Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: June 10, 2021

Abstract To flourish, cancers greatly depend on their surrounding tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in TME are critical for cancer occurrence progression because of versatile roles extracellular matrix remodeling, maintenance stemness, blood vessel formation, modulation metabolism, immune response, promotion cell proliferation, migration, invasion, therapeutic resistance. CAFs highly heterogeneous stromal cells crosstalk with is mediated by a complex intricate signaling network consisting transforming growth factor-beta, phosphoinositide 3-kinase/AKT/mammalian target rapamycin, mitogen-activated protein kinase, Wnt, Janus kinase/signal transducers activators transcription, epidermal factor receptor, Hippo, nuclear kappa-light-chain-enhancer activated B cells, etc., pathways. These signals exhibit own special characteristics during the have potential to be targeted anticancer therapy. Therefore, comprehensive understanding these cascades interactions between necessary fully realize pivotal cancers. Herein, this review, we will summarize enormous amounts findings mediating its related targets or trials. Further, hypothesize three targeting strategies, including, namely, epithelial–mesenchymal common targets, sequential perturbation, crosstalk-directed paving way CAF-directed host cell-directed antitumor

Language: Английский

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Liquid–liquid phase separation in human health and diseases

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Aug. 1, 2021

Abstract Emerging evidence suggests that liquid–liquid phase separation (LLPS) represents a vital and ubiquitous phenomenon underlying the formation of membraneless organelles in eukaryotic cells (also known as biomolecular condensates or droplets). Recent studies have revealed evidences indicate LLPS plays role human health diseases. In this review, we describe our current understanding summarize its physiological functions. We further development Additionally, review recently developed methods for studying LLPS. Although research is infancy—but fast-growing—it clear an essential pathophysiological conditions. This highlights need overview recent advances field to translate knowledge regarding into therapeutic discoveries.

Language: Английский

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The Hippo signalling pathway and its implications in human health and diseases

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

Published: Nov. 8, 2022

Abstract As an evolutionarily conserved signalling network, the Hippo pathway plays a crucial role in regulation of numerous biological processes. Thus, substantial efforts have been made to understand upstream signals that influence activity pathway, as well its physiological functions, such cell proliferation and differentiation, organ growth, embryogenesis, tissue regeneration/wound healing. However, dysregulation can cause variety diseases, including cancer, eye cardiac pulmonary renal hepatic immune dysfunction. Therefore, therapeutic strategies target dysregulated components might be promising approaches for treatment wide spectrum diseases. Here, we review key critical functions controlled by pathway. Additionally, diseases associated with alterations potential therapies targeting will discussed.

Language: Английский

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YAP/TAZ functions and their regulation at a glance

Journal of Cell Science, Journal Year: 2020, Volume and Issue: 133(2)

Published: Jan. 15, 2020

ABSTRACT YAP and TAZ proteins are transcriptional coactivators encoded by paralogous genes, which shuttle between the cytoplasm nucleus in response to multiple inputs, including Hippo pathway. In nucleus, they pair with DNA-binding factors of TEAD family regulate gene expression. Nuclear YAP/TAZ promote cell proliferation, organ overgrowth, survival stress dedifferentiation post-mitotic cells into their respective tissue progenitors. required for growth embryonic tissues, wound healing regeneration, where activated cell-intrinsic extrinsic cues. Surprisingly, this activity is dispensable many adult self-renewing constantly kept check. lay at center a complex regulatory network cell-autonomous but also cell- tissue-level structural features such as mechanical properties microenvironment, establishment cell–cell junctions basolateral polarity. Enhanced levels observed cancers, sustain tumor growth, drug resistance malignancy. Cell Science Glance article accompanying poster, we review biological functions mechanisms, highlight position signaling network.

Language: Английский

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Lipid metabolism in cancer progression and therapeutic strategies

MedComm, Journal Year: 2020, Volume and Issue: 2(1), P. 27 - 59

Published: Dec. 24, 2020

Dysregulated lipid metabolism represents an important metabolic alteration in cancer. Fatty acids, cholesterol, and phospholipid are the three most prevalent lipids that act as energy producers, signaling molecules, source material for biogenesis of cell membranes. The enhanced synthesis, storage, uptake contribute to cancer progression. rewiring has been linked activation oncogenic pathways cross talk with tumor microenvironment. resulting activity favors survival proliferation cells harsh conditions within tumor. Lipid also plays a vital role immunogenicity via effects on function noncancer microenvironment, especially immune-associated cells. Targeting altered shown potential promising anticancer therapy. Here, we review recent evidence implicating contribution reprogramming progression, discuss molecular mechanisms underlying cancer, therapeutic strategies directed toward This sheds new light fully understanding context provides valuable clues targeting

