bims-myxlip 2021-02-14 papers

bims-myxlip

Biomed News

on Myxoid liposarcoma

Issue of 2021–02–14
nine papers selected by
Laura Mannarino, Mario Negri Institute

Targeting Innate Immunity in Cancer Therapy.
Role of Base Excision Repair Pathway in the Processing of Complex DNA Damage Generated by Oxidative Stress and Anticancer Drugs.
Establishment and characterization of a novel cell line, NCC-DDLPS2-C1, derived from a patient with dedifferentiated liposarcoma.
Photodynamic Therapy Using Hippo Pathway Inhibitor Verteporfin: A Potential Dual Mechanistic Approach in Treatment of Soft Tissue Sarcomas.
DROSHA is recruited to DNA damage sites by the MRN complex to promote non-homologous end-joining.
Potential of enhancer of zeste homolog 2 inhibitors for the treatment of SWI/SNF mutant cancers and tumor microenvironment modulation.
Development and validation of an immune gene-set based prognostic signature for soft tissue sarcoma.
YEATS4 is associated with poor prognosis and promotes epithelial-to-mesenchymal transition and metastasis by regulating ZEB1 expression in breast cancer.
Novel method for the prediction of drug-drug Interaction based on Gene Expression profiles.

Vaccines (Basel). 2021 Feb 09. pii: 138. [Epub ahead of print]9(2):

Targeting Innate Immunity in Cancer Therapy.

Srikrishnan Rameshbabu, Brian W Labadie, Anna Argulian, Akash Patnaik.

  The majority of current cancer immunotherapy strategies target and potentiate antitumor adaptive immune responses. Unfortunately, the efficacy of these treatments has been limited to a fraction of patients within a subset of tumor types, with an aggregate response rate of approximately 20% to date across all malignancies. The success of therapeutic inhibition of programmed death protein 1 (PD-1), protein death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) with immune checkpoint inhibitors (ICI) has been limited to "hot" tumors characterized by preexisting T cell infiltration, whereas "cold" tumors, which lack T cell infiltration, have not achieved durable benefit. There are several mechanisms by which "cold" tumors fail to generate spontaneous immune infiltration, which converge upon the generation of an immunosuppressive tumor microenvironment (TME). The role of the innate immune system in tumor immunosurveillance and generation of antitumor immune responses has been long recognized. In recent years, novel strategies to target innate immunity in cancer therapy have emerged, including therapeutic stimulation of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs); the DNA sensing cGAS/STING pathway; nucleotide-binding oligomerization domain-like receptors (NLRs), such as NLRP3; and the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs). In addition, therapeutic modulation of key innate immune cell types, such as macrophages and natural killer cells, has been investigated. Herein, we review therapeutic approaches to activate innate immunity within the TME to enhance antitumor immune responses, with the goal of disease eradication in "cold" tumors. In addition, we discuss rational immune-oncology combination strategies that activate both innate and adaptive immunity, with the potential to enhance the efficacy of current immunotherapeutic approaches.

Keywords:  CD40; NK cells; NLRP3; RIG-I; STING; TLRs; cancer; cancer immunotherapy; innate immunity; oncolytic viruses; pattern recognition receptors; tumor-associated macrophages

DOI:  https://doi.org/10.3390/vaccines9020138
Front Cell Dev Biol. 2020 ;8 617884

Role of Base Excision Repair Pathway in the Processing of Complex DNA Damage Generated by Oxidative Stress and Anticancer Drugs.

Yeldar Baiken, Damira Kanayeva, Sabira Taipakova, Regina Groisman, Alexander A Ishchenko, Dinara Begimbetova, Bakhyt Matkarimov, Murat Saparbaev.

