Cell phenotypic plasticity requires autophagic flux driven by YAP/TAZ mechanotransduction

Totaro, Antonio; Zhuang, Qiuyu; Panciera, Tito; Battilana, Giusy; Azzolin, Luca; Brumana, Giulia; Gandin, Alessandro; Brusatin, Giovanna; Cordenonsi, Michelangelo; Piccolo, Stefano

doi:10.1073/pnas.1908228116

Cited by 104 publications

(113 citation statements)

References 36 publications

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“…Confirming these observations, cell line experiments revealed that sphere-forming stem cell-like PDAC cells have higher levels of the autophagy marker LC3-II compared to other cells [28]. Another link between autophagy and PDAC cancer stem cells is YAP/TAZ-signaling, shown to be required for cell dedifferentiation and the acquisition of self-renewing properties, i.e., stem cell formation [29]. YAP/TAZ has also been shown to be a positive autophagy regulator [30], and promotes autophagic flux by increasing Armus expression, a RAB7-GAP required for autophagosome turnover [29].…”

Section: Conflicting Roles Of Autophagy In Pdacmentioning

confidence: 68%

“…Another link between autophagy and PDAC cancer stem cells is YAP/TAZ-signaling, shown to be required for cell dedifferentiation and the acquisition of self-renewing properties, i.e., stem cell formation [29]. YAP/TAZ has also been shown to be a positive autophagy regulator [30], and promotes autophagic flux by increasing Armus expression, a RAB7-GAP required for autophagosome turnover [29]. The role of autophagy in PDAC survival is not limited to tumor cells alone, but extends to the tumor microenvironment.…”

Section: Conflicting Roles Of Autophagy In Pdacmentioning

confidence: 99%

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The Role of Autophagy in Pancreatic Cancer—Recent Advances

New

Tooze

2019

Biology

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Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with a 5-year survival rate of only 9%, despite ongoing efforts to improve treatment. This dismal prognosis is due to the difficulty of early stage diagnosis, drug resistance, and likelihood of metastasis development. It is therefore of great importance to identify appropriate therapeutic targets and gain a greater understanding of PDAC biology. Autophagy is a membrane-mediated degradation and recycling mechanism, which is crucial for cell homeostasis. There is evidence for both a tumor-suppressive and a tumor-promoting role of autophagy in cancer, and this is likely context dependent. Within PDAC, a large body of evidence points towards autophagy being required for tumor survival and metabolism. In this review, we describe the recent advances in the understanding of the role and regulation of autophagy in PDAC.

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Section: Conflicting Roles Of Autophagy In Pdacmentioning

confidence: 68%

Section: Conflicting Roles Of Autophagy In Pdacmentioning

confidence: 99%

The Role of Autophagy in Pancreatic Cancer—Recent Advances

New

Tooze

2019

Biology

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“…The ECM and cytoskeletal tension also profoundly impact on autophagic flux by YAP/TAZ directly promoting the expression of the GTPase-activating protein Armus. In normal and in tumor cells, YAP/TAZ-mediated autophagy in response to physical cues is responsible for dedifferentiation and the acquisition of self-renewing properties [92].…”

