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YAP and TAZ: a signalling hub of the tumour microenvironment

Abstract

YAP and TAZ are transcriptional activators pervasively induced in several human solid tumours and their functions in cancer cells are the focus of intense investigation. These studies established that YAP and TAZ are essential to trigger numerous cell-autonomous responses, such as sustained proliferation, cell plasticity, therapy resistance and metastasis. Yet tumours are complex entities, wherein cancer cells are just one of the components of a composite “tumour tissue”. The other component, the tumour stroma, is composed of an extracellular matrix with aberrant mechanical properties and other cell types, including cancer-associated fibroblasts and immune cells. The stroma entertains multiple and bidirectional interactions with tumour cells, establishing dependencies essential to unleash tumorigenesis. The molecular players of such interplay remain partially understood. Here, we review the emerging role of YAP and TAZ in choreographing tumour–stromal interactions. YAP and TAZ act within tumour cells to orchestrate responses in stromal cells. Vice versa, YAP and TAZ in stromal cells trigger effects that positively feed back on the growth of tumour cells. Recognizing YAP and TAZ as a hub of the network of signals exchanged within the tumour microenvironment provides a fresh perspective on the molecular principles of tumour self-organization, promising to unveil numerous new vulnerabilities.

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Fig. 1: Overview of YAP and TAZ functions in cancer cells.
Fig. 2: New functions of YAP and TAZ in metastasis.
Fig. 3: Yorkie/YAP and TAZ in the competition between emerging tumour cells and normal epithelial cells.
Fig. 4: YAP and TAZ are activated in stromal cells.

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Acknowledgements

The authors thank all members of the S.P. laboratory for discussion. The S.P. laboratory is supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 670126-DENOVOSTEM) and and by a FARE (Framework per l'Attrazione e il Rafforzamento delle Eccellenze) grant by the Italian Ministry of Education, University and Research.

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Nature Reviews Cancer thanks W. Hong, M. Oren and M. Sudol for their contribution to the peer review of this work.

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All authors contributed to researching data and discussing content. F.Z. and S.P. wrote the article.

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Correspondence to Stefano Piccolo.

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Glossary

Intratumoural phenotypic heterogeneity

The coexistence, within the same tumour, of cellular populations that differ in their molecular and biological properties, including clinically important phenotypes such as the ability to seed metastases and to survive therapy.

Self-organization

An emergent property of normal and tumour cell ensembles, by which patterns of differentiation and ordered tissue architectures occur as a product of cell–cell and cell–extracellular matrix contacts.

Cell of origin

The normal cell that is hit by the first transforming events, eventually growing into a tumour; depending on the tumour type, it can be either a differentiated cell or a resident stem cell.

Epigenome

A map of the genome-wide modifications made to DNA and the proteins associated with DNA that influence gene availability for transcription.

Self-sustaining positive loops

A circuit whereby a factor stabilizes or enhances its own activation by promoting the expression or function of a positive regulator.

Cell-fate reprogramming

A non-physiological change in cell identity, either to a less differentiated status or to a completely different lineage.

Cancer stem cells

The tumour cells that maintain tumour propagation, by virtue of their self-renewal capacity and multipotency.

Epithelial-to-mesenchymal transition

The acquisition, by epithelial cells, of a mesenchymal gene programme, which facilitates migration and invasion.

Chemotherapeutic drugs

Standard anticancer drugs that target cell division and DNA replication.

Molecularly targeted drugs

Drugs that target specific molecular alterations (such as mutated oncogenes) in cancer cells.

Cytoskeletal remodelling

Dynamic reshaping of the actin cytoskeleton, which is essential for the cell to adapt to changes in the physical properties of the extracellular environment or to migrate.

Anoikis

Apoptosis induced by loss of cell–cell or cell–extracellular matrix attachment.

Apico-basal cell polarity

A polarized organization of epithelial cells with a specialized apical membrane facing the outside of the body or lumen of internal cavities and a specialized basolateral membrane localized on the opposite side, established and maintained by specific protein complexes.

Desmoplastic reaction

Excessive production of extracellular matrix proteins and extensive proliferation of stromal fibroblasts, resulting in a dense and fibrous connective tissue around tumour cells.

Mechanotransduction

Mechanisms by which cells convert mechanical signals conveyed by the microenvironment into biochemical signals to adapt their behaviour to the environment.

ECM-modifying enzymes

Enzymes that modify extracellular matrix (ECM) proteins in the extracellular space; they comprise proteinases that degrade ECM components (for example, matrix metalloproteinases, ADAMTS, plasmin, cathepsins) and enzymes that modify ECM topography (for example, LOX enzymes, which crosslink collagen).

Disseminated cancer cells

Tumour cells that have left the primary tumour, passed through the vascular or lymphatic system and migrated to distant organs.

Dormancy

The condition of a cancer cell that remains alive but proliferatively inert.

Neutrophil-derived extracellular traps

Large, extracellular, web-like structures released by neutrophils, composed of cytosolic and granule proteins that are assembled on a scaffold of decondensed chromatin.

Immune surveillance

The ability of the immune system to identify and destroy nascent tumours.

Nonalcoholic steatohepatitis

Liver pathology (not associated with alcohol abuse) characterized by lipoapoptotic hepatocyte damage, inflammation and often fibrosis, which can evolve into cirrhosis and is associated with a higher risk of developing hepatocellular carcinoma.

Myeloid-derived suppressor cells

A heterogeneous population of immature cells of myeloid origin that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T cell responses.

Immune checkpoints

Stimulatory and inhibitory pathways that regulate the type, magnitude and duration of immune responses, allowing the immune system to react to infections while protecting tissues from any harm that may derive from excessive immune responses.

Humanized mouse models

Immunodeficient mice engrafted with functional human haematopoietic stem cells that develop into functional human immune systems.

Mass-imaging technologies

Highly multiplexed epitope-based imaging approaches, based on immunofluorescence or mass cytometry, that enable the analysis of dozens of proteins in thousands of cells in a single experiment while preserving tissue-level information on cell position and cell–cell interactions.

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Zanconato, F., Cordenonsi, M. & Piccolo, S. YAP and TAZ: a signalling hub of the tumour microenvironment. Nat Rev Cancer 19, 454–464 (2019). https://doi.org/10.1038/s41568-019-0168-y

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