  Chemical alterations in DNA induced by genotoxic factors can have a complex nature such as bulky DNA adducts, interstrand DNA cross-links (ICLs), and clustered DNA lesions (including double-strand breaks, DSB). Complex DNA damage (CDD) has a complex character/structure as compared to singular lesions like randomly distributed abasic sites, deaminated, alkylated, and oxidized DNA bases. CDD is thought to be critical since they are more challenging to repair than singular lesions. Although CDD naturally constitutes a relatively minor fraction of the overall DNA damage induced by free radicals, DNA cross-linking agents, and ionizing radiation, if left unrepaired, these lesions cause a number of serious consequences, such as gross chromosomal rearrangements and genome instability. If not tightly controlled, the repair of ICLs and clustered bi-stranded oxidized bases via DNA excision repair will either inhibit initial steps of repair or produce persistent chromosomal breaks and consequently be lethal for the cells. Biochemical and genetic evidences indicate that the removal of CDD requires concurrent involvement of a number of distinct DNA repair pathways including poly(ADP-ribose) polymerase (PARP)-mediated DNA strand break repair, base excision repair (BER), nucleotide incision repair (NIR), global genome and transcription coupled nucleotide excision repair (GG-NER and TC-NER, respectively), mismatch repair (MMR), homologous recombination (HR), non-homologous end joining (NHEJ), and translesion DNA synthesis (TLS) pathways. In this review, we describe the role of DNA glycosylase-mediated BER pathway in the removal of complex DNA lesions.

Keywords:  DNA glycosylase; Fanconi anemia; base excision repair; bulky DNA adduct; inter-strand DNA crosslink; nucleotide excision repair

DOI:  https://doi.org/10.3389/fcell.2020.617884
Hum Cell. 2021 Feb 08.

Establishment and characterization of a novel cell line, NCC-DDLPS2-C1, derived from a patient with dedifferentiated liposarcoma.

Rei Noguchi, Yuki Yoshimatsu, Takuya Ono, Akane Sei, Kaoru Hirabayashi, Iwao Ozawa, Kazutaka Kikuta, Tadashi Kondo.

  Dedifferentiated liposarcoma (DDLPS) is a highly aggressive subtype of liposarcoma that is histologically a transition form between an atypical lipomatous tumor/well-differentiated liposarcoma and a non-lipogenic sarcoma. DDLPS is genetically characterized by a complex karyotype with copy number variations and genomic complexity. DDLPS has a poor prognosis, a high local recurrence rate, and refractory behaviors for chemotherapy and radiation, which indicate a requirement for a novel therapeutic strategy for better clinical outcomes. We report here, a novel DDLPS cell line (NCC-DDLPS2-C1) developed from a tumor tissue. NCC-DDLPS2-C1 cells showed an amplified 12q13-15 region and exhibited constant growth, spheroid formation, and invasion. High-throughput drug screening revealed distinct sensitivity between monolayer- and three-dimensional cells. Romidepsin and trabectedin especially showed high anti-proliferative effects in both culture methods of NCC-DDLPS2-C1. Thus, the NCC-DDLPS2-C1 cell line may serve as a useful resource for DDLPS studies.

Keywords:  Dedifferentiated liposarcoma; Monolayer-culture; Patient-derived cell line; Sarcoma; Three-dimensional culture

DOI:  https://doi.org/10.1007/s13577-021-00497-0
Cancers (Basel). 2021 Feb 08. pii: 675. [Epub ahead of print]13(4):

Photodynamic Therapy Using Hippo Pathway Inhibitor Verteporfin: A Potential Dual Mechanistic Approach in Treatment of Soft Tissue Sarcomas.

Jeffrey D Rytlewski, Nicholas Scalora, Keith Garcia, Munir Tanas, Fatima Toor, Benjamin Miller, Bryan Allen, Mohammed Milhem, Varun Monga.

  Sarcoma is a widely varied and devastating oncological subtype, with overall five-year survival of 65% that drops to 16% with the presence of metastatic disease at diagnosis. Standard of care for localized sarcomas is predicated on local control with wide-local resection and radiation therapy, or, less commonly, chemotherapy, depending on tumor subtype. Verteporfin has the potential to be incorporated into this standard of care due to its unique molecular properties: inhibition of the upregulated Hippo pathway that frequently drives soft tissue sarcoma and photodynamic therapy-mediated necrosis due to oxidative damage. The initial anti-proliferative effect of verteporfin is mediated via binding and dissociation of YAP/TEAD proteins from the nucleus, ultimately leading to decreased cell proliferation as demonstrated in multiple in vitro studies. This effect has the potential to be compounded with use of photodynamic therapy to directly induce cellular necrosis with use of a clinical laser. Photodynamic therapy has been incorporated into multiple malignancies and has the potential to be incorporated into sarcoma treatment.

Keywords:  Hippo pathway; YAP/TAZ; photodynamic therapy; soft tissue sarcoma; verteporfin

DOI:  https://doi.org/10.3390/cancers13040675
J Cell Sci. 2021 Feb 08. pii: jcs.249706. [Epub ahead of print]

DROSHA is recruited to DNA damage sites by the MRN complex to promote non-homologous end-joining.

