Desmosomes: new perpetrators in tumour suppression

Abstract

Adherens junctions, which are intercellular adhesive complexes that are crucial for maintaining epithelial homeostasis, are downregulated in many cancers to promote tumour progression. However, the role of desmosomes - adhesion complexes that are related to adherens junctions - in carcinogenesis has remained elusive. Recent studies using mouse genetic approaches have uncovered a role for desmosomes in tumour suppression, demonstrating that desmosome downregulation occurs before that of adherens junctions to drive tumour development and early invasion, suggesting a two-step model of adhesion dysfunction in cancer progression.

Figure 1. Desmosome deficiency can promote cancer in multiple ways

Stable adherens junctions and desmosomes facilitate adhesion between epithelial cells. The best-characterized components are shown; the position of p53 apoptosis effector related to PMP-22 (PERP) in the desmosome is speculative. Several mechanisms through which disrupted desmosomes could promote cancer are indicated. Junction plakoglobin (JUP) is the desmosome component with the best-characterized effect on the phenotypic changes that occur in cancer cells. At high levels, JUP can compete with β-catenin for inclusion in adherens junctions and/or for interaction with the adenomatous polyposis coli (APC)-mediated degradation machinery, which regulates cellular β-catenin levels (not shown). Both scenarios result in increased nuclear β-catenin, which can stimulate the transcription of LEF/TCF -dependent target genes, promoting oncogenic effects (part a). JUP itself can also shuttle between adhesion junctions at the plasma membrane and the nucleus, where it can increase expression of LEF/TCF target genes independently of β-catenin (part b). Additionally, plakophilins (PKPs) can also shuttle between the desmosome and the nucleus, and PKP2 has been demonstrated to interact with β-catenin and to enhance LEF/TCF-mediated transactivation (part b). JUP and PKPs may also have dedicated LEF/TCF-independent target genes (part c). PKPs may also function in the cytoplasm to stimulate translational initiation (part d). Other uncharacterized molecular mechanisms of cancer promotion might also exist (part e). DSC, desmocollin; DSG, desmoglein; E-cad, E-cadherin; NRCAM, neuronal cell adhesion molecule; p120, p120 cadherin.

Figure 2. The p53–p63 pathway regulates homeostasis in epithelial tissues

This figure represents some of the ways in which p53 and p63 family members can regulate epithelial homeostasis. a | During the development and maintenance of epithelial tissues, p63 can directly or indirectly regulate the expression of various classes of genes, including genes that encode cell–cell adhesion proteins, such as p53 apoptosis effector related to PMP-22 (PERP). These proteins can then assemble into the intercellular adhesive complexes adherens junctions and desmosomes, which promote adhesion between adjacent epithelial cells. Adhesion between cells within a tissue contributes to its integrity, organization and function. b | Cellular stressors such as DNA damage or oncogene expression activate p53. As a sensor of stress, p53 induces the expression of genes that are involved in apoptosis, including PERP and NOXA. PERP and NOXA, and other proteins, contribute to the apoptotic programme, triggering the death of cells the survival of which would be detrimental to a tissue. Both cell–cell adhesion and apoptosis are important cellular mechanisms that contribute to tumour suppression.

Figure 3. Desmosome downregulation is one in a series of steps occurring during cancer development

Two recent studies using mouse cancer models in which desmosome components were ablated have demonstrated key contributions of desmosome deficiency to epithelial cancer development and progression. Mutations in proto-oncogenes or tumour suppressors drive the development of nascent tumours in epithelia. In this context, desmosome deficiency, occurring before adherens junction loss, promotes several cellular phenotypes that can contribute to cancer progression: decreased desmosome-mediated intercellular adhesion, increased cell survival and inflammatory cell recruitment in ultraviolet B (UVB)-induced squamous cell carcinomas in p53 apoptosis effector related to PMP-22 (Perp)-deficient mice and increased local invasion in desmoplakin (Dsp)-deficient Rip1Tag2-driven pancreatic neuroen-docrine tumours. Subsequent dissolution of adherens junctions in tumours is associated with impaired adherens junction-mediated adhesion, enhanced global invasion and increased distant metastasis, which are features of full-blown malignancy. As desmosome downmodulation precedes that of adherens junctions, and as early diagnosis and treatment is key to achieving the optimal clinical outcome, establishing the status of desmosome and adherens junction constituents in tumours could potentially augment the current tools that are used in the staging, prognostication or treatment of cancers.