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  • Many extracellular matrix ECM proteins are ligands and regul

    2021-09-14

    Many extracellular matrix (ECM) proteins are ligands and regulators of integrin/FAK signaling and are involved in various aspects of cancer progression, including growth, survival, invasion, and metastasis (Lu et al., 2012). Tubulointerstitial nephritis antigen-like 1 (Tinagl1), a secreted extracellular protein, was initially identified as a putative component of the ECM (Li et al., 2007). Our previous study indicated that secretion of Tinagl1 is mediated by Sec23a-dependent endoplasmic reticulum-Golgi protein trafficking pathway, and Tinagl1 knockdown in breast cancer cells led to increased metastatic lung colonization (Korpal et al., 2011). In this study, we explored the mechanism underlying how Tinagl1 regulates breast cancer progression and evaluated its therapeutic potential for TNBC.
    Results
    Discussion During cancer progression, both cancer cells and stromal cells produce various components or remodelers of the ECM to promote metastatic progression (Lu et al., 2012). However, relatively little is known regarding ECM components that inhibit tumor progression and metastasis. Our study establishes the ECM protein Tinagl1 as a suppressor of tumor growth and metastasis in TNBC. Tinagl1 interacts with EGFR and prevents its ligand-induced dimerization and receptor activation. Tinagl1 also interacts with integrin α5β1 and αvβ1 and suppresses FN-induced integrin/FAK signaling (Figure 8D). Consistent with our finding that high Tinagl1 expression correlated with good clinical outcomes in TNBC patients, ectopic expression of Tinagl1 in cancer cells inhibited tumor growth and lung metastasis. Importantly, recombinant Tinagl1 protein treatment suppressed tumor progression without causing significant toxicity in mice, indicating potential therapeutic application of Tinagl1. Integrins are key cell surface receptors connecting intracellular structures and ECM components, and serve important signaling functions. Tumor-expressed integrins, such as integrins α5β1, αvβ1, and αvβ3, interact with FN and other ECM proteins to facilitate cancer progression (reviewed in Desgrosellier and Cheresh, 2010). In line with these findings, β1 functional blocking reverse transcriptase showed tumor-inhibiting ability (Park et al., 2006). ATN-161, a small peptide antagonist of integrin α5β1 that inhibits TNBC progression in MDA-MB-231 xenograft models (Cianfrocca et al., 2006), is also under clinical evaluation. However, limited responses were observed in patients undergoing integrin-targeted therapy alone (Desgrosellier and Cheresh, 2010), suggesting that other signaling pathways compensated for its tumor-promoting function. One pathway that could contribute to therapeutic resistance to integrin therapy is EGFR signaling. Consistent with previous findings indicating that the integrin signaling pathway is regulated by EGFR activation (Adelsman et al., 1999), we observed a group of FAK inhibitor-resistant genes induced by EGFR signaling, suggesting that EGFR downstream genes may compensates for integrin/FAK inhibition. Clinical trials targeting EGFR have been performed to evaluate its therapeutic potential based on its elevated expression in TNBC (Nakai et al., 2016). Combining cetuximab with carboplatin in metastatic TNBC produced responses in fewer than 20% of patients (Carey et al., 2012). While the EGFR pathway is active in most TNBCs, cetuximab blocked expression of the EGFR pathway in only a minority of patients, suggesting that other signaling may compensate and activate EGFR. Studies indicate that the integrin β1 subunit is required for the full activation of EGFR in normal epithelial cells (Cabodi et al., 2009). In the cancer context, the integrin β1 subunit was reported to control EGFR signaling to promote tumorigenesis (Morello et al., 2011). Moreover, integrin-mediated signaling was demonstrated to drive tumor resistance to EGFR inhibition (Brown and Wendt, 2014, Seguin et al., 2014). These findings suggest that, mirroring the compensation of integrin/FAK inhibition by EGFR activation, integrin/FAK signaling compensates for EGFR in cancer progression. In line with this, we found a set of EGFR inhibitor-resistant genes that are activated by integrin/FAK signaling. Furthermore, combined EGFR and integrin therapy had significantly better performance than EGFR targeted treatment alone in TNBC. However, both EGFR and integrin/FAK inhibitors have severe toxicities due to both on-target and off-target activities (Bell-McGuinn et al., 2011, Linda et al., 2009, Widakowich et al., 2007), potentially limiting the clinical application of the combined therapy. Embryonic lethality and other severe defects of mice genetically deficient of EGFR, integrin β1 subunit, and FAK also underscored the significant toxicity associated with the targeting of these pathways (Fassler and Meyer, 1995, Ilic et al., 1995, Threadgill et al., 1995). In contrast, mice treated with r-Tinagl1 did not show significant toxicity in our current study, and Tinagl1 knockout mice are largely normal except for subfertility phenotypes in female animals (Takahashi et al., 2016), suggesting potential better tolerance for the alteration of Tinagl1 levels.