bims-myxlip 2021-03-14 papers

Issue of 2021–03–14
five papers selected by
Laura Mannarino, Humanitas Research

Eur J Cancer. 2021 Mar 05. pii: S0959-8049(21)00065-4. [Epub ahead of print]147 164-169

Perioperative chemotherapy and regional hyperthermia for high-risk adult-type soft tissue sarcomas.

Lars H Lindner, Jean-Yves Blay, Alexander M M Eggermont, Rolf D Issels.

A group of patients with adult-type soft tissue sarcoma is at high risk of local recurrence and distant metastases. Age, tumour site, histological subtype, tumour size and grade have been identified as the most important independent adverse prognostic factors. Macroscopically complete tumour resection is considered as the mainstay of treatment with the addition of preoperative or postoperative radiotherapy for extremity or trunk localisation. Retroperitoneal localisation requires compartmental resection and is associated with a worse prognosis. Here, radiotherapy is of no proven value. Perioperative chemotherapy is considered to treat micrometastatic disease not detectable at the time of diagnosis. The neoadjuvant application gives the risk of distant metastasis the greatest importance as therapy is carried out at the earliest possible time, whereas adjuvant chemotherapy is delayed by surgery and the necessary wound healing. With reported response rates up to 30%, both the operability may be improved and the risk of intraoperative tumour cell dissemination may be reduced, resulting also in reduced local relapse rates. However, the potential risk of early tumour progression may counteract this benefit. Optimised strategies with multimodality approaches including chemotherapy, regional hyperthermia (RHT) and immunotherapeutic agents have been shown to improve survival in high-risk patients. Here, we focus on the data from available randomised studies investigating the use of perioperative chemotherapy in patients with high-risk adult-type soft tissue sarcoma, including the use of RHT for local enhancement of chemotherapy effect and immune induction.

Keywords: Chemotherapy; Hyperthermia; Immunology; Neoadjuvant; Perioperative; Soft tissue sarcoma

DOI: https://doi.org/10.1016/j.ejca.2021.02.002

Hum Cell. 2021 Mar 06.

Establishment and characterization of NCC-DDLPS3-C1: a novel patient-derived cell line of dedifferentiated liposarcoma.

Ryuto Tsuchiya, Yuki Yoshimatsu, Rei Noguchi, Takuya Ono, Akane Sei, Fumitaka Takeshita, Jun Sugaya, Suguru Fukushima, Akihiko Yoshida, Seiji Ohtori, Akira Kawai, Tadashi Kondo.

Dedifferentiated liposarcoma (DDLPS) is a highly malignant subtype of liposarcoma, with characteristic amplification of MDM2 and CDK4 (12q14-15). It is caused by the dedifferentiation of well-differentiated liposarcoma. DDLPS is refractory to conventional chemotherapy; thus, surgical resection is the primary treatment modality. However, complete resection of DDLPS is difficult because of its deep location, which results in poor prognosis. Therefore, novel systemic chemotherapy is required to improve the clinical outcome. Patient-derived cell lines are important tools in the development of novel chemotherapy. However, there are no DDLPS cell lines available from public cell banks. In this study, we established a novel DDLPS cell line, NCC-DDLPS3-C1, using a surgically resected specimen from a patient with DDLPS. NCC-DDLPS3-C1 cells retained the characteristic gene amplification of MDM2 and CDK4. In addition, other gene amplifications and losses related to the poor prognosis of DDLPS were also observed in concordance with the original tumor. The cells also exhibited rapid cell proliferation, aggressive invasion ability, spheroid formation ability, and tumorigenic ability in nude mice. Furthermore, a drug-screening test showed significant antiproliferative effects of proteasome inhibitors and HDAC inhibitors. Thus, the NCC-DDLPS3-C1 cell line should be a useful tool for the development of novel chemotherapy for DDLPS.

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

DOI: https://doi.org/10.1007/s13577-021-00515-1

BMC Cancer. 2021 Mar 07. 21(1): 241

Acquisition of cancer stem cell capacities after spontaneous cell fusion.

Candice Merle, Pauline Lagarde, Lydia Lartigue, Frédéric Chibon.

