Isabel Mayayo-Peralta, Donna O Debets, Stefan Prekovic, Karianne Schuurman, Suzanne Beerthuijzen, Mathilde Almekinders, Joyce Sanders, Cathy B Moelans, Sandra Saleiro, Jelle Wesseling, Paul J van Diest, Rui Henrique, Carmen Jerónimo, Maarten Altelaar, Wilbert Zwart
Breast cancer (BCa) is a highly heterogeneous disease, with hormone receptor status being a key factor in patient prognostication and treatment decision-making. The majority of primary tumours are positive for estrogen receptor alpha (ERα), which plays a key role in tumorigenesis and disease progression, and represents the major target for treatment of BCa. However, around one third of patients with ERα-positive BCa relapse and progress into the metastatic stage, with 20% of metastatic cases characterised by loss of ERα expression after endocrine treatment, known as ERα-conversion...
October 19, 2023: Molecular Oncology
Sara Bønløkke, Torben Steiniche, Boe Sandahl Sorensen, Gitte-Bettina Nyvang, Jacob Christian Lindegaard, Jan Blaakaer, Jesper Bertelsen, Katrine Fuglsang, Mikael Lenz Strube, Suzan Lenz, Magnus Stougaard
For cervical cancer (CC), circulating cell-free HPV DNA (ccfHPV) may establish disease severity. Furthermore, HPV integration has been correlated to viral load and survival. In this study, pre-treatment plasma from 139 CC cases (50 primary surgery patients, 22 primary surgery+adjuvant oncological therapy patients, and 67 primary oncological therapy patients) was collected (2018-2020). Furthermore, plasma from 25 cervical intraepithelial neoplasia grade 3 (CIN3) patients and 15 healthy women (negative controls) were collected...
October 19, 2023: Molecular Oncology
Xue Yang, Zexuan Liu, Weiwei Tang, Uday P Pratap, Alexia B Collier, Kristin A Altwegg, Rahul Gopalam, Xiaonan Li, Yaxia Yuan, Daohong Zhou, Zhao Lai, Yidong Chen, Gangadhara R Sareddy, Philip T Valente, Edward R Kost, Suryavathi Viswanadhapalli, Ratna K Vadlamudi
Endometrial carcinoma (ECa) is the fourth most common cancer among women. The oncogene PELP1 is frequently overexpressed in a variety of cancers, including ECa. We recently generated SMIP34, a small-molecule inhibitor of PELP1 that suppresses PELP1 oncogenic signaling. In this study, we assessed the effectiveness of SMIP34 in treating ECa. Treatment of established and primary patient-derived ECa cells with SMIP34 resulted in a significant reduction of cell viability, colony formation ability and induction of apoptosis...
October 19, 2023: Molecular Oncology
Arun Everest-Dass, Stepan Nersisyan, Hanna Maar, Victor Novosad, Jennifer Schröder-Schwarz, Vera Freytag, Johanna L Stuke, Mia C Beine, Alina Schiecke, Marie-Therese Haider, Malte Kriegs, Omar Elakad, Hanibal Bohnenberger, Lena-Christin Conradi, Maria Raygorodskaya, Linda Krause, Mark von Itzstein, Alexander Tonevitsky, Udo Schumacher, Diana Maltseva, Daniel Wicklein, Tobias Lange
Hematogenous metastasis limits the survival of colorectal cancer (CRC) patients. Here, we illuminated the roles of CD44 isoforms in this process. Isoforms 3 and 4 were predominantly expressed in CRC patients. CD44 isoform 4 indicated poor outcome and correlated with epithelial-mesenchymal transition (EMT) and decreased oxidative phosphorylation in patients; opposite associations were found for isoform 3. Pan-CD44 knockdown (kd) independently impaired primary tumor formation and abrogated distant metastasis in CRC xenografts...
October 18, 2023: Molecular Oncology
Yao-Yu Hsieh, Jia-Ling Du, Pei-Ming Yang
Microtubule-targeting agents represent one of the most successful classes of anticancer agents. However, the development of drug resistance and the appearance of adverse effects hamper their clinical implementation. Novel microtubule-targeting agents without such limitations are urgently needed. By employing a gene expression-based drug repositioning strategy, this study identifies VU-0365114, originally synthesized as a positive allosteric modulator of human muscarinic acetylcholine receptor M5 (M5 mAChR), as a novel type of tubulin inhibitor by destabilizing microtubules...
October 16, 2023: Molecular Oncology
Edgar Creus-Bachiller, Juana Fernández-Rodríguez, Miriam Magallón-Lorenz, Sara Ortega-Bertran, Susana Navas-Rutete, Cleofe Romagosa, Tulio M Silva, Maria Pané, Anna Estival, Diana Perez Sidelnikova, Mireia Morell, Helena Mazuelas, Meritxell Carrió, Tereza Lausová, David Reuss, Bernat Gel, Alberto Villanueva, Eduard Serra, Conxi Lázaro
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with a poor survival rate, presenting either sporadically or in the context of neurofibromatosis type 1 (NF1). The histological diagnosis of MPNSTs can be challenging, with different tumors exhibiting great histological and marker expression overlap. This heterogeneity could be partly responsible for the observed disparity in treatment response due to the inherent diversity of the preclinical models used. For several years, our group has been generating a large patient-derived orthotopic xenograft (PDOX) MPNST platform for identifying new precision medicine treatments...
