Utilizing cell line-derived organoids to evaluate the efficacy of a novel LIFR-inhibitor, EC359 in targeting pancreatic tumor stroma

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.

MgFe‐LDH Nanoparticles: A Promising Leukemia Inhibitory Factor Replacement for Self‐Renewal and Pluripotency Maintenance in Cultured Mouse Embryonic Stem Cells

“…EC359 is capable of directly interacting with LIFR such that the LIF/LIFR interaction is effectively blocked. [ 31,32 ]…”

Identifying MMP14 and COL12A1 as a potential combination of prognostic biomarkers in pancreatic ductal adenocarcinoma using integrated bioinformatics analysis

“…ECM-receptor interactions play important roles in the processes of cell shedding, adhesion, degradation, migration, differentiation, hyperplasia, and apoptosis (Bao et al, 2019). PSCs secrete several ECM proteins, including collagen, fibronectin, fibulin-2, and laminin, as well as hyaluronan (Hall et al, 2019). Moreover, COL1A1 and COL3A1 were significantly downregulated in PC (p <0.0001) after treatment with gemcitabine in combination with EC359 (Hall et al, 2019).…”

“…PSCs secrete several ECM proteins, including collagen, fibronectin, fibulin-2, and laminin, as well as hyaluronan (Hall et al, 2019). Moreover, COL1A1 and COL3A1 were significantly downregulated in PC (p <0.0001) after treatment with gemcitabine in combination with EC359 (Hall et al, 2019). The gene COL1A1 encodes the pro-alpha 1 chain of type I collagen, which is closely associated with MMP14.…”

InferAMP, a python web app for copy number inference from discrete gene-level amplification signals noted in clinical tumor profiling reports

“…In any case in which a healthcare professional might consider targeting a non-assayed gene predicted by this algorithm to be amplified (e.g. LIFR 11 in Use case 2 and Use case 3 ), further clinical testing to directly confirm gene amplification would be warranted.…”