Tumor budding is a prognostic factor linked to epithelial mesenchymal transition in pancreatic ductal adenocarcinoma. Study report and literature review

Chouat, Ezzeddine; Zehani, Alia; Chelly, Inès; Njima, Manel; Maghrebi, Houcine; Bani, Mohamed Amine; Njim, Leïla; Zakhama, Abdelfattah; Haouet, Slim; Kchir, Nidhameddine

doi:10.1016/j.pan.2017.11.010

Cited by 33 publications

(44 citation statements)

References 17 publications

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“…Support for this comes from previous studies showing that RAC1B suppressed SERPINE1 (encoding plasminogen-activator inhibitor 1), MMP9 (encoding MMP9) [17], and TGFBRI (encoding the TGF-β type I receptor activin receptor-like kinase 5) [20]. Here we analyzed if the intermediate filament protein Vimentin (encoded by VIM), a marker for EMT [29] associated with pancreatic tumor budding [7], is also targeted for inhibition by RAC1B. Strikingly, knockdown of RAC1B increased TGF-β1-regulated protein ( Figure 4A) and mRNA (Supplementary Figure S5) expression of Vimentin indicating relief from inhibition by RAC1B.…”

Section: Rac1b Inhibits the Expression Of Mesenchymal Genes And Theirmentioning

confidence: 81%

“…Tumor budding has been associated with EMT and occurs frequently in pancreatic cancer [7,46]. It is defined as the presence of detached, isolated single cells or small cell clusters scattered in the stroma at the invasive tumor front, essentially reflecting a type of diffusely infiltrative growth.…”

Section: Discussionmentioning

confidence: 99%

“…EMT is an evolutionary conserved genetic program that has been adopted by many carcinomas to facilitate invasion and metastasis, cancer stem cell formation, as well as therapy resistance and cancer relapse [5]. In fact, EMT strongly correlates with the systemic aggressiveness of pancreatic tumors [6] and is associated with tumor budding as inferred from association with the EMT marker Vimentin [7].…”

Section: Introductionmentioning

confidence: 99%

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RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition

Zinn

Otterbein

Lehnert

et al. 2019

Cells

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The small GTPase Ras-related C3 botulinum toxin substrate 1B (RAC1B) has been shown to potently inhibit transforming growth factor (TGF)-β1-induced cell migration and epithelial-mesenchymal transition (EMT) in pancreatic and breast epithelial cells, but the underlying mechanism has remained obscure. Using a panel of pancreatic ductal adenocarcinoma (PDAC)-derived cell lines of different differentiation stages, we show that RAC1B is more abundantly expressed in well differentiated as opposed to poorly differentiated cells. Interestingly, RNA interference-mediated knockdown of RAC1B decreased expression of the epithelial marker protein E-cadherin, encoded by CDH1, and enhanced its TGF-β1-induced downregulation, whereas ectopic overexpression of RAC1B upregulated CDH1 expression and largely prevented its TGF-β1-induced silencing of CDH1. Conversely, knockdown of RAC1B, or deletion of the RAC1B-specific exon 3b by CRISPR/Cas-mediated genomic editing, enhanced basal and TGF-β1-induced upregulation of mesenchymal markers like Vimentin, and EMT-associated transcription factors such as SNAIL and SLUG. Moreover, we demonstrate that knockout of RAC1B enhanced the cells’ migratory activity and derepressed TGF-β1-induced activation of the mitogen-activated protein kinase ERK2. Pharmacological inhibition of ERK1/2 activation in RAC1B-depleted cells rescued cells from the RAC1B knockdown-induced enhancement of cell migration, TGF-β1-induced downregulation of CDH1, and upregulation of SNAI1. We conclude that RAC1B promotes epithelial gene expression and suppresses mesenchymal gene expression by interfering with TGF-β1-induced MEK-ERK signaling, thereby protecting cells from undergoing EMT and EMT-associated responses like acquisition of cell motility.