Section: Yap and Taz As Relays Of Mechanosensorsmentioning

confidence: 99%

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Kovar

Bierbaumer

Radic-Sarikas

2020

Cells

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YAP and TAZ are intracellular messengers communicating multiple interacting extracellular biophysical and biochemical cues to the transcription apparatus in the nucleus and back to the cell/tissue microenvironment interface through the regulation of cytoskeletal and extracellular matrix components. Their activity is negatively and positively controlled by multiple phosphorylation events. Phenotypically, they serve an important role in cellular plasticity and lineage determination during development. As they regulate self-renewal, proliferation, migration, invasion and differentiation of stem cells, perturbed expression of YAP/TAZ signaling components play important roles in tumorigenesis and metastasis. Despite their high structural similarity, YAP and TAZ are functionally not identical and may play distinct cell type and differentiation stage-specific roles mediated by a diversity of downstream effectors and upstream regulatory molecules. However, YAP and TAZ are frequently looked at as functionally redundant and are not sufficiently discriminated in the scientific literature. As the extracellular matrix composition and mechanosignaling are of particular relevance in bone formation during embryogenesis, post-natal bone elongation and bone regeneration, YAP/TAZ are believed to have critical functions in these processes. Depending on the differentiation stage of mesenchymal stem cells during endochondral bone development, YAP and TAZ serve distinct roles, which are also reflected in bone tumors arising from the mesenchymal lineage at different developmental stages. Efforts to clinically translate the wealth of available knowledge of the pathway for cancer diagnostic and therapeutic purposes focus mainly on YAP and TAZ expression and their role as transcriptional co-activators of TEAD transcription factors but rarely consider the expression and activity of pathway modulatory components and other transcriptional partners of YAP and TAZ. As there is a growing body of evidence for YAP and TAZ as potential therapeutic targets in several cancers, we here interrogate the applicability of this concept to bone tumors. To this end, this review aims to summarize our current knowledge of YAP and TAZ in cell plasticity, normal bone development and bone cancer.Cells 2020, 9, 972 2 of 34 co-activators Yes-associated protein 1 (YAP-1, YAP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ, WWTR1), which are typically controlled on the post-translational level by upstream regulatory signaling pathways in organ development and tissue homeostasis [2,3]. YAP and TAZ were reported to affect self-renewal and lineage commitment of stem cells [4][5][6][7], while hyperactivation of YAP and TAZ have been linked to cancer growth and metastasis in various tumors [8][9][10]. TAZ levels are elevated in approximately 20% of cancers and drive invasion and metastasis [11,12], while YAP is frequently overexpressed or amplified in cancer and was shown to promote resistance to chemotherapy in oncogene-addicted tumors up...

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“…It has been reported that YAP-/TAZ-regulated autophagy is essential in normal cells and in tumor cells [ 27 ]; however, the effect of YAP/TAZ on autophagy in RA-FLS has not been elucidated. In order to define the relationship between YAP/TAZ and autophagy in RA-FLS, we first checked for the effect of knockdown of YAP/TAZ on the expression of autophagy-related genes by RT-qPCR and western blotting assays.…”

Section: Resultsmentioning

confidence: 99%

Knockdown of YAP/TAZ Inhibits the Migration and Invasion of Fibroblast Synovial Cells in Rheumatoid Arthritis by Regulating Autophagy

Zhou

Shen

Wang

et al. 2020

Journal of Immunology Research

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The purpose of this study was to investigate the effect of knockdown of the yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) on the migration and invasion of the rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and to preliminarily elucidate the mechanisms between YAP/TAZ and autophagy in the migration and invasion of RA-FLS. RA-FLS stable knockdown of YAP or TAZ was successfully established by using lentiviral-mediated gene knockdown techniques. Wound healing assay and Transwell assay were used to evaluate the effect of knockdown of YAP or TAZ on the migration and invasion of RA-FLS. Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and western blotting assays were performed to examine the expression of indicated genes. The results showed that YAP and TAZ were upregulated in RA-FLS, and knockdown of YAP or TAZ inhibited the migration and invasion, reduced the expression of N-cadherin and Vimentin, and increased the accumulation of E-cadherin and β-catenin in RA-FLS. Our results also demonstrated that knockdown of YAP or TAZ promoted autophagy which increased the accumulation of LC3B-II and ULK1 and decreased the amount of SQSTM1/p62 in RA-FLS. Furthermore, our data displayed that inhibition of autophagy either with 3-MA or CQ can partially reverse the decrease of migration and invasion induced by YAP and TAZ knockdown in RA-FLS. Our experiments preliminarily revealed that YAP/TAZ and autophagy play important roles in the migration and invasion of RA-FLS, which might provide novel targets for the treatment of RA.

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Cell phenotypic plasticity requires autophagic flux driven by YAP/TAZ mechanotransduction

Cited by 104 publications

References 36 publications

The Role of Autophagy in Pancreatic Cancer—Recent Advances

The Role of Autophagy in Pancreatic Cancer—Recent Advances

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Knockdown of YAP/TAZ Inhibits the Migration and Invasion of Fibroblast Synovial Cells in Rheumatoid Arthritis by Regulating Autophagy

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