Regulation of epithelial-mesenchymal transition by tumor microenvironmental signals and its implication in cancer therapeutics DOI Creative Commons
Jing Zhang, Zhimin Hu,

Calista A. Horta

et al.

Seminars in Cancer Biology, Journal Year: 2022, Volume and Issue: 88, P. 46 - 66

Published: Dec. 13, 2022

Epithelial–mesenchymal transition (EMT) has been implicated in various aspects of tumor development, including invasion and metastasis, cancer stemness, therapy resistance. Diverse stroma cell types along with biochemical biophysical factors the microenvironment impinge on EMT program to impact progression. Here we provide an in-depth review microenvironmental signals that regulate cancer. We discuss molecular mechanisms underlying role resistance highlight new therapeutic approaches targeting

Language: Английский

Metastasis DOI Creative Commons

Stefanie Gerstberger,

Qingwen Jiang, Karuna Ganesh

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(8), P. 1564 - 1579

Published: April 1, 2023

Language: Английский

Citations

364
Lineage tracing reveals the phylodynamics, plasticity, and paths of tumor evolution DOI Creative Commons
Dian Yang, Matthew G. Jones,

Santiago Naranjo

et al.

Cell, Journal Year: 2022, Volume and Issue: 185(11), P. 1905 - 1923.e25

Published: May 1, 2022

Tumor evolution is driven by the progressive acquisition of genetic and epigenetic alterations that enable uncontrolled growth expansion to neighboring distal tissues. The study phylogenetic relationships between cancer cells provides key insights into these processes. Here, we introduced an evolving lineage-tracing system with a single-cell RNA-seq readout mouse model Kras;Trp53(KP)-driven lung adenocarcinoma tracked tumor from single-transformed metastatic tumors at unprecedented resolution. We found loss initial, stable alveolar-type2-like state was accompanied transient increase in plasticity. This followed adoption distinct transcriptional programs rapid and, ultimately, clonal sweep subclones capable metastasizing. Finally, develop through stereotypical evolutionary trajectories, perturbing additional suppressors accelerates progression creating novel trajectories. Our elucidates hierarchical nature more broadly, enables in-depth studies progression.

Language: Английский

Citations

223
Cancer cell plasticity during tumor progression, metastasis and response to therapy DOI
Andrea Pérez-González, Kevin Bévant, Cédric Blanpain

et al.

Nature Cancer, Journal Year: 2023, Volume and Issue: 4(8), P. 1063 - 1082

Published: Aug. 3, 2023

Language: Английский

Citations

146
Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities DOI Creative Commons
Zhao Huang, Zhe Zhang, Chengwei Zhou

et al.

MedComm, Journal Year: 2022, Volume and Issue: 3(2)

Published: May 18, 2022

Abstract Epithelial–mesenchymal transition (EMT) is a program wherein epithelial cells lose their junctions and polarity while acquiring mesenchymal properties invasive ability. Originally defined as an embryogenesis event, EMT has been recognized crucial process in tumor progression. During EMT, cell–cell cell–matrix attachments are disrupted, the cytoskeleton remodeled to enhance mobility of cells. This phenotype largely driven by group key transcription factors, typically Snail, Twist, ZEB, through epigenetic repression markers, transcriptional activation matrix metalloproteinases, reorganization cytoskeleton. Mechanistically, orchestrated multiple pathways, especially those involved such TGFβ, Wnt, Hedgehog, Hippo, suggesting intrinsic link between embryonic development cancer In addition, redox signaling also emerged critical modulator. confers with increased metastatic potential drug resistant capacity, which accounts for recurrence most clinic cases. Thus, targeting can be therapeutic option providing chance cure patients. Here, we introduce brief history summarize recent advances understanding mechanisms, well highlighting opportunities treatment.

Language: Английский

Citations

94
Heterogeneity and plasticity of epithelial–mesenchymal transition (EMT) in cancer metastasis: Focusing on partial EMT and regulatory mechanisms DOI Creative Commons

Dandan Li,

Lingyun Xia,

Pan Huang

et al.

Cell Proliferation, Journal Year: 2023, Volume and Issue: 56(6)

Published: Feb. 19, 2023

Epithelial-mesenchymal transition (EMT) or mesenchymal-epithelial (MET) plays critical roles in cancer metastasis. Recent studies, especially those based on single-cell sequencing, have revealed that EMT is not a binary process, but heterogeneous and dynamic disposition with intermediary partial states. Multiple double-negative feedback loops involved by EMT-related transcription factors (EMT-TFs) been identified. These between drivers MET finely regulate the state of cell. In this review, general characteristics, biomarkers molecular mechanisms different states were summarized. We additionally discussed direct indirect tumour More importantly, article provides evidence heterogeneity closely related to poor prognosis gastric cancer. Notably, seesaw model was proposed explain how cells themselves remain specific states, including epithelial state, hybrid/intermediate mesenchymal state. Additionally, also review current status, limitations future perspectives signalling clinical applications.

