A novel role for junctional adhesion molecule‐A in tumor proliferation: Modulation by an anti‐JAM‐A monoclonal antibody

Abstract

To identify new potential targets in oncology, functional approaches were developed using tumor cells as immunogens to select monoclonal antibodies targeting membrane receptors involved in cell proliferation. For that purpose cancer cells were injected into mice and resulting hybridomas were screened for their ability to inhibit cell proliferation in vitro. Based on this functional approach coupled to proteomic analysis, a monoclonal antibody specifically recognizing the human junctional adhesion molecule-A (JAM-A) was defined. Interestingly, compared to both normal and tumor tissues, we observed that JAM-A was mainly overexpressed on breast, lung and kidney tumor tissues. In vivo experiments demonstrated that injections of anti-JAM-A antibody resulted in a significant tumor growth inhibition of xenograft human tumors. Treatment with monoclonal antibody induced a decrease of the Ki67 expression and downregulated JAM-A levels. All together, our results show for the first time that JAM-A can interfere with tumor proliferation and suggest that JAM-A is a potential novel target in oncology. The results also demonstrate that a functional approach coupled to a robust proteomic analysis can be successful to identify new antibody target molecules that lead to promising new antibody-based therapies against cancers.Targeted therapies have revolutionized the treatment of cancers. However, there is a need for innovative targets susceptible to bring new medical treatments. Discovering novel cancer targets, and molecules to interfere with, is a major challenge in oncology research. Among new emerging targets, molecules implicated in cell adhesion, migration and polarity provide promising opportunities to combat tumor proliferation, invasion and metastasis. This is the case of tetraspanins for examples, 1 such as CD151 2 or CD9 3 known to exert prominent roles in cell migration and invasion. Furthermore, their interaction with distinct tyrosine kinase receptors (TKR) accounts for their capacity to modulate cell proliferation. 4 Similarly, integrins and some G protein-coupled receptors can crosstalk with TKR to modulate their activities. 5 Recently, molecules involved in cellular architecture (tight or adherent) junctions have been described as playing a role in the control of cell migration and/or proliferation. 6 The modulation of TKR can also affect cell adhesion molecules such as claudins. 7 In addition, these emerging targets can exert a direct effect by themselves on either tumor cell migration 8 or tumor growth regulation. 9 With the objective to identify new targets in oncology, we initiated a function-based approach to identify new antitumor monoclonal antibodies (Mabs). This innovative approach is based on generation and selection of Mabs that are primarily screened for their capacity to trigger cellular functions, including tumor cell proliferation or tumor apoptosis. By combining these two complementary experimental modalities, we were able to identify a set of tumor-active Mabs and subsequently, for the most potent...

Overexpression of junctional adhesion molecule-A and EphB2 predicts poor survival in lung adenocarcinoma patients

“…Previous research showed that low levels of JAM-A in the normal lung tissues are detected, compared with cancer tissues, but prognostic analysis is not performed. 5 Therefore, our research fills the gaps in this field.…”

“…3 Junctional adhesion molecules (JAMs), members of immunoglobulin superfamily proteins, are located at the lateral membrane of endothelial and epithelial cells. 4 Recent studies showed that dysregulation of junctional adhesion molecule-A (JAM-A), an important component of JAMs as well as TJs, is associated with cancer progression, 5 demonstrating that potential clinical values in cancers. However, the exact roles and clinical significances of JAM-A in cancers remain unknown.…”

Ductal barriers in mammary epithelium

“…Another exciting potential target is JAM-A, given the positive association between its overexpression and poor prognosis in breast cancer patients 91 , 92 , 94 and following a recent publication demonstrating anti-proliferative efficacy of a function-blocking JAM-A antibody in xenograft murine models of breast cancer 221 . Unpublished work from our group has also shown promising in vitro and pre-clinical in vivo efficacy of a novel small molecule inhibitor of JAM-A, which we sp.eculate could be particularly valuable in aggressive breast cancers concomitantly overexpressing HER2 and JAM-A.…”

The Contribution of Ig-Superfamily and MARVEL D Tight Junction Proteins to Cancer Pathobiology

“…Further evidence implicating JAM-A in breast cancer cell survival signaling has accrued from a study in which it was described as a novel regulator of HER2 protein degradation and signaling (15). In terms of the therapeutic potential of targeting JAM-A, its pharmacological inhibition using a monoclonal antibody has been demonstrated to significantly inhibit tumor growth in murine xenograft models of human tumors (17).…”