TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

Thakur, A K; Nigri, Jérémy; Lac, Sophie; Leca, Julie; Bressy, Christian; Berthézène, P.; Bartholin, Laurent; Chan, Philippe; Calvo, Ézéquiel; Iovanna, Juan; Vasseur, Sophie; Guillaumond, Fabienne; Tomasini, Richard

doi:10.1038/cdd.2016.18

Cited by 42 publications

(35 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When comparing the two basal subpopulations, we found that the main systematic differences were linked to extracellular matrix (ECM) proteins or epithelial-to-mesenchymal transition (EMT) signatures, which were strongly upregulated in the tumor-specific basal subset. Specifically, we observed a more than two-fold upregulation of the EMT master regulator Snai2 and strong induction of other characteristic genes such as Serpine2, Sparc, Acta2, S100a6 or the TGF-β modulator Bgn 53 (Fig. 4c, Supplementary Fig.…”

Section: Resultsmentioning

confidence: 92%

Tracing tumorigenesis in a solid tumor model at single-cell resolution

et al. 2020

View full text Add to dashboard Cite

Characterizing the complex composition of solid tumors is fundamental for understanding tumor initiation, progression and metastasis. While patient-derived samples provide valuable insight, they are heterogeneous on multiple molecular levels, and often originate from advanced tumor stages. Here, we use single-cell transcriptome and epitope profiling together with pathway and lineage analyses to study tumorigenesis from a developmental perspective in a mouse model of salivary gland squamous cell carcinoma. We provide a comprehensive cell atlas and characterize tumor-specific cells. We find that these cells are connected along a reproducible developmental trajectory: initiated in basal cells exhibiting an epithelial-tomesenchymal transition signature, tumorigenesis proceeds through Wnt-differential cancer stem cell-like subpopulations before differentiating into luminal-like cells. Our work provides unbiased insights into tumor-specific cellular identities in a whole tissue environment, and emphasizes the power of using defined genetic model systems.

show abstract

Section: Resultsmentioning

confidence: 92%

Tracing tumorigenesis in a solid tumor model at single-cell resolution

et al. 2020

View full text Add to dashboard Cite

show abstract

“…p53 family can be considered among the most powerful family of genes for the wide range of functions covering from tumour suppression, homeostasis and development [1][2][3][4][5][6][7][8][9][10][11]. In this context the p53 family member p73 plays critical roles such as tumour suppression [12][13][14][15][16][17], neuronal development and differentiation [18][19][20][21][22][23][24], metabolic control [25][26][27][28][29][30][31][32][33], and spermatogenesis and the maintenance of male and female fertility [34][35][36][37]. However, despite the important effort placed in investigating p73 functioning, a full dissections of its transcriptional programme and a clearly distinction of this from the transcriptome of its sibling p53 has not been completely elucidated.…”

Section: Introductionmentioning

confidence: 99%

Integrin-β4 is a novel transcriptional target of TAp73

Xie

Vikhreva

Annicchiarico-Petruzzelli

et al. 2018

Cell Cycle

View full text Add to dashboard Cite

As a member of p53 family, p73 has attracted intense investigations due to its structural and functional similarities to p53. Among more than ten p73 variants, the transactivation (TA) domain-containing isoform TAp73 is the one that imitates the p53's behavior most. TAp73 induces apoptosis and cell cycle arrest, which endows it the capacity of tumour suppression. Also, it can exert diverse biological influences on cells through activating a complex and context dependent transcriptional programme. The transcriptional activities further broaden its roles in more intricate biological processes. In this article, we report that p73 is a positive regulator of a cell adhesion related gene named integrin β4 (ITGB4). This finding may have implications for the dissection of the biological mechanisms underlining p73 functions.

show abstract

“…TGF-β activates SMAD signaling and induces EMT in CRC cells. TGF-β, a multifunctional cytokine, can induce EMT in tumor cells via both SMAD-dependent and SMAD-independent activation of EMT-related transcription factors (21,22). Firstly, it was confirmed that 10 ng/ml TGF-β could activate classic SMAD signaling in CRC cells.…”

Section: Adspred2 Inhibits the Emt Of Crc Cells In Vitromentioning

confidence: 87%

“…EMT, which plays crucial roles in both embryonic development and tumor metastasis, is characterized by the loss of epithelial markers and acquisition of mesenchymal markers (31)(32)(33). TGF-β, a pleiotropic cytokine, is a pivotal molecule in the EMT processing of tumor cells and can activate EMT-related transcription factors in both SMAD-dependent and SMAD-independent manners (21,22,34). It was confirmed that 10 ng/ml TGF-β could activate SMAD signaling and increase cellular migration in CRC cells by promoting reorganization of the actin cytoskeleton and upregulating vimentin expression.…”

Section: Discussionmentioning

confidence: 99%

Spred2 inhibits epithelial‑mesenchymal transition of colorectal cancer cells by impairing ERK signaling

Wang¹,

Liu²,

Kong³

et al. 2020

Oncol Rep

View full text Add to dashboard Cite

Downregulation of the sprouty-related EVH1 domain protein 2 (Spred2) is closely associated with highly metastatic phenotypes in various tumors. However, the roles of Spred2 in the development and progression of colorectal cancer (CRC) are still largely unexplored. As anticipated, Spred2 expression was significantly downregulated in clinical tumor tissues. To restore Spred2 levels, Ad.Spred2, an adenoviral vector expressing Spred2, was transduced into CRC cells. It was revealed that Ad.Spred2 inhibited the proliferation and decreased the survival and migration of SW480 cells. Epithelial-mesenchymal transition (EMT) is an essential event during tumor metastasis to distant sites. It was revealed that Ad.Spred2 markedly inhibited EMT by promoting F-actin reorganization, upregulating E-cadherin levels and reducing vimentin protein expression. Notably, extracellular-regulated kinase (ERK) signaling inhibition by PD98059 induced similar effects on EMT in CRC cells, indicating that Ad.Spred2 regulated EMT in CRC cells in an ERK-dependent manner. Transforming growth factor β (TGF-β), a well-known inducer of EMT, increased E-cadherin expression, decreased vimentin expression and promoted migration in CRC cells. However, neither Ad.Spred2 nor PD98059 had an obvious effect on the expression of SMAD2/3 or SMAD4 in SW480 cells, indicating that Ad.Spred2 inhibited EMT in a SMAD-independent manner. Notably, Ad.Spred2 transduction downregulated SAMD2/3 and SMAD4 levels in HCT116 cells in an ERK-independent manner. It was speculated that Ad.Spred2 inhibited the EMT of HCT116 cells by both blocking ERK signaling and reducing SMAD signaling. It was concluded that Spred2 inhibited EMT in CRC cells by interfering with ERK signaling, with or without reduced SMAD signaling. Therefore, the introduction of the clinical application of Spred2 has great potential for development as a gene therapy approach for CRC.

show abstract

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

Cited by 42 publications

References 60 publications

Tracing tumorigenesis in a solid tumor model at single-cell resolution

Tracing tumorigenesis in a solid tumor model at single-cell resolution

Integrin-β4 is a novel transcriptional target of TAp73

Spred2 inhibits epithelial‑mesenchymal transition of colorectal cancer cells by impairing ERK signaling

Contact Info

Product

Resources

About