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Multifunctional role of the tumor associated monocytes/macrophages in the metastatic potential of inflammatory breast cancer

Mohamed, Mona Mostafa; Schneider, Robert J
Inflammatory breast cancer (IBC) is the most aggressive and lethal phenotype form of breast cancer, which afflicts young women at high incidence in North Africa compared to other continents of the world. IBC is characterized by highly metastatic behavior and possesses specific pathobiological properties different from non-IBC. IBC disease displays unusual common properties at typical presentation, including positive metastatic lymph-nodes, high infiltration of tumor associated monocytes/macrophages, rapid progression to distant metastasis, and possibly the production of a unique repertoire of growth factors, cytokines and chemokines, as well as a striking association with different polarized macrophages compared to non-IBC. Indeed, tumor associated monocytes/macrophages (TAM/M) play a crucial role in breast cancer development. Previously, we showed that cross talk between IBC cells and patient derived TAMs occurs via secretion of inflammatory mediators from TAMs that act on specific extracellular domain receptors activating down-stream signaling pathways that promote the epithelial-to-mesenchymal transition, cancer cell invasion, IBC stem cell properties, drug resistance, local and metastatic recurrence of residual tumor cells and other key markers of malignancy, including in vitro colony formation capacity. In this mini review, we will discuss the role of TAMs in IBC cancer metastatic potential and molecules involved. The review also discusses the recent discoveries in the field of IBC research.
PMID: 39437012
ISSN: 1460-2393
CID: 5739752

Novel Inhibition of Central Carbon Metabolism Pathways by Rac and CDC42 inhibitor MBQ167 and Paclitaxel

Cruz-Collazo, Ailed M; Katsara, Olga; Grafals-Ruiz, Nilmary; Colon Gonzalez, Jessica; Dorta-Estremera, Stephanie; Carlo, Victor P; Chorna, Nataliya; Schneider, Robert J; Dharmawardhane, Suranganie
Triple negative breast cancer (TNBC) represents a therapeutic challenge in which standard chemotherapy is limited to paclitaxel. MBQ167, a clinical stage small molecule inhibitor that targets Rac and Cdc42, inhibits tumor growth and metastasis in mouse models of TNBC. Herein, we investigated the efficacy of MBQ167 in combination with paclitaxel in TNBC preclinical models, as a prelude to safety trials of this combination in patients with advanced breast cancer. Individual MBQ167 or combination therapy with paclitaxel was more effective at reducing TNBC cell viability and increasing apoptosis compared with paclitaxel alone. In orthotopic mouse models of human TNBC (MDA-MB231 and MDA-MB468), individual MBQ167, paclitaxel, or the combination reduced mammary tumor growth with similar efficacy, with no apparent liver toxicity. However, paclitaxel single agent treatment significantly increased lung metastasis, whereas MBQ167, single or combined, reduced lung metastasis. In the syngeneic 4T1/BALB/c model, combined MBQ167 and paclitaxel decreased established lung metastases by ∼80%. To determine the molecular basis for the improved efficacy of the combined treatment on metastasis, 4T1 tumor extracts from BALB/c mice treated with MBQ167, paclitaxel, or the combination were subjected to transcriptomic analysis. Gene set enrichment identified specific downregulation of central carbon metabolic pathways by the combination of MBQ167 and paclitaxel but not individual compounds. Biochemical validation, by immunoblotting and metabolic Seahorse analysis, shows that combined MBQ167 and paclitaxel reduces glycolysis. This study provides a strong rationale for the clinical testing of MBQ167 in combination with paclitaxel as a potential therapeutic for TNBC and identifies a unique mechanism of action.
PMCID:11534544
PMID: 39087451
ISSN: 1538-8514
CID: 5766422

