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Evette Radisky



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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-01 - MMP1 Secreted by Cancer Cells Induces a Pro-Tumorigenic Senescent Phenotype in Fibroblasts in Large Cell Carcinoma of the Lung (ID 2195)

      10:15 - 18:15  |  Author(s): Evette Radisky

      • Abstract
      • Slides

      Background

      Tumor associated fibroblasts (TAFs) are key effector cells of cancer progression. Senescent TAFs have been reported in a growing list of aggressive cancer subtypes including the aggressive subtype large cell carcinoma (LCC) of the lung. We previously reported that LCC cells induce fibroblast senescence in normal fibroblasts after co-culture, revealing that paracrine signaling must be involved. Moreover, we found that senescent fibroblasts secrete factors that stimulate the growth and invasion of LCC cells beyond the stimulation elicited by non-senescent fibroblasts, supporting that fibroblast senescence may contribute to the aggressive nature of LCC. Whole-genome transcriptional profiling on a panel of non-small cell lung cancer (NSCLC) cell lines, including adenocarcinoma (ADC), squamous cell carcinoma (SCC) and LCC, identified MMP1 as highly overexpressed in LCC cells compared to non-LCC cells. Here we examined the role of MMP1 in LCC cells in the paracrine induction of fibroblast senescence.

      Method

      We silenced MMP-1 expression in LCC cancer cell lines by shRNA and analyzed common senescence markers after co-culture with normal fibroblasts, including β-galactosidase staining as well as the expression of common factors of the senescence-associated secretory phenotype (SASP) by qRT-PCR. In addition, the growth and invasion pro-tumorigenic effects elicited by the conditioned medium of fibroblasts co-cultured with shMMP1 or shscramble LCC cells was analyzed.

      Result

      Knocking-down MMP1 in LCC cells was sufficient to abrogate fibroblast senescence induction in co-cultures with LCC cells, as well as the growth and invasion enhancement of LCC cells elicited by the conditioned medium of fibroblasts. The addition of active recombinant MMP1 partially rescued the fibroblast senescent phenotype in co-culture, yet it was not sufficient to induce senescence when added to fibroblasts cultured alone.

      Conclusion

      Our results unveil a process of “niche construction” by LCC cells that is driven by the overexpression of MMP1, which induces senescence in adjacent fibroblasts. Moreover, our results unveil a novel biological function of MMP1 (i.e. paracrine senescence induction in fibroblasts), that is strikingly different from its well-known collagenolytic function. Our results also show that MMP1 is necessary but not sufficient to induce fibroblast senescence. Moreover, our findings support that the aberrant carcinoma cell-fibroblast crosstalk mediated by MMP1 may be a suitable therapeutic target in LCC.

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