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Cédric Zeltz



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    P3.03 - Biology (Not CME Accredited Session) (ID 969)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.03-18 - Collagen Type XI Promotes Lung Adenocarcinoma Dissemination Via Integrin α2 and DDR1 (ID 14009)

      12:00 - 13:30  |  Presenting Author(s): Cédric Zeltz

      • Abstract

      Background

      Our previous studies showed that non-small cell lung cancer (NSCLC) stroma is an important actor of lung tumorigenesis. We found integrin α11, a fibrillar collagen receptor expressed on cancer-associated fibroblasts (CAF), to be strongly up-regulated in NSCLC stroma and to promote NSCLC growth in vivo. Collagen XI is a fibrillar collagen that expression is increased in NSCLC and is correlated with integrin α11 expression. The purpose of the present study is to determine whether integrin α11-mediated lung tumorigenesis is induced via collagen XI and how that collagen may affect lung carcinoma cell invasion.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To study the effects of collagen XI, collagen XI has been incorporated in a matrix of collagen I at a ratio 1:3 (collagen I/XI). For tumor cell invasion, lung adenocarcinoma H1975 cells were allowed to form spheroids before being embedded in a collagen I or a mix of collagen I/XI matrix. Area of dissemination and migration pattern has been analyzed 48 hours later. In order to identify the collagen receptor interacting with collagen XI, we used cell attachment and ELISA assay. Knockout of integrin α2 and DDR1 has been performed using the CRISPR-Cas9 strategy in H1975 cell line.

      4c3880bb027f159e801041b1021e88e8 Result

      We showed that high collagen XI expression is associated with high risk of recurrence in the UHN cohort of 165 NSCLC patients (hazard ratio= 1.97, 95% confidence interval 1.09-3.56, P<0.026). Surprisingly, CAF embedded in a mix of collagen I/XI matrix failed to reorganize the collagen matrix as efficient as embedded CAFs in only collagen I matrix and displayed inhibition of migration in presence of collagen XI. In contrast, collagen XI greatly enhanced invasion of lung adenocarcinoma H1975 cells in a mix collagen matrix with a different invasion pattern compared to H1975 cell invasion in collagen I. Although integrin α11 expression correlates with collagen XI expression in NSCLC, this integrin bound poorly to collagen XI. Instead we found integrin α2 and DDR1 to interact with collagen type XI (Kd=5nM and Kd=24nM, respectively). Knockout of integrin α2 or DDR1 in H1975 cells suppressed collagen XI-increased invasion in a collagen I/XI matrix, indicating that both collagen receptors are required to mediate collagen XI effect on lung adenocarcinoma dissemination.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We showed that the presence of collagen XI in NSCLC stroma could enhance lung adenocarcinoma dissemination via integrin α2 and DDR1. Thus, targeting these two collagen receptors may be a new strategy to improve the outcome of lung cancer.

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      P3.03-19 - The Lysyl Oxidase like-1 Promotes NSCLC Tumorigenecity Through Increased Matrix Reorganization and Stiffness (ID 14048)

      12:00 - 13:30  |  Presenting Author(s): Cédric Zeltz

      • Abstract

      Background

      The importance of the stroma in tumorigenicity has been increasingly recognized in the past few years and targeting tumor stroma has become a new strategy for the development of new therapies. The lysyl oxidase like-1 (LOXL1) is a matrix cross-linking enzyme, essentially secreted by cancer-associated fibroblasts (CAFs) in the stroma. We previously showed that LOXL1 expression strongly correlated with integrin α11 expression, a collagen receptor that promotes NSCLC tumorigenecity, suggesting that LOXL1 may also contribute to lung tumor growth and metastasis by modifying the stromal collagen matrix.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Primary CAFs (CAF094) isolated from a NSCLC resection specimen and immortalized with hTERT were infected with full length LOXL1 (LOXL1 overexpression), LOXL1 shRNA (LOXL1 knockdown) or with their respective controls, using a lentiviral system. To investigate the impact of LOXL1 on collagen matrix reorganization, we allowed CAFs expressing different levels of LOXL1 to contract collagen matrices. Contracted collagen matrices have then been submitted to second harmonic generation to analyze collagen fibers. We established the role of LOXL1 in lung carcinoma invasion and growth using an in vitro organotypic model and an in vivo xenograft model, respectively.

      4c3880bb027f159e801041b1021e88e8 Result

      LOXL1-overexpressing CAFs embedded in collagen lattices displayed greater ability to reorganize the collagen matrix than those with lower LOXL1 expression. Furthermore, analysis of the collagen matrix demonstrated that LOXL1 contributed to more linear and dense collagen fibers organization. As a consequence of collagen matrix reorganization, invasion of the lung carcinoma H661 cell line significantly increased in an organotypic model in presence of LOXL1-overexpressing CAFs. Moreover, we showed that loss of Loxl1 in mice inhibited subcutaneous growth of the lung adenocarcinoma H4006 cell line compared to the mouse wild-type counterparts.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We demonstrated that overexpression of LOXL1 in NSCLC tumor stroma results in an increased of tumor growth and invasion, due to a change in the matrix reorganization. Thus, LOXL1 appears as an interesting target to improve the outcome of lung cancer.

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