In summary although there are still several

In summary, although there are still several important questions open on the mechanisms that trigger FAK nuclear localization and FAK-dependent gene regulation, Cardoso et al. (2016) provide important new insights on FAK/MEF2-mediated initiation of cardiac hypertrophy.
Acknowledgments The author thanks Cardoso et al. (2016) for providing coordinates prior to public release and apologizes for not citing or discussing related work due to the limited space available. The author is supported by grants from the Autonomous Community of Madrid (S2010/BMD-2457), the Volkswagen Foundation (Az: 86 416-1), and Worldwide Cancer Research (15-1177).
Introduction In traditional concepts, the B-lineage lymphocytes are the sole source of immunoglobulins (Igs), which are generated with an enormous diversity in response to the challenge of various antigens. The biogenesis and function of B-cell-derived Ig in the form of LLY507 have been extensively characterized [1]. Interestingly, growing evidence indicate that a wide range of non-B cells also express Ig molecules with activities distinct from antibodies, extending the perimeter of Ig beyond the humoral immunity. In particular, our laboratory and other research groups have revealed that various human carcinomas, including breast [2], lung [3,4], colon [5], esophagus [6], ovarian [7], prostate [8] and bladder cancers [9], can express surface or secreted Ig with unique molecular characteristics. Overexpression of such cancer-derived Ig (CIg) has been implicated in malignant tumor progression, often associated with poor prognosis of patients [4,10,11]. For example, our recent study revealed that cancer cells with stem cell-like features have high expression levels of CIgG, which contributes to tumor initiation and metastasis [10]. However, the signaling mechanisms underlying the activities of CIg molecules remain elusive. RP215 is a monoclonal antibody that was originally raised against the extract of OC-3-VGH, an ovarian cancer cell line, in search of cancer-associated antigens [12]. It was later discovered that the antigen recognized by RP215 is in fact CIgG molecules expressed in a broad spectrum of human cancers [13,14]. In line with the essential roles of CIgG in cancer progression, RP215 treatments can induce apoptosis among a variety of cancer cells, suggesting that RP215 could block the function of CIgG [15]. Importantly, RP215 has little cross-reactivity with normal IgG, therefore providing an unparalleled advantage over regular anti-human IgG antibodies in studying CIgG [16]. Although studies have suggested that the cancer-specificity of RP215 lies in a unique glycosylation profile on the heavy chain of CIgG [14], the exact molecular identity of the RP215-epitope is still unknown. Here we report that non-small cell lung carcinomas (NSCLC), especially lung squamous cell carcinomas (LSCC), display high expression levels of the RP215-epitope. We determined that the epitope contains N-glycan mapped to the CH1 domain on the heavy chain of CIgG, which we term RP215-CIgG. In LSCC cells, we show that RP215-CIgG promotes tumor growth and migration through binding to integrin α6β4 and activating downstream FAK signaling pathways. Finally, using a patient derived xenograft (PDX) model, we demonstrate that RP215 inhibits the in vivo tumor progression of LSCC. Collectively, our studies reveal the nature of RP215-specific epitope in LSCC cells, leading to the identification of a novel CIgG-integrin pathway that promotes tumor progression. We propose that RP215-CIgG is an attractive biomarker and therapeutic target for LSCC.
Materials and methods
Results
Discussion In this study, we identified that LSCC cells express high levels of IgG molecules recognized by RP215, a monoclonal antibody. Using biochemical and mutagenesis analyses, we determined that the RP215 recognizes an N-glycan epitope at a non-classical site in the CH1 domain of LSCC IgG. Functionally, RP215-CIgG interacts with integrin α6β4 and activates the downstream oncogenic pathways including the FAK and Src signaling (Fig. 7). Silencing of RP215-CIgG strongly inhibited survival and migration of LSCC cells. Interestingly, while the N-glycan epitope plays an essential role in activating FAK and Src signaling, it is not required for the interaction between RP215-CIgG and integrin. Finally, RP215 specifically blocks the pro-oncogenic activity of CIgG and inhibits in vivo growth of PDX tumors, providing a potential diagnostic and therapeutic strategy for LSCC.