Non-canonical mRNA translation initiation in cell stress and cancer

Mahé, Mélanie; Rios-Fuller, Tiffany; Katsara, Olga; Schneider, Robert J
The now well described canonical mRNA translation initiation mechanism of m7G 'cap' recognition by cap-binding protein eIF4E and assembly of the canonical pre-initiation complex consisting of scaffolding protein eIF4G and RNA helicase eIF4A has historically been thought to describe all cellular mRNA translation. However, the past decade has seen the discovery of alternative mechanisms to canonical eIF4E mediated mRNA translation initiation. Studies have shown that non-canonical alternate mechanisms of cellular mRNA translation initiation, whether cap-dependent or independent, serve to provide selective translation of mRNAs under cell physiological and pathological stress conditions. These conditions typically involve the global downregulation of canonical eIF4E1/cap-mediated mRNA translation, and selective translational reprogramming of the cell proteome, as occurs in tumor development and malignant progression. Cancer cells must be able to maintain physiological plasticity to acquire a migratory phenotype, invade tissues, metastasize, survive and adapt to severe microenvironmental stress conditions that involve inhibition of canonical mRNA translation initiation. In this review we describe the emerging, important role of non-canonical, alternate mechanisms of mRNA translation initiation in cancer, particularly in adaptation to stresses and the phenotypic cell fate changes involved in malignant progression and metastasis. These alternate translation initiation mechanisms provide new targets for oncology therapeutics development.
PMCID:11140632
PMID: 38828390
ISSN: 2632-8674
CID: 5664882

Engineered coiled-coil HIF1α protein domain mimic

Britton, Dustin; Katsara, Olga; Mishkit, Orin; Wang, Andrew; Pandya, Neelam; Liu, Chengliang; Mao, Heather; Legocki, Jakub; Jia, Sihan; Xiao, Yingxin; Aristizabal, Orlando; Paul, Deven; Deng, Yan; Schneider, Robert; Wadghiri, Youssef Z; Montclare, Jin Kim
The development of targeted anti-cancer therapeutics offers the potential for increased efficacy of drugs and diagnostics. Utilizing modalities agnostic to tumor type, such as the hypoxic tumor microenvironment (TME), may assist in the development of universal tumor targeting agents. The hypoxia-inducible factor (HIF), in particular HIF1, plays a key role in tumor adaptation to hypoxia, and inhibiting its interaction with p300 has been shown to provide therapeutic potential. Using a multivalent assembled protein (MAP) approach based on the self-assembly of the cartilage oligomeric matrix protein coiled-coil (COMPcc) domain fused to the critical residues of the C-terminal transactivation domain (C-TAD) of the α subunit of HIF1 (HIF1α), we generate HIF1α-MAP (H-MAP). The resulting H-MAP demonstrates picomolar binding affinity to p300, the ability to downregulate hypoxia-inducible genes, and in vivo tumor targeting capability.
PMID: 38656316
ISSN: 2047-4849
CID: 5663092

Coiled-Coil Protein Hydrogels Engineered with Minimized Fiber Diameters for Sustained Release of Doxorubicin in Triple-Negative Breast Cancer

Britton, Dustin; Legocki, Jakub; Paul, Deven; Katsara, Olga; Aristizabal, Orlando; Pandya, Neelam; Mishkit, Orin; Xiao, Yingxin; Aristizabal, Matias; Rahman, Neha; Schneider, Robert; Wadghiri, Youssef Z; Montclare, Jin Kim
Triple-negative breast cancer (TNBC) lacks expressed protein targets, making therapy development challenging. Hydrogels offer a promising new route in this regard by improving the chemotherapeutic efficacy through increased solubility and sustained release. Moreover, subcutaneous hydrogel administration reduces patient burden by requiring less therapy and shorter treatment times. We recently established the design principles for the supramolecular assembly of single-domain coiled-coils into hydrogels. Using a modified computational design algorithm, we designed Q8, a hydrogel with rapid assembly for faster therapeutic hydrogel preparation. Q8 encapsulates and releases doxorubicin (Dox), enabling localized sustained release via subcutaneous injection. Remarkably, a single subcutaneous injection of Dox-laden Q8 (Q8•Dox) significantly suppresses tumors within just 1 week. This work showcases the bottom-up engineering of a fully protein-based drug delivery vehicle for improved TBNC treatment via noninvasive localized therapy.
PMCID:11094684
PMID: 38622760
ISSN: 2373-9878
CID: 5655802

Breast cancer cell mesenchymal transition and metastasis directed by DAP5/eIF3d-mediated selective mRNA translation

