Protein Kinase D1, Reduced in Human Pancreatic Tumors, Increases Secretion of Small Extracellular Vesicles From Cancer Cells That Promote Metastasis to Lung in Mice

Armacki, Milena; Polaschek, Sandra; Waldenmaier, Mareike; Morawe, Mareen; Ruhland, Claudia; Schmid, Rebecca Rosa; Lechel, André; Tharehalli, Umesh; Steup, Christoph; Bektas, Yasin; Li, Hongxia; Kraus, Johann M.; Kestler, Hans A.; Krüger, Stephan; Ormanns, Steffen; Walther, Paul; Eiseler, Tim; Seufferlein, Thomas

doi:10.1053/j.gastro.2020.05.052

Cited by 56 publications

(58 citation statements)

References 76 publications

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“…Unphosphorylated CFL1 translocates to the mitochondrion after induction of apoptosis [122][123][124][125] and acts as a carrier for BAX [126]. [130,131] TCF7L2 (active) GSE15471, GSE16515, GSE32676 (see Figure 4b) AURKA (active) GSE15471, GSE16515, GSE32676 (see Figure 4a) SSH1L (active) [ First, we concentrated on processes leading to overexpression and activation of CFL1. Following the progression towards cancer, our model shows an imbalance between the two opponents ras homolog family member A (RHOA) and ras-related botulinum toxin substrate 1 (RAC1) in favor of RAC1 (Figure 3b).…”

Section: Ssh1lmentioning

confidence: 99%

Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer

Werle

Schwab

Tatura

et al. 2021

Cancers

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Cofilin-1 (CFL1) overexpression in pancreatic cancer correlates with high invasiveness and shorter survival. Besides a well-documented role in actin remodeling, additional cellular functions of CFL1 remain poorly understood. Here, we unraveled molecular tumor-promoting functions of CFL1 in pancreatic cancer. For this purpose, we first show that a knockdown of CFL1 results in reduced growth and proliferation rates in vitro and in vivo, while apoptosis is not induced. By mechanistic modeling we were able to predict the underlying regulation. Model simulations indicate that an imbalance in actin remodeling induces overexpression and activation of CFL1 by acting on transcription factor 7-like 2 (TCF7L2) and aurora kinase A (AURKA). Moreover, we could predict that CFL1 impacts proliferation and apoptosis via the signal transducer and activator of transcription 3 (STAT3). These initial model-based regulations could be substantiated by studying protein levels in pancreatic cancer cell lines and human datasets. Finally, we identified the surface protein CD44 as a promising therapeutic target for pancreatic cancer patients with high CFL1 expression.

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Section: Ssh1lmentioning

confidence: 99%

Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer

Werle

Schwab

Tatura

et al. 2021

Cancers

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“…Additional evidence has demonstrated that PaCaExos that are positive for integrin αvβ5 usually reach the liver, whereas integrin α6β4- and α6β1-containing exosomes are transported to the lungs [ 116 ]. A recent study has demonstrated that protein kinase D1 (PRKD-1) expression is significantly downregulated in PaCa tissues when compared to non-tumor tissues [ 131 ]. Particularly, PRKD-1 knockout can induce PaCa cells (Panc-1) to produce more exosomes.…”

Section: Exosomes and Paca Metastasismentioning

confidence: 99%

“…Moreover, PaCa xenograft mouse experiments have confirmed that PRKD-1 knockout can increase the content of exosomes in the serum, thus promoting PaCa invasion. Mechanistic analysis has showed that alteration on PRKD-1 may stimulate PaCa cells to produce more integrin α6β4 positive exosomes to promote PaCa lung metastasis [ 131 ]. Furthermore, Li and colleagues have figured out that the formation of a pre-metastatic niche also requires the generation of new blood vessels [ 128 ].…”

Section: Exosomes and Paca Metastasismentioning

confidence: 99%

The potential roles of exosomes in pancreatic cancer initiation and metastasis

Sun

Ren

et al. 2020

Mol Cancer

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Pancreatic cancer (PaCa) is an insidious and highly metastatic malignancy, with a 5-year survival rate of less than 5%. So far, the pathogenesis and progression mechanisms of PaCa have been poorly characterized. Exosomes correspond to a class of extracellular nanovesicles, produced by a broad range of human somatic and cancerous cells. These particular nanovesicles are mainly composed by proteins, genetic substances and lipids, which mediate signal transduction and material transport. A large number of studies have indicated that exosomes may play decisive roles in the occurrence and metastatic progression of PaCa. This article summarizes the specific functions of exosomes and their underlying molecular mechanisms in mediating the initiation and metastatic capability of PaCa.

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“…MVBs are involved in promoting virtually all aspects of cancer progression, including tumor expansion, immune responses, and drug resistance [2,28,30,71,143]. Studies have shown that MVBs, as important mediators of many aspects of cellular homeostasis, undergo significant changes in adapting to various stress conditions that enable cancer cells to maintain its homeostasis [3,24,40].…”

Section: Mvbs In Tumor Progressionmentioning

confidence: 99%

Focus on the morphogenesis, fate and the role in tumor progression of multivesicular bodies

Peng

Yang

et al. 2020

Cell Commun Signal

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Multivesicular bodies (MVBs) are endosome organelles that are gradually attracting research attention. Initially, MVBs were considered as important components of the endosomal-lysosomal degradation pathway. In recent years, with an increase in extracellular vesicle (EV) research, the biogenesis, fate, and pathological effects of MVBs have been increasingly studied. However, the mechanisms by which MVBs are sorted to the lysosome and plasma membrane remain unclear. In addition, whether the trafficking of MVBs can determine whether exosomes are released from cells, the factors are involved in cargo loading and regulating the fate of MVBs, and the roles that MVBs play in the development of disease are unknown. Consequently, this review focuses on the mechanism of MVB biogenesis, intraluminal vesicle formation, sorting of different cargoes, and regulation of their fate. We also discuss the mechanisms of emerging amphisome-dependent secretion and degradation. In addition, we highlight the contributions of MVBs to the heterogeneity of EVs, and their important roles in cancer. Thus, we attempt to unravel the various functions of MVBs in the cell and their multiple roles in tumor progression.

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Protein Kinase D1, Reduced in Human Pancreatic Tumors, Increases Secretion of Small Extracellular Vesicles From Cancer Cells That Promote Metastasis to Lung in Mice

Cited by 56 publications

References 76 publications

Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer

Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer

The potential roles of exosomes in pancreatic cancer initiation and metastasis

Focus on the morphogenesis, fate and the role in tumor progression of multivesicular bodies

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