Language: Английский

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The Hippo pathway in cancer: YAP/TAZ and TEAD as therapeutic targets in cancer

Clinical Science, Journal Year: 2022, Volume and Issue: 136(3), P. 197 - 222

Published: Feb. 1, 2022

Abstract Tumorigenesis is a highly complex process, involving many interrelated and cross-acting signalling pathways. One such pathway that has garnered much attention in the field of cancer research over last decade Hippo pathway. Consisting two antagonistic modules, plays an integral role both tumour suppressive oncogenic processes, generally via regulation diverse set genes involved range biological functions. This review discusses history within context explores some most recent discoveries as to how this critical transducer cellular can influence progression. A special focus on various efforts therapeutically target key effectors preclinical clinical settings.

Language: Английский

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Glycogen accumulation and phase separation drives liver tumor initiation

Cell, Journal Year: 2021, Volume and Issue: 184(22), P. 5559 - 5576.e19

Published: Oct. 1, 2021

Language: Английский

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A combat with the YAP/TAZ-TEAD oncoproteins for cancer therapy

Theranostics, Journal Year: 2020, Volume and Issue: 10(8), P. 3622 - 3635

Published: Jan. 1, 2020

The transcriptional co-regulators YAP and TAZ pair primarily with the TEAD family of transcription factors to elicit a gene expression signature that plays prominent role in cancer development, progression metastasis. endow cells various oncogenic traits such they sustain proliferation, inhibit apoptosis, maintain stemness, respond mechanical stimuli, engineer metabolism, promote angiogenesis, suppress immune response develop resistance therapies. Therefore, inhibiting YAP/TAZ- is an attractive viable option for novel therapy. It exciting know many drugs already clinic restrict YAP/TAZ activities several inhibitors are currently under development. We have classified YAP/TAZ-inhibiting into three groups. Group I act on upstream regulators stimulators activities. Many potential be repurposed as indirect treat solid cancers. II modalities directly or TEADs disrupt their interaction; targeting has emerged YAP/TAZ, major mediators programs. can also leveraged using small molecules activate YAP/TAZ-dependent use regenerative medicine. III focus one downstream target genes. With right strategy impetus, it not far-fetched expect group drug combat cancers near future.

Language: Английский

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Mechanoregulation of YAP and TAZ in Cellular Homeostasis and Disease Progression

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: May 24, 2021

Biophysical cues, such as mechanical properties, play a critical role in tissue growth and homeostasis. During organ development injury repair, compressive tensional forces generated by cell-extracellular matrix or cell-cell interaction are key factors for cell fate determination. In the vascular system, hemodynamic forces, shear stress, cyclic stretch modulate phenotypes susceptibility to atherosclerosis. Despite that emerging efforts have been made investigate how mechanotransduction is involved tuning functions various contexts, regulatory mechanisms remain largely unknown. One of challenges understand signaling cascades transmit cues from plasma membrane cytoplasm then nuclei generate mechanoresponsive transcriptomes. YAP its homolog TAZ, Hippo pathway effectors, identified mechanotransducers sense stimuli relay signals control transcriptional programs proliferation, differentiation, transformation. However, upstream mechanosensors YAP/TAZ downstream transcriptome responses following activation repression not well characterized. Moreover, mechanoregulation literature highly context-dependent. this review, we summarize biomechanical microenvironment provide an update on roles physiological pathological conditions.

Language: Английский

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Small Molecule Inhibitors of TEAD Auto-palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2-deficient Mesothelioma

Molecular Cancer Therapeutics, Journal Year: 2021, Volume and Issue: 20(6), P. 986 - 998

Published: April 13, 2021

Mutations in the neurofibromatosis type 2 (NF2) gene that limit or abrogate expression of functional Merlin are common malignant mesothelioma. activates Hippo pathway to suppress nuclear translocation YAP and TAZ, major effectors associate with TEAD transcription factors nucleus promote genes involved cell proliferation survival. In this article, we describe discovery compounds selectively inhibit YAP/TAZ-TEAD promoted transcription, block auto-palmitoylation, disrupt interaction between YAP/TAZ TEAD. Optimization led potent analogs excellent oral bioavailability pharmacokinetics NF2-deficient mesothelioma vitro growth subcutaneous tumor xenografts vivo These highly selective inhibitors provide a way target Hippo-YAP pathway, which thus far has been undruggable is dysregulated frequently other YAP-driven cancers diseases.

Language: Английский

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