Matteo Cabrini, Marco Roncador, Alessandro Galbiati, Lina Cipolla, Antonio Maffia, Fabio Iannelli, Simone Sabbioneda, Fabrizio d'Adda di Fagagna, Sofia Francia.

  The DNA damage response (DDR) is the signaling cascade that recognizes DNA double-strand breaks (DSB) and promotes their resolution via the DNA repair pathways of Non-Homologous End Joining (NHEJ) or Homologous Recombination (HR). We and others have shown that DDR activation requires DROSHA. However, whether DROSHA exerts its functions by associating with damage sites, what controls its recruitment and how DROSHA influences DNA repair, remains poorly understood. Here we show that DROSHA associates to DSBs independently from transcription. Neither H2AX, nor ATM nor DNA-PK kinase activities are required for its recruitment to break site. Rather, DROSHA interacts with RAD50 and inhibition of MRN by Mirin treatment abolishes this interaction. MRN inactivation by RAD50 knockdown or mirin treatment prevents DROSHA recruitment to DSB and, as a consequence, also 53BP1 recruitment. During DNA repair, DROSHA inactivation reduces NHEJ and boosts HR frequency. Indeed, DROSHA knockdown also increase the association of downstream HR factors such as RAD51 to DNA ends. Overall, our results demonstrate that DROSHA is recruited at DSBs by the MRN complex and direct DNA repair toward NHEJ.

Keywords:  DNA DAMAGE; DROSHA; RNA

DOI:  https://doi.org/10.1242/jcs.249706
Drug Dev Res. 2021 Feb 09.

Potential of enhancer of zeste homolog 2 inhibitors for the treatment of SWI/SNF mutant cancers and tumor microenvironment modulation.

Karolina Pyziak, Agnieszka Sroka-Porada, Tomasz Rzymski, Józef Dulak, Agnieszka Łoboda.

  Enhancer of zeste homolog 2 (EZH2), a catalytic component of polycomb repressive complex 2 (PRC2), is commonly overexpressed or mutated in many cancer types, both of hematological and solid nature. Till now, plenty of EZH2 small molecule inhibitors have been developed and some of them have already been tested in clinical trials. Most of these inhibitors, however, are effective only in limited cases in the context of EZH2 gain-of-function mutated tumors such as lymphomas. Other cancer types with aberrant EZH2 expression and function require alternative approaches for successful treatment. One possibility is to exploit synthetic lethal strategy, which is based on the phenomenon that concurrent loss of two genes is detrimental but the deletion of either of them leaves cell viable. In the context of EZH2/PRC2, the most promising synthetic lethal target seems to be SWItch/Sucrose Non-Fermentable chromatin remodeling complex (SWI/SNF), which is known to counteract PRC2 functions. SWI/SNF is heavily involved in carcinogenesis and its subunits have been found mutated in approximately 20% of tumors of different kinds. In the current review, we summarize the existing knowledge of synthetic lethal relationships between EZH2/PRC2 and components of the SWI/SNF complex and discuss in detail the potential application of existing EZH2 inhibitors in cancer patients harboring mutations in SWI/SNF proteins. We also highlight recent discoveries of EZH2 involvement in tumor microenvironment regulation and consequences for future therapies. Although clinical studies are limited, the fundamental research might help to understand which patients are most likely to benefit from therapies using EZH2 inhibitors.

Keywords:  EZH2; PRC2; SWI/SNF; epigenetics; synthetic lethality

DOI:  https://doi.org/10.1002/ddr.21796
BMC Cancer. 2021 Feb 08. 21(1): 144

Development and validation of an immune gene-set based prognostic signature for soft tissue sarcoma.

Rui Shen, Bo Liu, Xuesen Li, Tengbo Yu, Kuishuai Xu, Jinfeng Ma.

