Weifeng Liu, Huanqing Cheng, Zhen Huang, Yaping Li, Yanrui Zhang, Yongkun Yang, Tao Jin, Yang Sun, Zhiping Deng, Qing Zhang, Feng Lou, Shanbo Cao, Huina Wang, Xiaohui Niu
Osteosarcoma (OS) is a rare but aggressive malignancy. Despite previous reports, molecular characterization of this disease is not well understood, and little is known regarding OS in Chinese patients. Herein, we analyzed the genomic signatures of 73 Chinese OS cases. TP53, NCOR1, LRP1B, ATRX, RB1 and TFE3 were the most frequently mutated gene in our OS cohort. In addition, the genomic analysis of Western OS patients was performed. Notably, there were remarkable disparities in mutational landscape, base substitution pattern and tumor mutational burden between the Chinese and Western OS cohorts...
September 20, 2023: Molecular Oncology
Lydia Kuhnert, Robert Kuhnert, Menyhárt B Sárosi, Cathleen Lakoma, Birte K Scholz, Peter Lönnecke, Evamarie Hey-Hawkins, Walther Honscha
Success of chemotherapy is often hampered by multidrug resistance. One mechanism for drug resistance is the elimination of anticancer drugs through drug transporters, such as breast cancer resistance protein (BCRP; also known as ABCG2), and causes a poor 5-year survival rate of human patients. Co-treatment of chemotherapeutics and natural compounds, such as baicalein, is used to prevent chemotherapeutic resistance but is limited by rapid metabolism. Boron-based clusters as meta-carborane are very promising phenyl mimetics to increase target affinity; we therefore investigated the replacement of a phenyl ring in baicalein by a meta-carborane to improve its affinity towards the human ABCG2 efflux transporter...
September 20, 2023: Molecular Oncology
Misato Horie, Kurara Takagane, Go Itoh, Sei Kuriyama, Kazuyoshi Yanagihara, Masakazu Yashiro, Michinobu Umakoshi, Akiteru Goto, Junichi Arita, Masamitsu Tanaka
Peritoneal dissemination of cancer affects patient survival. The behavior of peritoneal mesothelial cells (PMCs) and immune cells influences the establishment of a microenvironment that promotes cancer cell metastasis in the peritoneum. Here, we investigated the roles of lactosylceramide alpha-2,3-sialyltransferase (ST3G5; also known as ST3GAL5 and GM3 synthase) in the exosome-mediated pre-metastatic niche in peritoneal milky spots (MSs). Exosomes secreted from ST3G5high cancer cells (ST3G5high -cExos) were found to contain high levels of hypoxia-inducible factor 1-alpha (HIF1α) and accumulated in MSs via uptake in macrophages (MΦs) owing to increased expression of sialic acid binding Ig like lectin 1 (CD169; also known as SIGLEC1)...
September 16, 2023: Molecular Oncology
Anat Gershoni, Ori Hassin, Nishanth Belugali Nataraj, Sivan Baruch, Adi Avioz-Seligman, Anna Chiara Pirona, Liat Fellus-Alyagor, Tomer Meir Salame, Saptaparna Mukherjee, Giuseppe Mallel, Yosef Yarden, Yael Aylon, Moshe Oren
The core Hippo pathway module consists of a tumor-suppressive kinase cascade that inhibits the transcriptional coactivators Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1; also known as TAZ). When the Hippo pathway is downregulated, as often occurs in breast cancer, YAP/TAZ activity is induced. To elaborate the roles of TAZ in triple-negative breast cancer (TNBC), we depleted Taz in murine TNBC 4T1 cells, using either CRISPR/Cas9 or small hairpin RNA (shRNA). TAZ-depleted cells and their controls, harboring wild-type levels of TAZ, were orthotopically injected into the mammary fat pads of syngeneic BALB/c female mice, and mice were monitored for tumor growth...
September 16, 2023: Molecular Oncology
Bryan Leatham, Katie McNall, Hari K K Subramanian, Lucien Jacky, John Alvarado, Dominic Yurk, Mimi Wang, Donald C Green, Gregory J Tsongalis, Aditya Rajagopal, Jerrod J Schwartz
Digital PCR (dPCR) is emerging as an ideal platform for the detection and tracking of genomic variants in cancer due to its high sensitivity and simple workflow. The growing number of clinically actionable cancer biomarkers creates a need for fast, accessible methods that allow for dense information content and high accuracy. Here, we describe a proof-of-concept amplitude modulation-based multiplex dPCR assay capable of detecting 12 single-nucleotide and insertion/deletion (indel) variants in EGFR, KRAS, BRAF, and ERBB2, 14 gene fusions in ALK, RET, ROS1 and NTRK1, and MET exon 14 skipping present in non-small cell lung cancer (NSCLC)...