Alard, Amandine; Katsara, Olga; Rios-Fuller, Tiffany; Parra, Columba de la; Ozerdem, Ugur; Ernlund, Amanda; Schneider, Robert J
Cancer cell plasticity enables cell survival in harsh physiological environments and fate transitions such as the epithelial-to-mesenchymal transition (EMT) that underlies invasion and metastasis. Using genome-wide transcriptomic and translatomic studies, an alternate mechanism of cap-dependent mRNA translation by the DAP5/eIF3d complex is shown to be essential for metastasis, EMT, and tumor directed angiogenesis. DAP5/eIF3d carries out selective translation of mRNAs encoding EMT transcription factors and regulators, cell migration integrins, metalloproteinases, and cell survival and angiogenesis factors. DAP5 is overexpressed in metastatic human breast cancers associated with poor metastasis-free survival. In human and murine breast cancer animal models, DAP5 is not required for primary tumor growth but is essential for EMT, cell migration, invasion, metastasis, angiogenesis, and resistance to anoikis. Thus, cancer cell mRNA translation involves two cap-dependent mRNA translation mechanisms, eIF4E/mTORC1 and DAP5/eIF3d. These findings highlight a surprising level of plasticity in mRNA translation during cancer progression and metastasis.
PMCID:10895648
PMID: 37314929
ISSN: 2211-1247
CID: 5707782

eIF2Bδ blocks the integrated stress response and maintains eIF2B activity and cancer metastasis by overexpression in breast cancer stem cells

Gupta, Malavika; Walters, Beth A; Katsara, Olga; Granados Blanco, Karol; Geter, Phillip A; Schneider, Robert J
Breast cancer (BC) metastasis involves cancer stem cells (CSCs) and their regulation by micro-RNAs (miRs), but miR targeting of the translation machinery in CSCs is poorly explored. We therefore screened miR expression levels in a range of BC cell lines, comparing non-CSCs to CSCs, and focused on miRs that target translation and protein synthesis factors. We describe a unique translation regulatory axis enacted by reduced expression of miR-183 in breast CSCs, which we show targets the eIF2Bδ subunit of guanine nucleotide exchange factor eIF2B, a regulator of protein synthesis and the integrated stress response (ISR) pathway. We report that reduced expression of miR-183 greatly increases eIF2Bδ protein levels, preventing strong induction of the ISR and eIF2α phosphorylation, by preferential interaction with P-eIF2α. eIF2Bδ overexpression is essential for BC cell invasion, metastasis, maintenance of metastases, and breast CSC expansion in animal models. Increased expression of eIF2Bδ, a site of action of the drug ISRIB that also prevents ISR signaling, is essential for breast CSC maintenance and metastatic capacity.
PMCID:10104532
PMID: 37014850
ISSN: 1091-6490
CID: 5463682

Macrophage-Derived 25-Hydroxycholesterol Promotes Vascular Inflammation, Atherogenesis, and Lesion Remodeling

Canfrán-Duque, Alberto; Rotllan, Noemi; Zhang, Xinbo; Andrés-Blasco, Irene; Thompson, Bonne M; Sun, Jonathan; Price, Nathan L; Fernández-Fuertes, Marta; Fowler, Joseph W; Gómez-Coronado, Diego; Sessa, William C; Giannarelli, Chiara; Schneider, Robert J; Tellides, George; McDonald, Jeffrey G; Fernández-Hernando, Carlos; Suárez, Yajaira
BACKGROUND:Cross-talk between sterol metabolism and inflammatory pathways has been demonstrated to significantly affect the development of atherosclerosis. Cholesterol biosynthetic intermediates and derivatives are increasingly recognized as key immune regulators of macrophages in response to innate immune activation and lipid overloading. 25-Hydroxycholesterol (25-HC) is produced as an oxidation product of cholesterol by the enzyme cholesterol 25-hydroxylase (CH25H) and belongs to a family of bioactive cholesterol derivatives produced by cells in response to fluctuating cholesterol levels and immune activation. Despite the major role of 25-HC as a mediator of innate and adaptive immune responses, its contribution during the progression of atherosclerosis remains unclear. METHODS: RESULTS:We found that 25-HC accumulated in human coronary atherosclerotic lesions and that macrophage-derived 25-HC accelerated atherosclerosis progression, promoting plaque instability through autocrine and paracrine actions. 25-HC amplified the inflammatory response of lipid-loaded macrophages and inhibited the migration of smooth muscle cells within the plaque. 25-HC intensified inflammatory responses of lipid-laden macrophages by modifying the pool of accessible cholesterol in the plasma membrane, which altered Toll-like receptor 4 signaling, promoted nuclear factor-κB-mediated proinflammatory gene expression, and increased apoptosis susceptibility. These effects were independent of 25-HC-mediated modulation of liver X receptor or SREBP (sterol regulatory element-binding protein) transcriptional activity. CONCLUSIONS:Production of 25-HC by activated macrophages amplifies their inflammatory phenotype, thus promoting atherogenesis.
PMID: 36416142
ISSN: 1524-4539
CID: 5384202

