Harnessing Carcinoma Cell Plasticity Mediated by TGF-β Signaling

Wang, Xuecong; Thiery, Jean Paul

doi:10.3390/cancers13143397

Cited by 11 publications

(9 citation statements)

References 121 publications

(136 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In tumor cells, for example, intermediate (partial) EMT states were observed ( 3–5 ), and it was suggested that there is an association between intermediate EMT states and metastatic potentials ( 6 , 7 ). Interestingly, intermediate EMT states can also be observed in vitro with epithelial cell lines treated with EMT signals, such as TGF-β ( 3 , 8 ), and these in vitro experiments provide useful insights into molecular programs underlying partial EMT ( 9 ). For example, experiments with genetically perturbed cells have suggested that interconnected feedback loops in gene regulatory networks can generate multiple intermediate EMT states ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

Comparative single-cell transcriptomes of dose and time dependent epithelial–mesenchymal spectrums

Panchy

Watanabe

Takahashi

et al. 2022

NAR Genomics and Bioinformatics

View full text Add to dashboard Cite

Epithelial–mesenchymal transition (EMT) is a cellular process involved in development and disease progression. Intermediate EMT states were observed in tumors and fibrotic tissues, but previous in vitro studies focused on time-dependent responses with single doses of signals; it was unclear whether single-cell transcriptomes support stable intermediates observed in diseases. Here, we performed single-cell RNA-sequencing with human mammary epithelial cells treated with multiple doses of TGF-β. We found that dose-dependent EMT harbors multiple intermediate states at nearly steady state. Comparisons of dose- and time-dependent EMT transcriptomes revealed that the dose-dependent data enable higher sensitivity to detect genes associated with EMT. We identified cell clusters unique to time-dependent EMT, reflecting cells en route to stable states. Combining dose- and time-dependent cell clusters gave rise to accurate prognosis for cancer patients. Our transcriptomic data and analyses uncover a stable EMT continuum at the single-cell resolution, and complementary information of two types of single-cell experiments.

show abstract

Section: Introductionmentioning

confidence: 99%

Comparative single-cell transcriptomes of dose and time dependent epithelial–mesenchymal spectrums

Panchy

Watanabe

Takahashi

et al. 2022

NAR Genomics and Bioinformatics

View full text Add to dashboard Cite

show abstract

“…In tumor cells, for example, intermediate (partial) EMT states were observed [3-5], and it was suggested that there is an association between intermediate EMT states and metastatic potentials [6, 7]. Interestingly, intermediate EMT states can also be observed in vitro with epithelial cell lines treated with EMT signals, such as TGF-β [3, 8], and these in vitro experiments provide useful insights into molecular programs underlying partial EMT [9]. For example, experiments with genetically perturbed cells have suggested that interconnected feedback loops in gene regulatory networks can generate multiple intermediate EMT states [10].…”

Section: Introductionmentioning

confidence: 99%

Comparative single-cell transcriptomes of dose and time dependent epithelial-mesenchymal spectrums

Panchy

Watanabe

Takahashi

et al. 2022

Preprint

View full text Add to dashboard Cite

Epithelial-mesenchymal transition (EMT) is a key cellular process involved in development and disease progression. Single-cell transcriptomes can characterize intermediate EMT states observed in tumors and fibrotic tissues, but previous in vitro models focused on time-dependent responses after stimulation with single dose of EMT signals. It was therefore unclear whether single-cell transcriptomes support stable intermediate EMT phenotypes crucial for disease progression. We performed single-cell RNA-sequencing with human mammary epithelial cells treated with various concentrations of TGF-β. We found that the dose-dependent EMT harbors multiple intermediate states at the single-cell level after two weeks of treatment, suggesting a stable continuum. After correcting batch effects from experiments, we performed comparative analyses of the dose- and time-dependent EMT. We found that the dose-dependent EMT shows a stronger anti-correlation between epithelial and mesenchymal transcriptional programs and a better resolution of transition stages compared to the time-dependent process. These properties enable higher sensitivity to detect genes whose expressions are associated with core EMT regulatory networks. Nonetheless, we found cell clusters unique to the time-dependent EMT, which correspond to en route cell populations that do not appear at steady states. Furthermore, combining dose- and time-dependent cell clusters gave rise to more accurate prognosis for cancer patients compared to individual EMT spectrum. Our new data and analyses reveal a stable EMT continuum at the single-cell resolution and the transcriptomic level. The dose-dependent experimental model can complement the widely used time-course experiments to reflect physiologically or pathologically relevant EMT phenotypes in a comprehensive manner.