September 15, 2023: Molecular Oncology
Manuel Beltrán-Visiedo, Nelia Jiménez-Alduán, Rosana Díez, Marta Cuenca, Andrea Benedi, Alfonso Serrano Del Valle, Gemma Azaceta, Luis Palomera, Victor Peperzak, Alberto Anel, Javier Naval, Isabel Marzo
A better understanding of multiple myeloma (MM) biology has led to the development of novel therapies. However, MM is still an incurable disease and new pharmacological strategies are needed. Dinaciclib, a multiple cyclin-dependent kinase (CDK) inhibitor, which inhibits CDK1, 2, 5 and 9, displays significant anti-myeloma activity as found in Phase II clinical trials. In the present work, we have explored the mechanism of dinaciclib-induced death and evaluated its enhancement by different BH3 mimetics in MM cell lines as well as in plasma cells from MM patients...
September 13, 2023: Molecular Oncology
Yagmur Azbazdar, Yeliz Demirci, Guillaume Heger, Dogac Ipekgil, Mustafa Karabicici, Gunes Ozhan
Hepatocellular carcinoma (HCC) is largely associated with aberrant activation of Wnt/β-catenin signaling. Nevertheless, how membrane lipid composition is altered in HCC cells with abnormal Wnt signaling remains elusive. Here, by exploiting comprehensive lipidome profiling, we unravel the membrane lipid composition of six different HCC cell lines with mutations in components of Wnt/β-catenin signaling, leading to differences in their endogenous signaling activity. Among the differentially regulated lipids are diacylglycerol (DAG) and ceramide, which were downregulated at the membrane of HCC cells after Wnt3a treatment...
September 12, 2023: Molecular Oncology
Liwei Ren, Ziyin Li, Yu Zhou, Jun Zhang, Ziheng Zhao, Zhaofei Wu, Ye Zhao, Yurong Ju, Xuewen Pang, Xiuyuan Sun, Wei Wang, Yu Zhang
E3 SUMO-protein ligase CBX4 (CBX4), a key component of polycomb repressive complexes 1 (PRC1), has been reported to regulate a variety of genes implicated in tumor growth, metastasis and angiogenesis. However, its role in T-cell-mediated anti-tumor immunity remains elusive. To shed light on this issue, we generated mice with T-cell-specific deletion of Cbx4. Tumor growth was increased in the knockout mice. Additionally, their tumor-infiltrating lymphocytes exhibited impaired tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) production, with an elevated programmed cell death protein 1 (PD-1) level...
September 10, 2023: Molecular Oncology
Najmeh Bozorgmehr, Hussain Syed, Siavash Mashhouri, John Walker, Shokrollah Elahi
Human papillomavirus (HPV)-associated cancer continues to evade the immune system by promoting a suppressive tumor-microenvironment. Therefore, immunotherapy appears to be a promising approach for targeting HPV-associated tumors. We hypothesized that valproic acid (VA) as an epigenetic agent combined with avelumab may enhance the anti-tumor immunity in HPV-associated solid tumors. We performed bulk RNA-sequencing (RNA-seq) on total peripheral blood mononuclear cells (PBMCs) of seven non-responders (NRs) and four responders (Rs)...
September 8, 2023: Molecular Oncology
Barnabas Szakal, Dana Branzei
A new study by Longo, Roy et al. has solved the structure of the RAD51C-XRCC3 (CX3) heterodimer with a bound ATP analog, identifying two main structural interfaces and defining separable replication fork stability roles. One function relates to the ability of RAD51C to bind and assemble CX3 on nascent DNA, with impact on the ability of forks to restart upon replication stress. The other relates to effective CX3 heterodimer formation, required for 5' RAD51 filament capping, with effects on RAD51 filament disassembly, fork protection and influencing the persistence of reversed forks...
