Abstract
Survival of pancreatic cancer (PC) patient is poor due to lack of effective treatment modalities, which is partly due to the presence of dense desmoplasia that impedes the delivery of chemotherapeutics. Therefore, PC stroma-targeting therapies are expected to improve the efficacy of chemotherapeutics. However, in vitro evaluation of stromal-targeted therapies requires a culture system which includes components of both tumor stroma and parenchyma. We aim to generate a cell line-derived 3D organoids to test the efficacy of stromal-targeted, LIFR-inhibitor EC359. Murine PC (FC1245) and stellate (ImPaSC) cells were cultured to generate organoids that recapitulated the histological organization of PC with the formation of ducts by epithelial cells surrounded by activated fibroblasts, as indicated by CK19 and α-SMA staining, respectively. Analysis by qRT-PCR demonstrated a significant downregulation of markers of activated stroma, POSTN, FN1, MMP9, and SPARC (p<0.0001), when treated with gemcitabine in combination with EC359. Concurrently, collagen proteins including COL1A1, COL1A2, COL3A1, and COL5A1 were significantly downregulated (p <0.0001) after treatment with gemcitabine in combination with EC359. Overall, our study demonstrates the utility of cell lines-derived 3D organoids to evaluate the efficacy of stroma-targeted therapies as well as the potential of EC359 to target activated stroma in PC.
Highlights
Pancreatic cancer (PC) is the third leading cause of cancer-related mortality and is responsible for over fifty thousand deaths per year in the United States [1]
Existing data support the notion that targeting pancreatic cancer (PC) stroma will improve the delivery, and hopefully, the efficacy of the treatment regimens [21]
There is a significant need to create a useful in vitro 3D model to investigate the efficacy of therapeutics targeting PC stroma
Summary
Pancreatic cancer (PC) is the third leading cause of cancer-related mortality and is responsible for over fifty thousand deaths per year in the United States [1]. The majority of chemotherapeutic regimens have demonstrated little efficacy in the treatment of PC. This poor performance of the therapeutic regimen is, in part, due to the dense desmoplastic stroma, which interferes with the delivery of chemotherapeutic agents and promotes cancer cell growth, www.Genes&Cancer.com stemness and immune suppression [5,6,7,8,9]. The cellular complexity seen within pancreatic tumors is difficult to replicate, few studies have utilized PSCs or fibroblasts, the cells responsible for the desmoplastic response, to investigate the contribution of stroma in overall PC pathology [12,13,14]. No study so far has used complex in vitro stroma containing systems to evaluate the efficacy of stroma-targeted therapies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