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Section: Rac1b Inhibits the Expression Of Mesenchymal Genes And Theirmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition

Zinn

Otterbein

Lehnert

et al. 2019

Cells

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“…Accumulating evidences have implicated tumor budding as a strong and valuable independent prognostic factor in many solid cancers . Moreover, evaluation of tumor budding in biopsy specimens also might provide useful prognostic information, indicating a promising clinical application for patient diagnosis and treatment .…”

Section: Discussionmentioning

confidence: 99%

“…It is defined as a single, isolated cancer cell or small cluster composed of fewer than five cells . Those budding cells represent a phenotype undergoing epithelial‐mesenchymal transition (EMT) or dedifferentiation . Accumulating evidence indicates that tumor budding is a valuable prognostic marker in many solid tumors due to it is correlated with more aggressive behavior and poor prognosis .…”

Section: Introductionmentioning

confidence: 99%

Validation of the International Tumor Budding Consensus Conference (2016) recommendations in oral tongue squamous cell carcinoma

Xie

Liu

et al. 2019

J Oral Pathology Medicine

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Background Tumor budding is a valuable prognostic marker in oral tongue squamous cell carcinoma (OTSCC) but lacks a standardized scoring system. The aim of this study was to evaluate the prognostic value of tumor budding for OTSCC patients based on the scoring system recommended by the International Tumor Budding Consensus Conference (ITBCC) 2016. Methods Tumor budding was scored as ITBCC recommended in 255 patients with OTSCC. Then, associations between tumor budding and clinicopathologic parameters were examined. Among them, 136 patients with follow‐up data available were used to evaluate overall survival (OS) by the Kaplan‐Meier method. Prognostic value of tumor budding was assessed by Cox regression analysis. The inter‐observer and intra‐observer agreement was calculated by the kappa statistic. Results Tumor budding score was associated with lymph node metastasis, differentiation, invasive pattern, lymphoid infiltrate, tumor relapse, invasive depth, and reduced OS in OTSCC patients. The Cox analysis showed high budding score was an independent prognostic factor in patients with all clinical stage and patients with clinical early‐stage OTSCC. The high kappa values were achieved in intra‐observer and inter‐observer. Conclusions International Tumor Budding Consensus Conference scoring system is a simple, reliable, and reproducible method to measure tumor budding in OTSCC, which should be included in the routine pathological report.

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CD73, a Promising Therapeutic Target of Diclofenac, Promotes Metastasis of Pancreatic Cancer through a Nucleotidase Independent Mechanism

Liu

Yuan

et al. 2022

Advanced Science

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CD73, a cell surface-bound nucleotidase, facilitates extracellular adenosine formation by hydrolyzing 5′-AMP to adenosine. Several studies have shown that CD73 plays an essential role in immune escape, cell proliferation and tumor angiogenesis, making it an attractive target for cancer therapies. However, there are limited clinical benefits associated with the mainstream enzymatic inhibitors of CD73, suggesting that the mechanism underlying the role of CD73 in tumor progression is more complex than anticipated, and further investigation is necessary. In this study, CD73 is found to overexpress in the cytoplasm of pancreatic ductal adenocarcinoma (PDAC) cells and promotes metastasis in a nucleotidase-independent manner, which cannot be restrained by the CD73 monoclonal antibodies or small-molecule enzymatic inhibitors. Furthermore, CD73 promotes the metastasis of PDAC by binding to the E3 ligase TRIM21, competing with the Snail for its binding site. Additionally, a CD73 transcriptional inhibitor, diclofenac, a non-steroidal anti-inflammatory drug, is more effective than the CD73 blocking antibody for the treatment of PDAC metastasis. Diclofenac also enhances the therapeutic efficacy of gemcitabine in the spontaneous KPC (LSL-Kras G12D/+ , LSL-Trp53 R172H/+ , and Pdx-1-Cre) pancreatic cancer model. Therefore, diclofenac may be an effective anti-CD73 therapy, when used alone or in combination with gemcitabine-based chemotherapy regimen, for metastatic PDAC.

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Tumor budding is a prognostic factor linked to epithelial mesenchymal transition in pancreatic ductal adenocarcinoma. Study report and literature review

Cited by 33 publications

References 17 publications

RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition

RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition

Validation of the International Tumor Budding Consensus Conference (2016) recommendations in oral tongue squamous cell carcinoma

CD73, a Promising Therapeutic Target of Diclofenac, Promotes Metastasis of Pancreatic Cancer through a Nucleotidase Independent Mechanism

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