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Junctional Adhesion Molecules in Cancer: a Paradigm for the Diverse Functions of Cell–Cell Interactions in Tumor Progression Adam Lauko1,2,3, Zhaomei Mu4, David H

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Junctional Adhesion Molecules in Cancer: a Paradigm for the Diverse Functions of Cell–Cell Interactions in Tumor Progression Adam Lauko1,2,3, Zhaomei Mu4, David H Published OnlineFirst August 14, 2020; DOI: 10.1158/0008-5472.CAN-20-1829 CANCER RESEARCH | REVIEW Junctional Adhesion Molecules in Cancer: A Paradigm for the Diverse Functions of Cell–Cell Interactions in Tumor Progression Adam Lauko1,2,3, Zhaomei Mu4, David H. Gutmann5, Ulhas P. Naik4, and Justin D. Lathia1,2,6,7 ABSTRACT ◥ Tight junction (TJ) proteins are essential for mediating inter- stabilization of adjacent cell surface receptors on the same cell, actions between adjacent cells and coordinating cellular and and interactions between JAM and cell surface receptors organ responses. Initial investigations into TJ proteins and expressed on adjacent cells. Collectively, these diverse interac- junctional adhesion molecules (JAM) in cancer suggested a tions contribute to both the pro- and antitumorigenic functions tumor-suppressive role where decreased expression led to of JAM. In this review, we discuss these context-dependent increased metastasis. However, recent studies of the JAM family functions of JAM in a variety of cancers and highlight key areas members JAM-A and JAM-C have expanded the roles of these that remain poorly understood, including their potentially proteins to include protumorigenic functions, including inhibi- diverse intracellular signaling networks, their roles in the tumor tion of apoptosis and promotion of proliferation, cancer stem cell microenvironment, and the consequences of posttranslational biology, and epithelial-to-mesenchymal transition. JAM function modifications on their function. These studies have implications by interacting with other proteins through three distinct molec- in furthering our understanding of JAM in cancer and provide a ular mechanisms: direct cell–cell interaction on adjacent cells, paradigm for exploring additional roles of TJ proteins. Introduction epithelial and endothelial cells, as well as some leukocyte popula- tions and platelets (3, 4). Like other TJ proteins, JAM-A mediates Junctional adhesion molecule A (JAM-A), also known as JAM-1 epithelial barrier function but also has roles in platelet aggregation or F11R, is the founding member of the JAM subfamily, one and hemostasis, inflammation and immune homeostasis, and branch of the larger immunoglobulin superfamily of cell surface angiogenesis (5). Similarly, JAM-C is found at TJs, where it reg- proteins. JAM-A, JAM-B, and JAM-C, the focus of this review, are ulates epithelial cell migration, cell polarity, angiogenesis, and classical JAM molecules that display up to 35% amino acid sequence vascular permeability (6). JAMs mediate these functions through homology and contain a short cytoplasmic tail (40–50 residues) three distinct molecular mechanisms, including (i) direct cell–cell with a class II PSD-95/Discs-large/ZO-1 (PDZ) domain–binding interaction between adjacent cells, (ii) stabilization of adjacent cell motif at the C-terminus. There are also additional JAM-related surface receptors (such as integrins) on the same cell, and (iii) proteins, including JAM-4, JAM-L, CAR, CLMP, and ESAM, which interactions with cell surface receptors expressed on adjacent have a long cytoplasmic tail (98–120 residues) with a class I cells (7). These mechanisms control intracellular signaling poten- PDZ domain–binding motif (1). JAM-A was originally identified tially through interactions with a few well-characterized PDZ as the receptor of a monoclonal antibody that activates human domain–containing proteins, which are mediated through the C- platelets (2) and is expressed in the tight junctions (TJ) of both terminal PDZ domain–binding motif (see JAM-A Structure and Function section below; ref. 5). In cancer, cell–cell adhesion and migration are essential processes 1Department of Cardiovascular and Metabolic Sciences, Lerner Research Insti- that occur during the early stages of metastasis. As such, TJ proteins tute, Cleveland Clinic, Cleveland, Ohio. 2Department of Molecular Medicine, have well-established roles in tumor cell adhesion, polarity, invasion, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and migration. Prior landmark studies have demonstrated that the lack 3 Cleveland, Ohio. Department of Pathology, Case Western Reserve University, or loss of TJ-based cell adhesion and epithelial barrier function 4 Cleveland, Ohio. Cardeza Center for Vascular Biology, Department of Medicine, increases cell permeability, leading to increased tumor cell invasion, Thomas Jefferson University, Philadelphia, Pennsylvania. 5Washington Univer- sity School of Medicine, St. Louis, Missouri. 