Genetics of enzymatic dysfunctions in metabolic disorders and cancer

Mahé, Mélanie; Rios-Fuller, Tiffany J; Karolin, Andrea; Schneider, Robert J
Inherited metabolic disorders arise from mutations in genes involved in the biogenesis, assembly, or activity of metabolic enzymes, leading to enzymatic deficiency and severe metabolic impairments. Metabolic enzymes are essential for the normal functioning of cells and are involved in the production of amino acids, fatty acids and nucleotides, which are essential for cell growth, division and survival. When the activity of metabolic enzymes is disrupted due to mutations or changes in expression levels, it can result in various metabolic disorders that have also been linked to cancer development. However, there remains much to learn regarding the relationship between the dysregulation of metabolic enzymes and metabolic adaptations in cancer cells. In this review, we explore how dysregulated metabolism due to the alteration or change of metabolic enzymes in cancer cells plays a crucial role in tumor development, progression, metastasis and drug resistance. In addition, these changes in metabolism provide cancer cells with a number of advantages, including increased proliferation, resistance to apoptosis and the ability to evade the immune system. The tumor microenvironment, genetic context, and different signaling pathways further influence this interplay between cancer and metabolism. This review aims to explore how the dysregulation of metabolic enzymes in specific pathways, including the urea cycle, glycogen storage, lysosome storage, fatty acid oxidation, and mitochondrial respiration, contributes to the development of metabolic disorders and cancer. Additionally, the review seeks to shed light on why these enzymes represent crucial potential therapeutic targets and biomarkers in various cancer types.
PMCID:10433910
PMID: 37601653
ISSN: 2234-943x
CID: 5598152

DDX60 selectively reduces translation off viral type II internal ribosome entry sites

Sadic, Mohammad; Schneider, William M; Katsara, Olga; Medina, Gisselle N; Fisher, Ashley; Mogulothu, Aishwarya; Yu, Yingpu; Gu, Meigang; de Los Santos, Teresa; Schneider, Robert J; Dittmann, Meike
Co-opting host cell protein synthesis is a hallmark of many virus infections. In response, certain host defense proteins limit mRNA translation globally, albeit at the cost of the host cell's own protein synthesis. Here, we describe an interferon-stimulated helicase, DDX60, that decreases translation from viral internal ribosome entry sites (IRESs). DDX60 acts selectively on type II IRESs of encephalomyocarditis virus (EMCV) and foot and mouth disease virus (FMDV), but not by other IRES types or by 5' cap. Correspondingly, DDX60 reduces EMCV and FMDV (type II IRES) replication, but not that of poliovirus or bovine enterovirus 1 (BEV-1; type I IRES). Furthermore, replacing the IRES of poliovirus with a type II IRES is sufficient for DDX60 to inhibit viral replication. Finally, DDX60 selectively modulates the amount of translating ribosomes on viral and in vitro transcribed type II IRES mRNAs, but not 5' capped mRNA. Our study identifies a novel facet in the repertoire of interferon-stimulated effector genes, the selective downregulation of translation from viral type II IRES elements.
PMID: 36256515
ISSN: 1469-3178
CID: 5360422