   BACKGROUND: Sarcomas is a group of heterogeneous malignant tumors originated from mesenchymal tissue and different types of sarcomas have disparate outcomes. The present study aims to identify the prognostic value of immune-related genes (IRGs) in sarcoma and establish a prognostic signature based on IRGs.
METHODS: We collected the expression profile and clinical information of 255 soft tissue sarcoma samples from The Cancer Genome Atlas (TCGA) database and 2498 IRGs from the ImmPort database. The LASSO algorithm and Cox regression analysis were used to identify the best candidate genes and construct a signature. The prognostic ability of the signature was evaluated by ROC curves and Kaplan-Meier survival curves and validated in an independent cohort. Besides, a nomogram based on the IRGs and independent prognostic clinical variables was developed.
RESULTS: A total of 19 IRGs were incorporated into the signature. In the training cohort, the AUC values of signature at 1-, 2-, and 3-years were 0.938, 0.937 and 0.935, respectively. The Kaplan-Meier survival curve indicated that high-risk patients were significantly worse prognosis (P < 0.001). In the validation cohort, the AUC values of signature at 1-, 2-, and 3-years were 0.730, 0.717 and 0.647, respectively. The Kaplan-Meier survival curve also showed significant distinct survival outcome between two risk groups. Furthermore, a nomogram based on the signature and four prognostic variables showed great accuracy in whole sarcoma patients and subgroup analyses. More importantly, the results of the TF regulatory network and immune infiltration analysis revealed the potential molecular mechanism of IRGs.
CONCLUSIONS: In general, we identified and validated an IRG-based signature, which can be used as an independent prognostic signature in evaluating the prognosis of sarcoma patients and provide potential novel immunotherapy targets.

Keywords:  Immune infiltration; Immune-related gene; Nomogram; Soft tissue sarcoma

DOI:  https://doi.org/10.1186/s12885-021-07852-2
Am J Cancer Res. 2021 ;11(2): 416-440

YEATS4 is associated with poor prognosis and promotes epithelial-to-mesenchymal transition and metastasis by regulating ZEB1 expression in breast cancer.

Yang Li, Lei Li, Junyi Wu, Jun Qin, Xueming Dai, Tao Jin, Junming Xu.

YEATS domain-containing protein 4 (YEATS4) is implicated in several oncogenic signaling pathways, and its expression is involved in various types of cancer; regardless, the pathophysiologic effects of YEATS4 on breast cancer remain unclear. This study finds that YEATS4 is increasingly expressed with breast cancer progression, and its expression is related to poor outcome and distant metastasis. YEATS4 overexpression in breast cancer cells strengthens their malignant characteristics in vitro and in vivo, particularly inducing epithelial-to-mesenchymal transition (EMT) and consequently, metastatic capability in breast cancer cells. By contrast, deleting YEATS4 in breast cancer cells with high-grade malignancy reduced these characteristics. With regard to the molecular mechanism, YEATS4 mediates histone H3K27ac at specific sites of the ZEB1 promoter to regulate its expression at the transcription level. Depleting ZEB1 blocks YEATS4-induced EMT, migration, invasion, and metastasis. YEATS4 expression is also positively correlated with ZEB1 expression in patients with breast cancer. Co-expression of YEATS4 and ZEB1 correlates with the shortest distant metastasis-free period. Taken together, our data reveal the critical role of YEATS4 in the progression and metastasis of breast cancer, as well as support YEATS4 as a potential therapeutic target and prognostic biomarker for breast cancer.

Keywords: EMT; YEATS4; ZEB1; breast cancer; metastasis
Eur J Pharm Sci. 2021 Feb 03. pii: S0928-0987(21)00044-0. [Epub ahead of print] 105742

Novel method for the prediction of drug-drug Interaction based on Gene Expression profiles.

Yh Taguchi, Turki Turki.

  The accurate prediction of new interactions between drugs is important for avoiding unknown (mild or severe) adverse reactions to drug combinations. The development of effective in silico methods for evaluating drug interactions based on gene expression data requires an understanding of how various drugs alter gene expression. Current computational methods for the prediction of drug-drug interactions (DDIs) utilize data for known DDIs to predict unknown interactions. However, these methods are limited in the absence of known predictive DDIs. To improve DDIs interpretation, a recent study has demonstrated strong non-linear (i.e., dose-dependent) effects of DDIs. In this study, we present a new unsupervised learning approach involving tensor decomposition (TD)-based unsupervised feature extraction (FE) in 3D. We utilize our approach to reanalyze available gene expression profiles for Saccharomyces cerevisiae. We found that non-linearity is possible, even for single drugs. Thus, non-linear dose-dependence cannot always be attributed to DDIs. Our analysis provides a basis for the design of effective methods for evaluating DDIs.

Keywords:  Bioinformatics; Drug-drug interaction; Feature extraction; Gene expression; Tensor decomposition; Unsupervised learning

DOI:  https://doi.org/10.1016/j.ejps.2021.105742