A non-proliferative role of pyrimidine metabolism in cancer

Molecular Metabolism, Journal Year: 2020, Volume and Issue: 35, P. 100962 - 100962

Published: Feb. 13, 2020

Nucleotide metabolism is a critical pathway that generates purine and pyrimidine molecules for DNA replication, RNA synthesis, cellular bioenergetics. Increased nucleotide supports uncontrolled growth of tumors hallmark cancer. Agents inhibiting synthesis incorporation nucleotides in are widely used as chemotherapeutics to reduce tumor growth, cause damage, induce cell death. Thus, the research on cancer primarily focused its role proliferation. However, addition proliferation, established ligands purinergic signals. so far, pyrimidines has not been discussed beyond growth. In this review we present key evidence from recent pivotal studies supporting notion non-proliferative (PyM) cancer, with special focus effect differentiation cancers different origins. leukemic cells, catabolism induces terminal toward monocytic lineage check aberrant whereas some solid (e.g., triple negative breast hepatocellular carcinoma), catalytic degradation maintains mesenchymal-like state driven by epithelial-to-mesenchymal transition (EMT). This further broadens concept understand PyM metastasis and, ultimately, delivers rationale investigate involvement oncometabolites. Overall, understanding will lead improvement existing antimetabolites development new therapeutic options.

Language: Английский

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In primary airway epithelial cells, the unjamming transition is distinct from the epithelial-to-mesenchymal transition

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Oct. 7, 2020

Abstract The epithelial-to-mesenchymal transition (EMT) and the unjamming (UJT) each comprises a gateway to cellular migration, plasticity remodeling, but extent which these core programs are distinct, overlapping, or identical has remained undefined. Here, we triggered partial EMT (pEMT) UJT in differentiated primary human bronchial epithelial cells. After triggering UJT, cell-cell junctions, apico-basal polarity, barrier function remain intact, cells elongate align into cooperative migratory packs, mesenchymal markers of unapparent. pEMT other metrics versus diverge. A computational model attributes effects mainly diminished junctional tension those augmented propulsion. Through actions working independently, sequentially, interactively, tissues that subject development, injury, disease become endowed with rich mechanisms for plasticity, self-repair, regeneration.

Language: Английский

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Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

Frontiers in Oncology, Journal Year: 2020, Volume and Issue: 10

Published: Oct. 26, 2020

Metabolism Rewiring is a hallmark of cancer. As one the most abundant free amino acids in human blood, glutamine supports bioenergetics and biosynthesis, tumor growth, production antioxidants through glutaminolysis In dependent cancer cells, more than half TCA metabolites are derived from glutamine. Glutaminolysis controls process converting into cycle regulation multiple enzymes, while glutaminase shows importance as very first step this process. Targeting inhibition emerges promising strategy to disrupt metabolism progression. Here, we review role metastasis. Furthermore, highlight inhibitor based metabolic therapy their applications clinical set up.

Language: Английский

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Tumor biomarkers for diagnosis, prognosis and targeted therapy

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: May 20, 2024

Abstract Tumor biomarkers, the substances which are produced by tumors or body’s responses to during tumorigenesis and progression, have been demonstrated possess critical encouraging value in screening early diagnosis, prognosis prediction, recurrence detection, therapeutic efficacy monitoring of cancers. Over past decades, continuous progress has made exploring discovering novel, sensitive, specific, accurate tumor significantly promoted personalized medicine improved outcomes cancer patients, especially advances molecular biology technologies developed for detection biomarkers. Herein, we summarize discovery development including history conventional innovative used biomarker classification biomarkers based on tissue origins, application clinical management. In particular, highlight recent advancements biomarker-based anticancer-targeted therapies emerging as breakthroughs promising strategies. We also discuss limitations challenges that need be addressed provide insights perspectives turn into opportunities this field. Collectively, multiple emphasized review may guidance precision medicine, broaden horizons future research directions, expedite patients according their rather than organs origin.

Language: Английский

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Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer

The Journal of Experimental Medicine, Journal Year: 2020, Volume and Issue: 217(9)

Published: June 8, 2020

Tumor cells rely on glutamine to fulfill their metabolic demands and sustain proliferation. The elevated consumption of can lead intratumoral nutrient depletion, causing stress that has the potential impact tumor progression. Here, we show caused by deprivation leads induction epithelial–mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, demonstrate deficiency regulates EMT through up-regulation master regulator Slug, a process is dependent both MEK/ERK signaling ATF4. We find Slug required PDAC for deprivation–induced EMT, cell motility, survival. Importantly, decipher associated with tumors metastasis. These results delineate novel role response provide insight into how depletion might influence

Language: Английский

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Deterministic reprogramming of neutrophils within tumors

Science, Journal Year: 2024, Volume and Issue: 383(6679)

Published: Jan. 11, 2024

Neutrophils are increasingly recognized as key players in the tumor immune response and associated with poor clinical outcomes. Despite recent advances characterizing diversity of neutrophil states cancer, common trajectories mechanisms governing ontogeny relationship between these remain undefined. Here, we demonstrate that immature mature neutrophils enter tumors undergo irreversible epigenetic, transcriptional, proteomic modifications to converge into a distinct, terminally differentiated dcTRAIL-R1

