Maralice Conacci‐Sorrell

The adhesion of cells to their neighbors determines cellular and tissue morphogenesis and regulates major cellular processes including motility, growth, differentiation, and survival. Cell-cell adherens junctions (AJs), the most common (indeed, essentially ubiquitous) type of intercellular adhesions, are important for maintaining tissue architecture and cell polarity and can limit cell movement and proliferation. AJs assemble via homophilic interactions between the extracellular domains of calcium-dependent cadherin receptors on the surface of neighboring cells. The cytoplasmic domains of cadherins bind to the submembranal plaque proteins β-catenin or plakoglobin (γ-catenin), which are linked to the actin cytoskeleton via α-catenin (Figure ​(Figure1;1; refs. 1, 2). The transmembrane assembly of cadherin receptors with the cytoskeleton is necessary for the stabilization of cell-cell adhesions and normal cell physiology. Figure 1 The dual role of β-catenin in cell adhesion and transcriptional activation. β-Catenin (β) and plakoglobin (Pg) bind to cadherin adhesion receptors, and via α-catenin (α) they associate with the actin cytoskeleton ... Malignant transformation is often characterized by major changes in the organization of the cytoskeleton, decreased adhesion, and aberrant adhesion-mediated signaling. Disruption of normal cell-cell adhesion in transformed cells may contribute to tumor cells’ enhanced migration and proliferation, leading to invasion and metastasis. This disruption can be achieved by downregulating the expression of cadherin or catenin family members or by activation of signaling pathways that prevent the assembly of AJs. The importance of the major epithelial cell cadherin, E-cadherin (E-cad, the product of the CDH1 gene), in the maintenance of normal cell architecture and behavior is underscored by the observation that hereditary predisposition to gastric cancer results from germline mutations in CDH1. Loss of E-cad expression eliminates AJ formation and is associated with the transition from adenoma to carcinoma and acquisition of metastatic capacity (3). Re-establishment of AJs in cancer cells by restoration of cadherin expression (4) exerts tumor-suppressive effects, including decreased proliferation and motility. In this Perspective, we discuss the molecular mechanisms underlying the role of the cadherin-catenin system in the regulation of cell proliferation, invasion, and intracellular signaling during cancer progression.

Transcriptional repression of E-cadherin, characteristic of epithelial to mesenchymal transition, is often found also during tumor cell invasion. At metastases, migratory fibroblasts sometimes revert to an epithelial phenotype, by a process involving regulation of the E-cadherin-beta-catenin complex. We investigated the molecular basis of this regulation, using human colon cancer cells with aberrantly activated beta-catenin signaling. Sparse cultures mimicked invasive tumor cells, displaying low levels of E-cadherin due to transcriptional repression of E-cadherin by Slug. Slug was induced by beta-catenin signaling and, independently, by ERK. Dense cultures resembled a differentiated epithelium with high levels of E-cadherin and beta-catenin in adherens junctions. In such cells, beta-catenin signaling, ErbB-1/2 levels, and ERK activation were reduced and Slug was undetectable. Disruption of E-cadherin-mediated contacts resulted in nuclear localization and signaling by beta-catenin, induction of Slug and inhibition of E-cadherin transcription, without changes in ErbB-1/2 and ERK activation. This autoregulation of E-cadherin by cell-cell adhesion involving Slug, beta-catenin and ERK could be important in tumorigenesis.

Aberrant beta-catenin-TCF target gene activation plays a key role in colorectal cancer, both in the initiation stage and during invasion and metastasis. We identified the neuronal cell adhesion molecule L1, as a target gene of beta-catenin-TCF signaling in colorectal cancer cells. L1 expression was high in sparse cultures and coregulated with ADAM10, a metalloprotease involved in cleaving and shedding L1's extracellular domain. L1 expression conferred increased cell motility, growth in low serum, transformation and tumorigenesis, whereas its suppression in colon cancer cells decreased motility. L1 was exclusively localized in the invasive front of human colorectal tumors together with ADAM10. The transmembrane localization and shedding of L1 by metalloproteases could be useful for detection and as target for colon cancer therapy.

Tumors display increased uptake and processing of nutrients to fulfill the demands of rapidly proliferating cancer cells. Seminal studies have shown that the proto-oncogene MYC promotes metabolic reprogramming by altering glutamine uptake and metabolism in cancer cells. How MYC regulates the metabolism of other amino acids in cancer is not fully understood. Using high-performance liquid chromatography (HPLC)-tandem mass spectrometry (LC-MS/MS), we found that MYC increased intracellular levels of tryptophan and tryptophan metabolites in the kynurenine pathway. MYC induced the expression of the tryptophan transporters SLC7A5 and SLC1A5 and the enzyme arylformamidase (AFMID), involved in the conversion of tryptophan into kynurenine. SLC7A5, SLC1A5, and AFMID were elevated in colon cancer cells and tissues, and kynurenine was significantly greater in tumor samples than in the respective adjacent normal tissue from patients with colon cancer. Compared with normal human colonic epithelial cells, colon cancer cells were more sensitive to the depletion of tryptophan. Blocking enzymes in the kynurenine pathway caused preferential death of established colon cancer cells and transformed colonic organoids. We found that only kynurenine and no other tryptophan metabolite promotes the nuclear translocation of the transcription factor aryl hydrocarbon receptor (AHR). Blocking the interaction between AHR and kynurenine with CH223191 reduced the proliferation of colon cancer cells. Therefore, we propose that limiting cellular kynurenine or its downstream targets could present a new strategy to reduce the proliferation of MYC-dependent cancer cells.