show abstract

“…The transforming growth factor-β protein can regulate cellular function [ 27 ], which is essential for the homeostasis of epithelial cells, matrix compartments, and immune cells in the hepatopancreas and gastrointestinal system [ 28 ]. The transforming growth factor-β signaling pathway plays an important role in tumorigenesis by regulating cell proliferation, apoptosis, angiogenesis, immune surveillance, and metastasis [ 29 – 31 ]. The phosphorylation of the receptor-activated Smads (R-Smads) results in the formation of complexes with the common medium Smad (Co-Smad), which are introduced into the nucleus [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Overexpressed integrin alpha 2 inhibits the activation of the transforming growth factor β pathway in pancreatic cancer via the TFCP2-SMAD2 axis

Cai

Guo

Wen

et al. 2022

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background Integrin alpha 2 (ITGA2) has been recently reported to be an oncogene and to play crucial roles in tumor cell proliferation, invasion, metastasis, and angiogenesis. Our previous study showed that ITGA2 was overexpressed in pancreatic cancer and promoted its progression. However, the mechanism of ITGA2 overexpression and other mechanisms for promoting the progression of pancreatic cancer are still unclear. Methods The GEPIA database was used to confirm the expression of ITGA2 in pancreatic cancer. To verify the influence of ITGA2 and TGF-β on the morphological changes of pancreatic cancer and tumor cell progression, we conduct CCK8 test, plate cloning, flow cytometry experiments and animal experiments. Then we conduct Western blot, RT-qPCR to explore the relationship between ITGA2 and TGF-β, and then find the key molecules which can regulate them by immunoprecipitation, Western blot, RT-qPCR, CHIP, nuclear and cytoplasmic separation test. Results The results of the present study show that the abnormal activation of KRAS induced the overexpression of ITGA2 in pancreatic cancer. Moreover, ITGA2 expression significantly suppressed the activation of the TGF-β pathway. ITGA2 silencing enhanced the anti-pancreatic cancer proliferation and tumor growth effects of TGF-β. Mechanistically, ITGA2 expression suppressed the activation of the TGF-β pathway by inhibiting the SMAD2 expression transcriptionally. In addition, it interacted with and inhibited the nuclear translocation of TFCP2, which induced the SMAD2 expression as a transcription factor. Furthermore, TFCP2 also induced ITGA2 expression as a transcription factor, and the TFCP2 feedback regulated the ITGA2-TFCP2-SMAD2 pathway. Conclusions Taken together, these results indicated that ITGA2 expression could inhibit the activation of the TGF-β signaling pathway in pancreatic cancer via the TFCP2-SMAD2 axis. Therefore, ITGA2, by effectively enhancing the anti-cancer effects of TGF- β, might be a potential clinical therapeutic target for pancreatic cancer.

show abstract

Harnessing Carcinoma Cell Plasticity Mediated by TGF-β Signaling

Cited by 11 publications

References 121 publications

Comparative single-cell transcriptomes of dose and time dependent epithelial–mesenchymal spectrums

Comparative single-cell transcriptomes of dose and time dependent epithelial–mesenchymal spectrums

Comparative single-cell transcriptomes of dose and time dependent epithelial-mesenchymal spectrums

Overexpressed integrin alpha 2 inhibits the activation of the transforming growth factor β pathway in pancreatic cancer via the TFCP2-SMAD2 axis

Contact Info

Product

Resources

About