6Case Comprehensive Cancer Center, dissemination, and metastasis (8, 9). However, an increasing number Case Western Reserve University, Cleveland, Ohio. 7Rose Ella Burkhardt Brain of studies suggest that TJ proteins may not function as tumor Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio. suppressors but rather accelerate tumor progression, suggesting that A. Lauko and Z. Mu contributed equally to this article. TJ proteins function in a context-dependent manner in cancer (10). This context-dependent function has also been reported for JAM-A, as U.P. Naik and J.D. Lathia contributed equally to this article. multiple studies have demonstrated that increased JAM-A expression Corresponding Authors: Justin D. Lathia, Cleveland Clinic Lerner Research drives tumorigenesis and promotes metastasis by activating adhesion- Institute, 9500 Euclid Ave, NC-10, Cleveland, OH 44195. Phone: 216-445- independent intracellular signaling pathways (11–13). Similarly, there 7475; Fax: 216-444-9404; E-mail: [email protected]; and Ulhas P. Naik, Thomas are also reports that support a tumor-suppressive role for JAM- Jefferson University, 1020 Locust St., Suite 394, Philadelphia, PA 19107. fl Phone: 215-055-3824; Fax: 215-955-9170; E-mail: [email protected] A (14, 15). These functional differences are also re ected in an increase or decrease in JAM-A levels across a variety of cancers that either Cancer Res 2020;XX:XX–XX positively or negatively correlates with patient prognosis (16–19). For doi: 10.1158/0008-5472.CAN-20-1829 this reason, there is no clear consensus for the function of JAM-A in Ó2020 American Association for Cancer Research. cancer, likely reflecting the complexity of the three main mechanisms AACRJournals.org | OF1 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst August 14, 2020; DOI: 10.1158/0008-5472.CAN-20-1829 Lauko et al. of interaction of JAM-A and resulting diversity in downstream Table 1. JAM-A expression in different tumors and its association signaling. The expression of JAM-B is primarily limited to endothelial with clinical outcome. cells and hence is not discussed here. Although less studied, there is evidence for protumorigenic func- JAM-A level JAM-A tions of JAM-C, another JAM family member expressed on epithelial compared with correlation with Type of cancer normal tissue poor prognosis References cells, primarily in metastasis. Studies in the early 2000s identified JAM- C as necessary for both adhesion of tumor cells to endothelial cells (20) Breast Mixed Positive (13, 14, 17, 55) and for tumor cell intravasation into blood vessels (21), and the RVE Lung Increased Positive (16, 53, 58, 81) sequence in the amino terminal Ig domain was responsible for this Gastric Decreased Negative (18) binding (see JAM-A Structure and Function section below). A number Pancreatic Decreased Negative (19) of follow-up studies across a wide array of cancers have likewise Glioblastoma Increased Positive (11, 49, 83) implicated JAM-C in metastasis, including in non–small cell lung Nasopharyngeal Increased Positive (12, 84) Oral squamous cell Increased Positive (85) cancer (NSCLC; ref. 22), melanoma (23, 24), fibrosarcoma (25), carcinoma ovarian cancer (26), gliomas (27), renal cell carcinoma (28), and Ovarian Increased None (82) – multiple liquid tumors (29 31). Here, we discuss the underlying Anaplastic Thyroid Decreased Unknown (86) mechanisms through which JAMs function, using JAM-A as an illustrative example, to either suppress or drive tumor progression Note: Increased/decreased denotes JAM-A expression in tumor cells compared and examine how JAMs can serve as a paradigm to reveal additional with normal tissue. Positive/negative denotes the correlation between JAM-A roles for other TJ proteins in complex cancer phenotypes. and poor prognosis in each tumor. JAM-A Structure and Function Given the numerous functions of JAM-A in normal physiology, it is Given the diversity of cell types and tissues in which JAM-A is not surprising that JAM-A exhibits a multitude of functions in tumor expressed, this protein is likely involved in the regulation of numerous growth and metastasis in different tumor types. This is highlighted by physiologic processes, ranging from intercellular TJ assembly critical the diverse expression profiles of JAM-A across tumor types, where for maintaining junctional integrity and permeability to cellular both decreased and increased expressions of JAM-A are associated polarity, leukocyte transendothelial migration, platelet aggregation, with tumor progression and poor prognosis (Table 1). In addition to and angiogenesis (32–38). All JAM family members are type I trans- maintaining epithelial cell barrier integrity, JAM-A also regulates membrane glycoproteins and share a similar structure, which includes proliferation and differentiation. Dysregulation of JAM-A intercellular two extracellular immunoglobulin-like
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