September 8, 2023: Molecular Oncology
Zhou Lan, Ke-Long Zou, Hao Cui, Yu-Yue Zhao, Guang-Tao Yu
Bacteria are the causative agents of various infectious diseases; however, the anti-tumor effect of some bacterial species has attracted the attention of many scientists. The human oral cavity is inhabited by abundant and diverse bacterial communities, and some of these bacterial communities could play a role in tumor suppression. Therefore, it is crucial to find oral bacterial species that show anti-tumor activity on oral cancers. In the present study, we found that a high abundance of Porphyromonas gingivalis, an anaerobic periodontal pathogen, in the tumor microenvironment (TME) was positively associated with the longer survival of patients with oral squamous cell carcinoma (OSCC)...
September 4, 2023: Molecular Oncology
Colleen Ziegler, Alain Mir, Sangeetha Anandakrishnan, Patrick Martin, Elma Contreras, Isaiah Slemons, Barbara Witkowski, Chris DeSilva, Andrew Farmer, Semir Vranic, Zoran Gatalica, David Richardson, Dmitry N Derkach
The role of the tumor microenvironment (TME) in immuno-oncology has driven demand for technologies that deliver in situ, or spatial, molecular information. Compartmentalized heterogeneity that traditional methods miss is becoming key to predicting both acquired drug resistance to targeted therapies as well as patient response to immunotherapy. Here, we describe a novel method for assay-agnostic spatial profiling and demonstrate its ability to detect immune microenvironment signatures in breast cancer patients that are unresolved by the immunohistochemical (IHC) assessment of programmed cell death ligand-1 (PD-L1) on immune cells, which represents the only FDA microenvironment-based companion diagnostic test that has been approved for triple-negative breast cancer (TNBC)...
September 4, 2023: Molecular Oncology
Heidi Maria Namløs, Ksenia Khelik, Sigve Nakken, Daniel Vodák, Eivind Hovig, Ola Myklebost, Kjetil Boye, Leonardo A Meza-Zepeda
Patients with localized, high-risk gastrointestinal stromal tumours (GIST) benefit from adjuvant imatinib treatment. Still, approximately 40% of patients relapse within three years after adjuvant therapy and the clinical and histopathological features currently used for risk classification cannot precisely predict poor outcomes after standard treatment. This study aimed to identify genomic and transcriptomic profiles that could be associated with disease relapse and thus a more aggressive phenotype. Using a multi-omics approach, we analysed a cohort of primary tumours from patients with untreated, resectable high-risk GISTs...
August 25, 2023: Molecular Oncology
Amiram Sananes, Itay Cohen, Irit Allon, Oshrit Ben-David, Raghda Abu Shareb, Ksenia M Yegodayev, David Stepensky, Moshe Elkabets, Niv Papo
Targeted therapies for prostate, breast and ovarian cancers are based on their activity against primary tumors rather than their anti-metastatic activity. Consequently, there is an urgent need for new agents targeting the metastatic process. Emerging evidence correlates in vitro and in vivo cancer invasion and metastasis with increased activity of the proteases mesotrypsin (prostate and breast cancer) and kallikrein 6 (KLK6; ovarian cancer). Thus, mesotrypsin and KLK6 are attractive putative targets for therapeutic intervention...
August 23, 2023: Molecular Oncology
Xiaohui Pan, Wenxin Zhang, Longsheng Wang, Hongjie Guo, Mingming Zheng, Honghai Wu, Qinjie Weng, Qiaojun He, Ling Ding, Bo Yang
Recent studies have pointed to the role of Krüpple-like factor 12 (KLF12) in cancer-associated processes, including cancer proliferation, apoptosis, and metastasis. However, the role of KLF12 in tumor immunity remains obscure. Here, we found that KLF12 expression was significantly higher in non-small cell lung cancer (NSCLC) cells with higher programmed death-ligand 1 (PD-L1) expression. Additionally, a positive correlation between KLF12 and PD-L1 was observed in clinical patient tumor tissues. By chromatin immunoprecipitation (ChIP) analysis, KLF12 was identified to bind to the CACCC motif of the PD-L1 promoter...
