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Hepato-pancreato-biliary

E186: Targeting IL-6, CXCL12, and TGFB1: A Possible Approach to Suppress Pancreatic Cancer Invasion via Stromal Intervention

    ePoster Abstract Author(s)

  • FS

    Fatemeh Shojaeian, MD, MPH

    Postdoctoral Research Fellow
    Johns Hopkins University School of Medicine, United States

    • Submitter(s)

  • FS

    Fatemeh Shojaeian, MD, MPH

    Postdoctoral Research Fellow
    Johns Hopkins University School of Medicine, United States

    • Author(s)

  • KK

    Katrina Kuhn, BS

    MD/PhD Student
    Johns Hopkins University School of Medicine, United States

  • RB

    Richard A. Burkhart, MD

    Associate Professor
    Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Johns Hopkins Hospital, United States

  • LW

    Laura D. Wood, MD, PhD

    Associate Professor
    Johns Hopkins University School of Medicine, United States

Introduction: The complexity of the pancreatic cancer microenvironment, coupled with its aggressive invasion and resistance to treatment, emphasizes the necessity for innovative therapeutic approaches. Previous studies within our group have identified multiple mediators, including IL-6, CXCL12, and TGFB1, as ligands from stromal cells that may promote invasion in pancreatic cancer. Herein, we delved into a promising avenue, employing organoids as a platform to assess the impact of targeting IL-6, CXCL12, and TGFB1 within the pancreatic cancer stroma, aiming to enhance the prospects of pancreatic cancer management.

Methods: Fresh patient-derived organoids (PDOs) and cancer-associated fibroblasts (CAFs) were obtained from resected pancreatic ductal adenocarcinoma tumor samples following pancreatectomy. In the fresh PDO setting, tumor cells were directly cultured within a collagen gel, as an extracellular matrix (ECM) on the day of surgery to generate organoids for subsequent treatment. Passaged PDOs were initially developed by culturing the primary tumor within Matrigel ECM and following multiple rounds of in vitro regeneration in Matrigel and culture media, they were transferred to a collagen-based environment for treatment. The impact of IL6, CXCL12, and TGFB1 inhibitors on invasion was assessed by quantifying PDO invasion into collagen gels after 72 hours of treatment, using image J. CAFs were also cultured in vitro to induce differentiation into either inflammatory or myofibroblastic CAFs, and their conditioned media were collected after a 36-hour incubation.

Results: Treating six passaged PDOs with IL6, CXCL12, and TGFB1 inhibitors significantly reduced invasion compared to untreated cultures in all six samples. Subsequently, the same inhibitors reduced invasion in four out of six fresh PDO cultures. Notably, IL6, CXCL12, and TGFB1 were detected by ELISA, in the media collected from both inflammatory and myofibroblastic subtypes of CAFs obtained from the patients, confirming both CAF subtypes as a source of invasion-promoting ligands in the microenvironment.

Conclusions: Inhibiting IL-6, CXCL12, and TGFB1 in pancreatic tumoral stroma has the potential to reduce tumoral cell invasion. Additionally, given the variations across patient samples, patient-derived organoids can be a promising approach to evaluate the effectiveness of these inhibitors in preventing invasion within each patient's tumor.

Learning Objectives:

  • Assess the efficacy of IL-6, CXCL12, and TGFB1 inhibitors in organoid cultural system
  • Explore the impact of targeting specific mediators in vitro setting
  • Understand some detail about the role of stroma and cancer-associated fibroblasts in pancreatic cancer