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THE SIGNIFICANCE OF A STROMAL SECRETED ECM FACTOR IN PDAC LIVER METASTASIS
Lorena Llontop^*3, Alina-Sophie Markhoff³, Maren Drenckhan³, Andrew S. Liss¹, Susanne Sebens², Steffen Deichmann³, Rüdiger Braun³, Louisa Bolm³, Timo Gemoll³, Lennart von Fritsch³, Ulrich F. Wellner³, Tobias Keck³, Jannis Duhn³, Kim C. Honselmann^3
1Pancreatic Biology Laboratory, Department of Surgery, MGH/Harvard Medical School, Boston, MA; ²Institute of Experimental Cancer Research, Kiel University, Kiel, Schleswig-Holstein, Germany; ³Department of Surgery, University Medical Center Schleswig-Holstein, Campus Luebeck, Lübeck, Schleswig-Holstein, Germany

Introduction
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic stroma, which plays a critical role in the progression of the disease. Despite growing recognition of the involvement of the extracellular matrix (ECM) in PDAC, Corticotropin-Releasing Hormone Binding Protein (CRHBP), an ECM-secreted factor, remains unexplored.

Methods
We analyzed CRHBP expression in tumor bulk RNA-seq datasets from both primary and metastatic PDAC patients, as well as in PDX (patient-derived xenograft) mouse models. CRHBP expression was assessed in 20 primary PDAC fibroblast cell lines and 5 tumor cell lines by qPCR and western blot. CRHBP downregulation was performed using siRNA knockdown, and subsequent effects on cell growth and migration were evaluated using Resazurin and IBIDI-Culture-Insert 2 Well assays.

Results
RNA-seq data revealed a higher log2-fold-change (FC) of CRHBP in liver metastasis (FC = 1.64, p < 0.001, q < 0.001) compared to primary tumors. In contrast, expression in lung (FC = -0.34), lymph nodes (FC = 0.64), and peritoneum (FC = -0.05) was lower. PDX analysis confirmed CRHBP upregulation in liver metastasis, particularly in the metastatic stroma (FC = 4545.58, p = 0.004, q = 0.0003), compared to the tumor cell compartment (FC = 5.45, p = 0.004, q = 0.001). In a screen of PDAC stromal and cancer cell lines, CRHBP expression was detected in only 2 out of 25 evaluated lines (LueCAF21 and LueCAF9). CRHBP knockdown cells exhibited increased proliferation (Fig. 1) (1.59 times faster doubling time on day 12) and migrated 2.39 times more rapidly compared to wild-type cells (WT = 144?m, KD = 345.18?m) .

Conclusion
These preliminary findings suggest a potential anti-tumorigenic role for CRHBP, warranting further investigation.


Fig. 1) Cell migratory abilities of CRHBP Knockdown T009 primary PDAC fibroblast cell line and control were evaluated by wound healing migration assay (Left side: siRNA Scramble, right side: siRNA CRHBP)

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