Non-canonical functions of SNAIL drive context-specific cancer progression

Paul, Mariel C.; Schneeweis, Christian; Falcomatà, Chiara; Shan, Chuan; Rossmeisl, Daniel; Koutsouli, Stella; Klement, Christine; Żukowska, Magdalena; Widholz, Sebastian A.; Jesinghaus, Moritz; Heuermann, Konstanze K.; Engleitner, Thomas; Seidler, Barbara; Sleiman, Katia; Steiger, Katja; Tschurtschenthaler, Markus; Benjamín, Walter; Weidemann, Sören; Pietsch, Regina; Schnieke, Angelika; Schmid, Roland M.; Robles, María S.; Andrieux, Geoffroy; Boerries, Melanie; Rad, Roland; Schneider, Günter; Saur, Dieter

doi:10.1038/s41467-023-36505-0

Cited by 16 publications

(14 citation statements)

References 84 publications

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“…Many in vitro as well as computational studies have reported SNAIL as a key transcriptional regulator driving EMT and metastasis formation. However, a recent in vivo study on mouse model of pancreatic ductal adenocarcinomas (PDAC) provided a counter perspective by showing that SNAIL deletion does not block EMT and is thus not rate-limiting for EMT and metastasis 51 . Also, different member of SNAIL family of transcription factors have diverse functionality and not all of them induce EMT.…”

Section: Resultsmentioning

confidence: 99%

Combinatorial cooperativity can facilitate epithelial-mesenchymal transition in a miR200-Zeb feedback network

Rashid,

Devi,

Banerjee

2023

Preprint

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Carcinoma cells often utilize epithelial-mesenchymal transition (EMT) programs for cancer progression and metastasis. Numerous studies point to the SNAIL-induced miR200/Zeb feedback circuit as crucial in regulating EMT by shifting cancer cells to at least three (epithelial (E), hybrid (h E/M), mesenchymal (M)) phenotypic states arrayed along the epithelial-mesenchymal phenotypic spectrum. However, a coherent molecular-level understanding of how such a tiny circuit controls carcinoma cell entrance into and residence in various states is lacking. Here, we use molecular binding data and mathematical modeling to report that miR200/Zeb circuit can essentially utilize combinatorial cooperativity to control E-M phenotypic plasticity. We identify minimal combinatorial cooperativities that give rise to E, hybrid-E/M, and M phenotypes. We show that disrupting a specific number of miR200 binding sites on Zeb as well as Zeb binding sites on miR200 can have phenotypic consequences – the circuit can dynamically switch between two (E, M) and three (E, hybrid-E/M, M) phenotypes. Further, we report that in both SNAIL-induced and SNAIL knock-out miR200/Zeb circuits, cooperative transcriptional feedback on Zeb as well as Zeb translational inhibition due to miR200 are essential for the occurrence of intermediate hybrid-E/M phenotype. Finally, we demonstrate that SNAIL can be dispensable for EMT, and in the absence of SNAIL, the transcriptional feedback can control cell state transition from E to hybrid-E/M, to M state. Our results thus highlight molecular-level regulation of EMT in miR200/Zeb circuit and we expect these findings to be crucial to future efforts aiming to prevent EMT-facilitated dissemination of carcinomas.

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Section: Resultsmentioning

confidence: 99%

Combinatorial cooperativity can facilitate epithelial-mesenchymal transition in a miR200-Zeb feedback network

Rashid,

Devi,

Banerjee

2023

Preprint

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“…As shown in (Figure 7A), besides SNAI1 , no other genes exhibited robust upregulation upon acetyl-CoA supplementation in ACSL4 knockdown cells compared to control. Since SNAIL has been extensively and conclusively characterized as a master regulator of EMT process, initiating cancer cell plasticity, migration, and metastatic dissemination across diverse tumor types 32, 51, 52 . The downregulation of SNAIL in ACSL4 knockdown cells highlights its role in impeding the metastatic potential of TNBC, emphasizing the significance of lower SNAIL expression following ACSL4 activity loss.…”