Language: Английский

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FAK in Cancer: From Mechanisms to Therapeutic Strategies

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(3), P. 1726 - 1726

Published: Feb. 2, 2022

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is overexpressed and activated in many cancer types. FAK regulates diverse cellular processes, including growth factor signaling, cell cycle progression, survival, motility, angiogenesis, the establishment of immunosuppressive tumor microenvironments through kinase-dependent kinase-independent scaffolding functions cytoplasm nucleus. Mounting evidence has indicated that targeting FAK, either alone or combination with other agents, may represent promising therapeutic strategy for various cancers. In this review, we summarize mechanisms underlying FAK-mediated signaling networks during development. We also recent progress FAK-targeted small-molecule compounds anticancer activity from preclinical clinical evidence.

Language: Английский

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Mechanism of epithelial‐mesenchymal transition in cancer and its regulation by natural compounds

Medicinal Research Reviews, Journal Year: 2023, Volume and Issue: 43(4), P. 1141 - 1200

Published: March 17, 2023

Abstract Epithelial‐mesenchymal transition (EMT) is a complex process with primordial role in cellular transformation whereby an epithelial cell transforms and acquires mesenchymal phenotype. This plays pivotal tumor progression self‐renewal, exacerbates resistance to apoptosis chemotherapy. EMT can be initiated promoted by deregulated oncogenic signaling pathways, hypoxia, cells the microenvironment, resulting loss‐of‐epithelial polarity, cell–cell adhesion, enhanced invasive/migratory properties. Numerous transcriptional regulators, such as Snail, Slug, Twist, ZEB1/ZEB2 induce through downregulation of markers gain‐of‐expression markers. Additionally, cascades Wnt/β‐catenin, Notch, Sonic hedgehog, nuclear factor kappa B, receptor tyrosine kinases, PI3K/AKT/mTOR, Hippo, transforming growth factor‐β pathways regulate whereas they are often cancers leading aberrant EMT. Furthermore, noncoding RNAs, tumor‐derived exosomes, epigenetic alterations also involved modulation Therefore, regulation vital strategy control aggressive metastatic characteristics cells. Despite vast amount preclinical data on cancer progression, there lack clinical translation at therapeutic level. In this review, we have discussed thoroughly aforementioned transcription factors, RNAs (microRNAs, long RNA, circular RNA), modifications, exosomes cancers. We emphasized contribution drug possible interventions using plant‐derived natural products, their semi‐synthetic derivatives, nano‐formulations that described promising blockers.

Language: Английский

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Triple-negative breast cancer metastasis involves complex epithelial-mesenchymal transition dynamics and requires vimentin

Science Translational Medicine, Journal Year: 2022, Volume and Issue: 14(656)

Published: Aug. 3, 2022

Triple-negative breast cancer (TNBC) is an aggressive subtype associated with early metastatic recurrence and worse patient outcomes. TNBC tumors express molecular markers of the epithelial-mesenchymal transition (EMT), but its requirement during spontaneous metastasis in vivo remains incompletely understood. We demonstrated that from a genetically engineered mouse model (GEMM), multiple patient-derived xenografts, archival samples exhibited large populations hybrid E/M cells lead invasion ex while expressing both epithelial mesenchymal characteristics. The marker vimentin promoted repressed outgrowth. next tested for five EMT transcription factors observed distinct patterns utilization colony formation. These differences suggested sequential activation programs cascade. Consistent this model, our longitudinal single-cell RNA analysis detected three different EMT-related patterns. progressing to strongly pattern investigated relative versus state GEMM metastases. In contexts, we heterogeneity between within metastases same individual. complex spectrum epithelial, E/M, cell states metastases, suggesting there are successful strategies distant organ colonization. Together, results demonstrate important role metastasis.

Language: Английский

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Targeting polarized phenotype of microglia via IL6/JAK2/STAT3 signaling to reduce NSCLC brain metastasis

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Feb. 23, 2022

Tumor-associated macrophages have emerged as crucial factors for metastases. Microglia are indispensable components of the brain microenvironment and play vital roles in metastasis (BM). However, underlying mechanism how activated microglia promote non-small cell lung cancer (NSCLC) remains elusive. Here, we purified lines with brain-metastatic tropism employed a co-culture system to reveal their communication microglia. By single-cell RNA-sequencing transcriptome difference analysis, identified IL6 key regulator cells (A549-F3) induce anti-inflammatory via JAK2/STAT3 signaling, which turn promoted colonization process metastatic A549-F3 cells. In our clinical samples, patients higher levels serum showed propensity metastasis. Additionally, TCGA (The Cancer Genome Atlas) data revealed that NSCLC lower level had longer overall survival time compared those IL6. Overall, indicate targeting IL6/JAK2/STAT3 signaling may be promising new approach inhibiting patients.

Language: Английский

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