early clinical success. Targeted future clinical research will be key to unlocking the potential of CDK4/6 inhibition in sarcoma.

DOI: https://doi.org/10.1200/PO.21.00211

Clin Cancer Res. 2022 Feb 03. pii: clincanres.4239.2021. [Epub ahead of print]

Neoadjuvant therapy induces a potent immune response to sarcoma, dominated by myeloid and B cells.

PURPOSE: To characterize changes in the soft tissue sarcoma tumor immune microenvironment induced by standard neoadjuvant therapy with the goal of informing neoadjuvant immunotherapy trial design.
EXPERIMENTAL DESIGN: Paired pre- and post-neoadjuvant therapy specimens were retrospectively identified for 32 patients with soft tissue sarcomas and analyzed by three modalities: multiplexed immunohistochemistry, NanoString, and RNA sequencing with ImmunoPrism analysis.
RESULTS: All 32 patients, representing a variety of soft tissue sarcoma histologic subtypes, received neoadjuvant radiotherapy and 21 (66%) received chemotherapy prior to radiation therapy (RT). The most prevalent immune cells in the tumor before neoadjuvant therapy were myeloid cells (45% of all immune cells) and B cells (37%), with T (13%) and NK (natural killer) cells (5%) also present. Neoadjuvant therapy significantly increased the total immune cells infiltrating the tumors across all histologic subtypes for patients receiving neoadjuvant RT with or without chemotherapy. An increase in the percentage of monocytes and macrophages, particularly M2 macrophages, B cells, and CD4+ T cells was observed post-neoadjuvant therapy. Upregulation of genes and cytokines associated with antigen presentation was also observed, and a favorable pathological response ({greater than or equal to}90% necrosis post-neoadjuvant therapy) was associated with an increase in monocytic infiltrate. Upregulation of the T cell checkpoint TIM3 and downregulation of OX40 were observed post-treatment.
CONCLUSIONS: Standard neoadjuvant therapy induces both immunostimulatory and immunosuppressive effects within a complex sarcoma microenvironment dominated by myeloid and B cells. This work informs ongoing efforts to incorporate immune checkpoint inhibitors and novel immunotherapies into the neoadjuvant setting for soft tissue sarcomas.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-4239

Nucleic Acids Res. 2022 Jan 31. pii: gkac027. [Epub ahead of print]

Waves of sumoylation support transcription dynamics during adipocyte differentiation.

Xu Zhao, Ivo A Hendriks, Stéphanie Le Gras, Tao Ye, Lucía Ramos-Alonso, Aurélie Nguéa P, Guro Flor Lien, Fatemeh Ghasemi, Arne Klungland, Bernard Jost, Jorrit M Enserink, Michael L Nielsen, Pierre Chymkowitch.

Tight control of gene expression networks required for adipose tissue formation and plasticity is essential for adaptation to energy needs and environmental cues. However, the mechanisms that orchestrate the global and dramatic transcriptional changes leading to adipocyte differentiation remain to be fully unraveled. We investigated the regulation of nascent transcription by the sumoylation pathway during adipocyte differentiation using SLAMseq and ChIPseq. We discovered that the sumoylation pathway has a dual function in differentiation; it supports the initial downregulation of pre-adipocyte-specific genes, while it promotes the establishment of the mature adipocyte transcriptional program. By characterizing endogenous sumoylome dynamics in differentiating adipocytes by mass spectrometry, we found that sumoylation of specific transcription factors like PPARγ/RXR and their co-factors are associated with the transcription of adipogenic genes. Finally, using RXR as a model, we found that sumoylation may regulate adipogenic transcription by supporting the chromatin occurrence of transcription factors. Our data demonstrate that the sumoylation pathway supports the rewiring of transcriptional networks required for formation of functional adipocytes. This study also provides the scientists in the field of cellular differentiation and development with an in-depth resource of the dynamics of the SUMO-chromatin landscape, SUMO-regulated transcription and endogenous sumoylation sites during adipocyte differentiation.

DOI: https://doi.org/10.1093/nar/gkac027