August 22, 2023: Molecular Oncology
Timm M Reissig, Swetlana Ladigan-Badura, Anja Steinberg, Abdelouahid Maghnouj, Ting Li, Berlinda Verdoodt, Sven T Liffers, Michael Pohl, Heiner Wolters, Christian Teschendorf, Richard Viebahn, Jakob Admard, Nicolas Casadei, Andrea Tannapfel, Wolff Schmiegel, Stephan A Hahn, Deepak B Vangala
Although approximately half of all metastatic colorectal cancers (mCRCs) harbor mutations in KRAS or NRAS, hardly any progress has been made regarding targeted treatment for this group over the last few years. Here, we investigated the efficacy of vertical inhibition of the RAS-pathway by targeting epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase kinase (MEK) in patient-derived xenograft (PDX) tumors with primary KRAS mutation. In total, 19 different PDX models comprising 127 tumors were tested...
August 21, 2023: Molecular Oncology
Olga-Demetra Biziotis, Evangelia Evelyn Tsakiridis, Amr Ali, Elham Ahmadi, Jianhan Wu, Simon Wang, Bassem Mekhaeil, Kanwaldeep Singh, Gabe Menjolian, Thomas Farrell, Bassam Abdulkarim, Ranjan K Sur, Aruz Mesci, Peter Ellis, Tobias Berg, Jonathan L Bramson, Paola Muti, Gregory R Steinberg, Theodoros Tsakiridis
Non-small cell lung cancer (NSCLC) has a poor prognosis, and effective therapeutic strategies are lacking. The diabetes drug canagliflozin inhibits NSCLC cell proliferation and the mammalian target of rapamycin (mTOR) pathway, which mediates cell growth and survival, but it is unclear whether this drug can enhance response rates when combined with cytotoxic therapy. Here, we evaluated the effects of canagliflozin on human NSCLC response to cytotoxic therapy in tissue cultures and xenografts. Ribonucleic acid sequencing (RNA-seq), real-time quantitative PCR (RT-qPCR), metabolic function, small interfering ribonucleic acid (siRNA) knockdown, and protein expression assays were used in mechanistic analyses...
August 16, 2023: Molecular Oncology
Shengyu Zhou, Fayan Zhang, Mengxiang Xu, Lei Zhang, Zhengchuang Liu, Qiong Yang, Chunyang Wang, Baoming Wang, Tonghui Ma, Jiao Feng
ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) rearrangements are a crucial therapeutic target in non-small cell lung cancer (NSCLC). However, there is limited comprehensive analysis of the molecular patterns of ROS1 fusions. This study aimed to address this gap by analyzing 135 ROS1 fusions from 134 Chinese NSCLC patients using next-generation sequencing (NGS). The fusions were categorized into common and uncommon based on their incidence. Our study revealed, for the first time, a unique distribution preference of breakpoints within ROS1, with common fusions occurring in introns 31-33 and uncommon fusions occurring in introns 34 and 35...
August 16, 2023: Molecular Oncology
Yu Wei, Tingwei Zhang, Beihe Wang, Jian Pan, Shengming Jin, Bangwei Fang, Weijie Gu, Xiaojian Qin, Bo Dai, Guowen Lin, Hualei Gan, Junlong Wu, Dingwei Ye, Yao Zhu
Although there is a well-known disparity in prostate cancer (PC) incidence and mortality between Chinese and Western patients, the underlying genomic differences have been investigated only sparsely. This clinico-genomic study was conducted to reveal the genomic mutations contributing to the PC disparity across ethnicities and investigate the mutational profile of Chinese PC patients. A total of 1016 Chinese PC patients were prospectively enrolled and subjected to targeted sequencing, resulting in usable sequencing data for 41 genes from 859 patients...
August 16, 2023: Molecular Oncology
Susana Torres-Martínez, Silvia Calabuig-Fariñas, Andrea Moreno-Manuel, Giulia Bertolini, Alejandro Herreros-Pomares, Eva Escorihuela, Elena Duréndez-Saéz, Ricardo Guijarro, Ana Blasco, Luca Roz, Carlos Camps, Eloisa Jantus-Lewintre
Despite the success of therapies in lung cancer, more studies of new biomarkers for patient selection are urgently needed. The present study aims to analyze the role of galectin-3 (GAL-3) in the lung tumor microenvironment (TME) using tumorspheres as a model and explore its potential role as a predictive and prognostic biomarker in non-small cell lung cancer (NSCLC) patients. For in vitro studies, lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) primary cultures from early-stage patients and commercial cell lines were cultured, using tumorsphere-forming assays and adherent conditions for the control counterparts...
August 11, 2023: Molecular Oncology
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