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A. Gimenez



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    P1.01 - Poster Session 1 - Cancer Biology (ID 143)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.01-015 - Overabundance of activated stromal fibroblasts (TAFs) in NSCLC on response to extracellular matrix (ECM) rigidity (ID 2403)

      09:30 - 16:30  |  Author(s): A. Gimenez

      • Abstract

      Background
      Breathing demands our lungs to be soft and elastic. In contrast, lung tumors exhibit an abnormal tissue hardening concomitantly with an altered lung architecture and function, which brings the mechanical microenvironment of the tumor closer to that of muscle or bone. Carcinoma-associated fibroblasts (TAFs) within the tumor stroma are known to be conspirators of tumor progression. It remains unknown whether tissue hardening is sufficient to drive abnormal abundance of activated fibroblasts in the stroma of the different NSCLC subtypes. We aimed to determine the role of abnormal tumor tissue hardening in the overabundance of TAFs in different NSCLC subtypes

      Methods
      To address this question, we cultured the human lung fibroblast cell line CCD-19Lu or primary human lung fibroblasts on collagen-coated polyacrylamide gels exhibiting normal (soft) or tumour (stiff)-like substrates in the absence (0%) or presence (0.1%) of serum for 5 days. Primary cells were isolated from both tumor-free regions (referred to as control fibroblasts) or tumors of NSCLC patients diagnosed with either Adenocarcinoma (ADC, n=5) or Squamous Cell Carcinoma (SCC, n=5) histological subtypes.

      Results
      We observed a significantly higher density of CCD-19Lu fibroblasts in tumor-like gels compared to normal-like gels regardless the presence of serum. Similar results were obtained in both primary control fibroblasts and SCC-TAFs. In contrast, tumor-like gels induced a weaker density increase in primary ADC-TAFs. The increased fibroblast density in the tumor-like gels was associated with increased survival rather than proliferation, as revealed by a downregulation of caspase-3 and a rise in FAK and AKT phosphorylation. To further understand the apoptotic effect on stiffer substrates, we examined the expression of the mechanoreceptor integrin beta-1, responsible of sensing stiffness signals from the ECM. We found a significantly higher expression of integrin beta-1 in SCC compared to control and ADC primary fibroblasts .

      Conclusion
      Our results indicate that tumor extracellular hardening alone is sufficient to induce an increased density in activated lung fibroblasts, a well known conspirators of tumor progression, by activating pro-survival FAK-AKT pathways. Collectively these findings underline the major role of tissue hardening in the abnormal abundance of TAFs in NSCLC, particularly in the SCC subtype. These data warrants the development of novel targeted therapies against the pro-survival effects of tissue hardening.