Language: Английский

Citations

78
EMT/MET plasticity in cancer and Go-or-Grow decisions in quiescence: the two sides of the same coin? DOI Creative Commons
Azamat Akhmetkaliyev,

Noura Alibrahim,

Darya Shafiee

et al.

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: May 31, 2023

Epithelial mesenchymal transition (EMT) and epithelial (MET) are genetic determinants of cellular plasticity. These programs operate in physiological (embryonic development, wound healing) pathological (organ fibrosis, cancer) conditions. In cancer, EMT MET interfere with various signalling pathways at different levels. This results gross alterations the gene expression programs, which affect most, if not all hallmarks such as response to proliferative death-inducing signals, tumorigenicity, cell stemness. cancer cells involves large scale reorganisation cytoskeleton, loss integrity, gain traits, type migration. this regard, EMT/MET plasticity is highly relevant Go-or-Grow concept, postulates dichotomous relationship between motility proliferation. The decisions critically important processes takes central stage, mobilisation stem during healing, relapse, metastasis. Here we outline maintenance quiescence metastatic niches, focusing on implication regulatory networks switches. particular, discuss analogy residing hybrid quasi-mesenchymal states GAlert, an intermediate phase allowing quiescent enter cycle rapidly.

Language: Английский

Citations

74
The epithelial–mesenchymal plasticity landscape: principles of design and mechanisms of regulation DOI
Jef Haerinck, Steven Goossens, Geert Berx

et al.

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(9), P. 590 - 609

Published: May 11, 2023

Language: Английский

Citations

68
Analysis of Donor Pancreata Defines the Transcriptomic Signature and Microenvironment of Early Neoplastic Lesions DOI Creative Commons
Eileen S. Carpenter, Ahmed M. Elhossiny, Padma Kadiyala

et al.

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(6), P. 1324 - 1345

Published: April 6, 2023

Abstract The adult healthy human pancreas has been poorly studied given the lack of indication to obtain tissue from in absence disease and rapid postmortem degradation. We obtained pancreata brain dead donors, thus avoiding any warm ischemia time. 30 donors were diverse age race had no known disease. Histopathologic analysis samples revealed pancreatic intraepithelial neoplasia (PanIN) lesions most individuals irrespective age. Using a combination multiplex IHC, single-cell RNA sequencing, spatial transcriptomics, we provide first-ever characterization unique microenvironment sporadic PanIN lesions. compared cancer peritumoral observed distinct transcriptomic signatures fibroblasts and, lesser extent, macrophages. epithelial cells remarkably transcriptionally similar cells, suggesting that neoplastic pathways are initiated early tumorigenesis. Significance: Precursor characterized. analyzed donor discovered precursor detected at much higher rate than incidence cancer, setting stage for efforts elucidate microenvironmental cell-intrinsic factors restrain or, conversely, promote malignant progression. See related commentary by Hoffman Dougan, p. 1288. This article is highlighted In Issue feature, 1275

Language: Английский

Citations

63
Pharmacological targeting of netrin-1 inhibits EMT in cancer DOI

Justine Lengrand,

Ievgenia Pastushenko, Sebastiaan Vanuytven

et al.

Nature, Journal Year: 2023, Volume and Issue: 620(7973), P. 402 - 408

Published: Aug. 2, 2023

Language: Английский

Citations

62
Single-cell RNA-sequencing reveals radiochemotherapy-induced innate immune activation and MHC-II upregulation in cervical cancer DOI Creative Commons
Chao Liu, Xiaohui Li, Qingyu Huang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Jan. 30, 2023

Radiochemotherapy (RCT) is a powerful treatment for cervical cancer, which affects not only malignant cells but also the immune and stromal compartments of tumor. Understanding remodeling local ecosystem induced by RCT would provide valuable insights into improving strategies cancer. In this study, we applied single-cell RNA-sequencing to paired pre- post-RCT tumor biopsies from patients with cancer adjacent normal tissues. We found that residual population epithelial showed upregulated expression MHC class II genes. Moreover, led accumulation monocytic myeloid-derived suppressor increased pro-inflammatory features CD16+ NK higher cytotoxic gene signature. However, subclusters T no significant increase in post-RCT. These results reveal complex responses RCT, providing evidence activation innate immunity MHC-II upregulation

Language: Английский

Citations

55