Expanding ligand-receptor interaction networks for axon guidance: Structural insights into signal crosstalk and specificity DOI Creative Commons
Shaotong Zhu, A. Jaworski, Rob Meijers

et al.

Current Opinion in Neurobiology, Journal Year: 2025, Volume and Issue: 92, P. 102999 - 102999

Published: March 20, 2025

Guidance of nascent axons to their targets is mediated by attractive and repulsive cues that activate receptors on the axonal growth cone. The number ligand-receptor interactions implicated in axon pathfinding still expanding, large-scale cell-surface extracellular protein interactome studies have revealed extensive crosstalk between signaling axes once thought act independently. This raises question how apparent promiscuity molecular compatible with specific outcomes effects cone steering. Structural provided insights into modularity binding shown capacity engage multiple ligands. Here, we review recent findings about complexity interaction networks for guidance, structures complexes reveal mechanisms may specify output.

Language: Английский

Wnt/β-catenin-driven EMT regulation in human cancers DOI Creative Commons
Wenhua Xue, Lin Yang, Chengxin Chen

et al.

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: Feb. 9, 2024

Abstract Metastasis accounts for 90% of cancer-related deaths among the patients. The transformation epithelial cells into mesenchymal with molecular alterations can occur during epithelial–mesenchymal transition (EMT). EMT mechanism accelerates cancer metastasis and drug resistance ability in human cancers. Among different regulators EMT, Wnt/β-catenin axis has been emerged as a versatile modulator. Wnt is active form physiological condition due to function GSK-3β that destructs β-catenin, while ligand–receptor interaction impairs increase β-catenin stability promote its nuclear transfer. Regarding oncogenic Wnt/β-catenin, upregulation occurs cancers it accelerate EMT-mediated resistance. stimulation by binding ligands Frizzled receptors enhance accumulation cytoplasm stimulates related genes upon translocation. Wnt/β-catenin/EMT implicated augmenting both solid hematological tumors. Wnt/EMT-mediated promotes malignant behavior tumor cells, causing therapy be modulated upstream mediators which non-coding RNAs are main regulators. Moreover, pharmacological intervention, mainly using phytochemicals, suppresses Wnt/EMT suppression. Graphical abstract

Language: Английский

Citations

103
Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer DOI Creative Commons
Julien Dilly, Megan T. Hoffman, Laleh Abbassi

et al.

Cancer Discovery, Journal Year: 2024, Volume and Issue: 14(11), P. 2135 - 2161

Published: July 5, 2024

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated adagrasib or sotorasib, mutations PIK3CA and KRAS, amplifications of KRASG12C, MYC, MET, EGFR, CDK6 emerged at acquired resistance. In cell lines organoid models the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition PI3K-AKT-mTOR signaling associate to therapy. MRTX1133 treatment KrasLSL-G12D/+; Trp53LSL-R172H/+; p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug ultimately emerged, accompanied by Kras, Yap1, Myc, Cdk6, Abcb1a/b, co-evolution drug-resistant transcriptional programs. Moreover, KPC PDX models, mesenchymal basal-like states displayed increased response inhibition compared classical state. Combination chemotherapy significantly improved control models. Collectively, these data elucidate co-evolving mechanisms support multiple combination therapy strategies. Significance: Acquired may limit impact PDAC. Using samples preclinical we define heterogeneous genetic non-genetic that guide approaches improve durability promising therapies for patients. See related commentary Marasco Misale, p. 2018.

Language: Английский

Citations

36
How important is EMT for cancer metastasis? DOI Creative Commons
Toni Celià-Terrassa, Yibin Kang

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(2), P. e3002487 - e3002487

Published: Feb. 7, 2024

Epithelial-to-mesenchymal transition (EMT), a biological phenomenon of cellular plasticity initially reported in embryonic development, has been increasingly recognized for its importance cancer progression and metastasis. Despite tremendous progress being made the past 2 decades our understanding molecular mechanism functional EMT cancer, there are several mysteries around that remain unresolved. In this Unsolved Mystery, we focus on variety types metastasis, cooperative collective behaviors, spatiotemporal characterization EMT, strategies therapeutically targeting EMT. We also highlight new technical advances will facilitate efforts to elucidate unsolved

Language: Английский

Citations

28
Spatial Transcriptomics: A Powerful Tool in Disease Understanding and Drug Discovery DOI Creative Commons
Junxian Cao, Caifeng Li,

Zhao Cui

et al.

