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    Women's Health

    Tension in the Ovarian Tumor Microenvironment May Lead to Chemoresistance

    (M-496) Tension in the Ovarian Tumor Microenvironment May Lead to Chemoresistance

    Thursday, October 12, 2023
    9:30 AM – 10:30 AM PDT
    Location: Exhibit Hall - Row M - Poster # 496

      Presenting Author(s)

    • Kamari Marzette

      UAB Biomedical Engineering Student
      UAB Department of Biomedical Engineering
      Trussville, Alabama, United States

      • Co-Author(s)

    • MT

      Maranda Tidwell (she/her/hers)

      Graduate Student
      University of Alabama at Birmingham
      Birmingham, Alabama, United States

      • Primary Investigator(s)

    • MS

      MK Sewell-Loftin (she/her/hers)

      Assistant Professor
      The University of Alabama at Birmingham, United States

    Introduction::

    Ovarian cancer is the most lethal gynecologic cancer with high mortality rates due to late-stage disease detection and recurrent disease that is often resistant to chemotherapeutic treatment (1). Despite this fact, scientists know little of the role of the tumor microenvironment (TME) in metastasis and chemoresistance of ovarian cancer. The TME includes mechanically-active fibroblasts which increases the tension experienced by the ovarian cancer cells. It has previously been shown that mechanical stress in the TME has been shown to alter cancer cell behavior by making them more proliferative, migratory, and invasive (2). We hypothesize that ovarian cancer cells that have been pre-exposed to tensile strains have altered response to chemotherapy compared to non-strain treated cells. The objective of this study was to understand and show how ovarian cancer cells become more chemoresistant when exposed to tensile strains.



    Materials and Methods:: Human ovarian cancer cell line OVCAR8 was selected for the studies; OVCAR8 are non-serous cells that exhibit highly invasive behaviors (3). OVCAR8 cells were subjected to uniaxial strain while plated on a 2D FlexCell Collagen-I coated plate. Cells were treated with the FlexCell 6000 tension system for 24hr at 9% elongation and 0.3Hz. These parameters mimic strains induced by cancer-associated fibroblasts and respiration rates, respectively.  After 24hr, cells were harvested and embedded in a 10mg/mL fibrin gel held in place with a poly(dimethylsiloxane) (PDMS) ring per a previously described 3D microtissue model (4). Pre-treated strained and control cells from FlexCell plates that were not strained were loaded into the gels and fed RMPI media. After 24hr, the cells were treated with chemotherapy treatments including a low dosage of Cisplatin (LD Cis, 50 mM), high dosage Cisplatin (HD Cis,100 mM), and a vehicle control (VEH Cis) consisting of DPBS. Cisplatin is a clinically-utilized first line treatment for ovarian cancer. After 24hr of drug treatment, a Sytox assay was performed with Hoescht used as a counterstain. For each gel, a 100mm z-stack was collected and processed in FIJI to quantify dead and total cell counts.

    Results, Conclusions, and Discussions:: Our results show that both low dose and high dose cisplatin can increase the percent cell death compared to the vehicle control for the non-strained and pre-strained cells (Figure 1).  The non-strained cells saw an increase in cell death when exposed to both low dose cisplatin and high dose cisplatin. This was not observed in the cells that were pre-treated with strain for high dose cisplatin compared to low dose or vehicle controls (Figure 1). These results show that a pre-treatment with tensile strain can cause a plateau in the efficacy of chemotherapy treatment. Our results support our hypothesis that mechanical forces may regulate chemoresistance of ovarian cancer cells. Future studies include further testing the ovarian TME mechanical features by including hyaluronic acid to the fibrin matrix; hyaluronic acid is associated with significantly worse ovarian cancer progression. Furthermore, testing this matrix component will allow us to investigate potential mechanoreceptors that drive ovarian cancer chemoresistance, such as CD44. Ultimately, our studies will help identify novel mechanoregulation of ovarian cancer progression.

    Acknowledgements (Optional): :

    References (Optional): :

    (1) https://www.cancer.org/cancer/ovarian-cancer/about/key-statistics.htm, (2) Liu, Q, et al., Role of the mechanical microenvironment in cancer development and progression. Cancer Biol Med, 17(2): 282-292 (2020). (3) Hallas-Potts, A., et al. Ovarian cancer cell lines derived from non-serous carcinomas migrate and invade more aggressively than those derived from high-grade serous carcinomas. Sci Rep 9, 5515 (2019). (4) Sewell-Loftin, MK, et al. Cancer-associated fibroblasts support vascular growth through mechanical force. Sci Rep 7, 12574 (2017).