BACKGROUND: Cancer stem/Initiating cell (CS/IC) hypothesis argues that CS/ICs are responsible of tumour initiation, drug resistance, metastasis or disease relapse. Their detection in several cancers supports this concept. However, their origin is still misunderstood. Cell fusion is shown to take part in the formation of CS/ICs, i.e. fusion between mesenchymal stem cell and cancer cell. In a previous paper, we described that fusion leads to hybrids with metastatic capacity. This process triggered genomic rearrangements in hybrid cells together with increased metastasis development. Here, we hypothesize that cell fusion could be strong enough to provoke a cellular reprogramming and the acquisition of CS/IC properties, promoting metastasis formation.
METHODS: After spontaneous cell fusion between E6E7 (IMR90 with the oncogenes E6 and E7) and RST (IMR90 fully transformed) cell lines, hybrid cells were selected by dual antibiotic selection. Cancer stem cells capacities were evaluated regarding capacity to form spheres, expression of stem cell markers and the presence of ALDHhigh cells.
RESULTS: Our data show that after cell fusion, all hybrids contain a percentage of cells with CS/ICs properties, regarding. Importantly, we lastly showed that NANOG inhibition in H1 hybrid decreases this migration capacity while having no effect on the corresponding parental cells.
CONCLUSIONS: Altogether these results indicate that the combination of CS/ICs properties and genomic rearrangement in hybrids is likely to be key to tumour progression.

Keywords: Cancer stem cells; Cell fusion; Sarcoma

DOI: https://doi.org/10.1186/s12885-021-07979-2

J Surg Oncol. 2021 Mar 08.

Development of machine learning model algorithm for prediction of 5-year soft tissue myxoid liposarcoma survival.

Pramod N Kamalapathy, Dipak B Ramkumar, Aditya V Karhade, Sean Kelly, Kevin Raskin, Joseph Schwab, Santiago Lozano-Calderón.

BACKGROUND: Predicting survival in myxoid liposarcoma (MLS) patients is very challenging given its propensity to metastasize and the controversial role of adjuvant therapy. The purpose of this study was to develop a machine-learning algorithm for the prediction of survival at five years for patients with MLS and externally validate it using our institutional cohort.
METHODS: Two databases, the surveillance, epidemiology, and end results program (SEER) database and an institutional database, were used in this study. Five machine learning models were created based on the SEER database and performance was rated using the TRIPOD criteria. The model that performed best on the SEER data was again tested on our institutional database.
RESULTS: The net-elastic penalized logistic regression model was the best according to our performance indicators. This model had an area under the curve (AUC) of 0.85 when compared to the SEER testing data and an AUC of 0.76 when tested against institutional database. An application to use this calculator is available at https://sorg-apps.shinyapps.io/myxoid_liposarcoma/.
CONCLUSION: MLS is a soft-tissue sarcoma with adjunct treatment options that are, in part, decided by prognostic survival. We developed the first machine-learning predictive algorithm specifically for MLS using the SEER registry that retained performance during external validation with institutional data.

Keywords: liposarcoma; machine learning; survival

DOI: https://doi.org/10.1002/jso.26398

PLoS One. 2021 ;16(3): e0248140

Discovery of novel candidates for anti-liposarcoma therapies by medium-scale high-throughput drug screening.

Iwona Grad, Robert Hanes, Pilar Ayuda-Durán, Marieke Lydia Kuijjer, Jorrit M Enserink, Leonardo A Meza-Zepeda, Ola Myklebost.

Sarcomas are a heterogeneous group of mesenchymal orphan cancers and new treatment alternatives beyond traditional chemotherapeutic regimes are much needed. So far, tumor mutation analysis has not led to significant treatment advances, and we have attempted to bypass this limitation by performing direct drug testing of a library of 353 anti-cancer compounds that are either FDA-approved, in clinical trial, or in advanced stages of preclinical development on a panel of 13 liposarcoma cell lines. We identified and validated six drugs, targeting different mechanisms and with good efficiency across the cell lines: MLN2238 -a proteasome inhibitor, GSK2126458 -a PI3K/mTOR inhibitor, JNJ-26481585 -a histone deacetylase inhibitor, triptolide-a multi-target drug, YM155 -a survivin inhibitor, and APO866 (FK866)-a nicotinamide phosphoribosyl transferase inhibitor. GR50s for those drugs were mostly in the nanomolar range, and in many cases below 10 nM. These drugs had long-lasting effect upon drug withdrawal, limited toxicity to normal cells and good efficacy also against tumor explants. Finally, we identified potential genomic biomarkers of their efficacy. Being approved or in clinical trials, these drugs are promising candidates for liposarcoma treatment.

DOI: https://doi.org/10.1371/journal.pone.0248140