Theranostics, Journal Year: 2024, Volume and Issue: 14(7), P. 2946 - 2968

Published: Jan. 1, 2024

Recent advancements in modern science have provided robust tools for drug discovery. The rapid development of transcriptome sequencing technologies has given rise to single-cell transcriptomics and single-nucleus transcriptomics, increasing the accuracy accelerating discovery process. With evolution spatial (ST) technology emerged as a derivative approach. Spatial hot topic field omics research recent years; it not only provides information on gene expression levels but also offers expression. This shown tremendous potential disease understanding In this article, we introduce analytical strategies review its applications novel target mechanism unravelling. Moreover, discuss current challenges issues that need be addressed. conclusion, new perspective

Language: Английский

Citations

16
Decoding the interplay between genetic and non-genetic drivers of metastasis DOI
Panagiotis Karras, James R. Black, Nicholas McGranahan

et al.

Nature, Journal Year: 2024, Volume and Issue: 629(8012), P. 543 - 554

Published: May 15, 2024

Language: Английский

Citations

14
Custom microfluidic chip design enables cost-effective three-dimensional spatiotemporal transcriptomics with a wide field of view DOI Creative Commons
Junjie Zhu, Kun Pang, Beiyu Hu

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 10, 2024

Language: Английский

Citations

12
Immune checkpoints between epithelial-mesenchymal transition and autophagy: A conflicting triangle DOI Creative Commons
Marco Cordani, Raffaele Strippoli, Flavia Trionfetti

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 585, P. 216661 - 216661

Published: Feb. 2, 2024

Inhibitory immune checkpoint (ICP) molecules are pivotal in inhibiting innate and acquired antitumor responses, a mechanism frequently exploited by cancer cells to evade host immunity. These evasion strategies contribute the complexity of progression therapeutic resistance. For this reason, ICP have become targets for drugs, particularly monoclonal antibodies, collectively referred as inhibitors (ICI), that counteract such cancer-associated suppression restore responses. Over last decade, however, it has clear tumor cell-associated ICPs can also induce cell-intrinsic effects, particular epithelial-mesenchymal transition (EMT) macroautophagy (hereafter autophagy). Both these processes profound implications metastasis drug responsiveness. This article reviews positive or negative cross-talk undergo with autophagy EMT. We discuss upregulated response same stimuli Moreover, themselves, when overexpressed, an EMT-inducing stimulus. As regards autophagy, been shown either stimulate inhibit while itself up- downregulate expression ICPs. dynamic equilibrium extends autophagy-apoptosis axis, further emphasizing complexities cellular Eventually, we delve into intricate balance between apoptosis, elucidating its role broader interplay dynamics influenced In final part article, speculate about driving forces underlying contradictory outcomes reciprocal, inhibitory, stimulatory effects ICPs, EMT, autophagy. A conclusive identification may allow achieve improved using combinations ICIs compounds acting on EMT and/or Prospectively, translate increased broadened efficacy compared what is currently achieved ICI-based clinical protocols.

Language: Английский

Citations

9
Netrin-1 blockade inhibits tumor associated Myeloid-derived suppressor cells, cancer stemness and alleviates resistance to chemotherapy and immune checkpoint inhibitor DOI
Benjamin Ducarouge, Anna Rita Redavid,

Camille Victoor

et al.

Cell Death and Differentiation, Journal Year: 2023, Volume and Issue: 30(10), P. 2201 - 2212

Published: Aug. 26, 2023

Language: Английский

Citations

20
The role of stromal cells in epithelial–mesenchymal plasticity and its therapeutic potential DOI Creative Commons

Juanjing Wang,

Junmei Peng, Yonglin Chen

et al.

Discover Oncology, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 20, 2024

Language: Английский

Citations

5
Spatial transcriptomics in cancer research and potential clinical impact: a narrative review DOI Creative Commons
Michael A. Cilento, Christopher J. Sweeney, Lisa M. Butler

et al.

Journal of Cancer Research and Clinical Oncology, Journal Year: 2024, Volume and Issue: 150(6)

Published: June 8, 2024

Spatial transcriptomics (ST) provides novel insights into the tumor microenvironment (TME). ST allows quantification and illustration of gene expression profiles in spatial context tissues, including both cancer cells which they are found. In research, has already provided metastasis, prognosis, immunotherapy responsiveness. The clinical precision oncology application next-generation sequencing (NGS) RNA profiling tumors relies on bulk methods that lack context. ability to preserve information is now possible, as it us capture heterogeneity multifocality. this narrative review, we summarize oncology, discuss clinic, review available research methods, seqFISH, MERFISH (Vizgen), CosMx SMI (NanoString), Xenium (10x), Visium Stereo-seq (STOmics), GeoMx DSP (NanoString). We then current literature with a focus solid organized by type. Finally, conclude addressing an important question: how will ultimately help patients cancer?

Language: Английский

Citations

5