Section: Resultsmentioning

confidence: 99%

ACSL4 activity drives TNBC metastasis by positively regulating Histone H3 Acetylation mediated SNAIL expression

Sinha,

Saini,

Tripathi

et al. 2023

Preprint

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Triple-Negative Breast Cancer (TNBC) has profound unmet medical need globally for its devastating clinical outcome associated with rapid metastasis and lack of targeted therapies. Recently, lipid metabolic reprogramming has emerged as a major driver of breast cancer metastasis. Here, we unveil a strong association between the heightened expression of fatty acid metabolic enzyme, acyl-CoA synthetase 4 (ACSL4) and TNBC, which is primarily attributed by the selective absence of progesterone receptor (PR). Loss of ACSL4 function, either through genetic ablation or pharmacological inhibition significantly reduces metastatic potential of TNBC. Global transcriptome analysis reveals that ACSL4 activity markedly influences the gene expression pattern associated with TNBC migration. Mechanistically, ACSL4 alters fatty acid oxidation (FAO) and cellular acetyl-CoA levels, leading to the hyper- acetylation of particularly H3K27Ac and H3K9Ac marks resulting in overexpression of SNAIL during the course of TNBC metastatic spread to lymph node and lungs. Further, human TNBC metastasis exhibits positive correlation between ACSL4 and SNAIL expression. Altogether, our findings provide new molecular insights regarding the intricate interplay between metabolic alterations and epigenetic modifications, intertwined to orchestrate TNBC metastasis and posit a rational understanding for the development of ACSL4 inhibitors as a targeted therapy against TNBC.

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“…In PDAC, mouse models revealed that EMT occurs extremely early in disease progression in disseminating tumor cells, even before the development of a primary tumor [ 12 ]. In contrast, intriguing recent studies have suggested that metastasis can occur in the absence of EMT [ 24 , 25 , 28 ], and that canonical EMT factors may promote tumor progression by EMT-independent pathways [ 29 ]. For example, Zheng reported that EMT is not required for invasion or metastasis in PDAC [ 30 ].…”

Section: Epithelial-to-mesenchymal Transition In Pdacmentioning

confidence: 99%

The Cell Biology of Metastatic Invasion in Pancreatic Cancer: Updates and Mechanistic Insights

Joshi

Ruiz

Razidlo

2023

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality worldwide. This is largely due to the lack of routine screening protocols, an absence of symptoms in early-stage disease leading to late detection, and a paucity of effective treatment options. Critically, the majority of patients either present with metastatic disease or rapidly develop metastatic disease. Thus, there is an urgent need to deepen our understanding of metastasis in PDAC. During metastasis, tumor cells escape from the primary tumor, enter the circulation, and travel to a distant site to form a secondary tumor. In order to accomplish this relatively rare event, tumor cells develop an enhanced ability to detach from the primary tumor, migrate into the surrounding matrix, and invade across the basement membrane. In addition, cancer cells interact with the various cell types and matrix proteins that comprise the tumor microenvironment, with some of these factors working to promote metastasis and others working to suppress it. In PDAC, many of these processes are not well understood. The purpose of this review is to highlight recent advances in the cell biology of the early steps of the metastatic cascade in pancreatic cancer. Specifically, we will examine the regulation of epithelial-to-mesenchymal transition (EMT) in PDAC and its requirement for metastasis, summarize our understanding of how PDAC cells invade and degrade the surrounding matrix, and discuss how migration and adhesion dynamics are regulated in PDAC to optimize cancer cell motility. In addition, the role of the tumor microenvironment in PDAC will also be discussed for each of these invasive processes.

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Non-canonical functions of SNAIL drive context-specific cancer progression

Cited by 16 publications

References 84 publications

Combinatorial cooperativity can facilitate epithelial-mesenchymal transition in a miR200-Zeb feedback network

Combinatorial cooperativity can facilitate epithelial-mesenchymal transition in a miR200-Zeb feedback network

ACSL4 activity drives TNBC metastasis by positively regulating Histone H3 Acetylation mediated SNAIL expression

The Cell Biology of Metastatic Invasion in Pancreatic Cancer: Updates and Mechanistic Insights

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