October 5, 2023: Molecular Oncology
Richard Bayliss, Elżbieta Sarnowska, Sharon Yeoh, Josephina Sampson
Immune checkpoint inhibitors (ICIs) are utilized in treating non-small cell lung cancer (NSCLC) by enhancing the immune response against cancer cells. However, they are not effective against cancers with certain genetic alterations. A recent study by Mota et al. focused on understanding why ALK+ NSCLC cancers are immune cold and making them more receptive to ICIs using a vaccine-based approach. The study highlighted cell-specific differences in the presentation of immunogenic peptides and the location of tumours as factors in the poor immune response...
October 5, 2023: Molecular Oncology
Mark T Burgess, Jill Gluskin, Katja Pinker
A breakthrough study from Du et al. has developed a wearable, ultrasound imaging patch for standardized and reproducible breast tissue imaging. The technology utilizes a honeycomb patch design to facilitate guided movement of the ultrasound array, enabling comprehensive, multi-angle breast imaging. The system was validated in vitro and in vivo with a single human subject and has the potential for early-stage breast cancer detection. This study addressed the current limitations of wearable ultrasound technologies, including imaging over large, curvilinear organs and integration of superior piezoelectric materials for high-performance ultrasound arrays...
September 27, 2023: Molecular Oncology
Qiaoxi Xia, Zepeng Du, Mantong Chen, Xiao Zhou, Wenjing Bai, Xiaoqi Zheng, Ling Lin, Yan Zhao, Jiyu Ding, Zhisheng Wu, Haiying Zou, Shaohong Wang, Liyan Xu, Enmin Li, Bingli Wu
During malignant tumor development, the extracellular matrix (ECM) is usually abnormally regulated. Dysregulated expression of lysyl oxidase-like 2 (LOXL2), matrix metalloproteinase 9 (MMP9) and lipocalin 2 (LCN2) are associated with ECM remodeling. In this study, protein-protein interaction assays indicated that LCN2 and LOXL2 interactions and LCN2 and MMP9 interactions occurred both intracellularly and extracellularly, but interactions between LOXL2 and MMP9 only occurred intracellularly. The LCN2/LOXL2/MMP9 ternary complex promoted migration and invasion of esophageal squamous cell carcinoma (ESCC) cells, as well as tumor growth and malignant progression in vivo, while the iron chelator deferoxamine mesylate (DFOM) inhibited ESCC tumor growth...
September 27, 2023: Molecular Oncology
Alamelu G Bharadwaj, Meghan E McLean, Margaret L Dahn, Hannah F Cahill, Marie-Claire D Wasson, Raj Pranap Arun, Olivia L Walker, Brianne M Cruickshank, Wasundara Fernando, Jaganathan Venkatesh, Penelope J Barnes, Gillian Bethune, Gregory Knapp, Lucy K Helyer, Carman A Giacomantonio, David M Waisman, Paola Marcato
Aldehyde dehydrogenase 1A3 (ALDH1A3) is a cancer stem cell marker that promotes metastasis. Triple-negative breast cancer (TNBC) progression has been linked to ALDH1A3-induced gene expression changes. To investigate the mechanism of ALDH1A3-mediated breast cancer metastasis, we assessed the effect of ALDH1A3 on the expression of proteases and the regulators of proteases that degrade the extracellular matrix, a process that is essential for invasion and metastasis. This revealed that ALDH1A3 regulates the plasminogen activation pathway; it increased the levels and activity of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA)...
September 27, 2023: Molecular Oncology
Goran Rac, Hiten D Patel, Christopher James, Shalin Desai, Vincent M Caruso, Daniel S Fischer, Peter S Lentz, Ceressa T Ward, Brian C Mazzarella, Kevin G Phillips, Chirag Doshi, Vincent T Bicocca, Trevor G Levin, Alan J Wolfe, Gopal N Gupta
Intravesical therapy (IVT) is the standard of care to decrease risk of recurrence and progression for high-grade nonmuscle-invasive bladder cancer. However, post-IVT recurrence remains common and the ability to risk-stratify patients before or after IVT is limited. In this prospectively designed and accrued cohort study, we examine the utility of urinary comprehensive genomic profiling (uCGP) for predicting recurrence risk following transurethral resection of bladder tumor (TURBT) and evaluating longitudinal IVT response...
September 27, 2023: Molecular Oncology
Sisi Deng, Yuming Pan, Na An, Fengyi Chen, Huan Chen, Heng Wang, Xiaojing Xu, Rui Liu, Linlin Yang, Xiaomei Wang, Xin Du, Qiaoxia Zhang
Reticulocalbin-1 (RCN1) is expressed aberrantly and at a high level in various tumors, including acute myeloid leukemia (AML), yet its impact on AML remains unclear. In this study, we demonstrate that RCN1 knockdown significantly suppresses the viability of bone marrow mononuclear cells (BMMNCs) from AML patients but does not affect the viability of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSCs) from healthy donors in vitro. Downregulation of RCN1 also reduces the viability of AML cell lines...
September 25, 2023: Molecular Oncology
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
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