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Targeting cancer-associated fibroblast-mediated LIF/LIFR axis improves the therapeutic efficacy of gemcitabine and nab-paclitaxel in pancreatic cancer

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) responds poorly to chemotherapeutics due to inherent drug resistance orchestrated by crosstalk between cancer cells and cancer-associated fibroblasts (CAFs). The LIF/LIFR axis activated by this crosstalk contributes significantly to cancer cell stemness and is a potential therapeutic target. Combined targeting of LIFR with small molecular inhibitors along with standard of care remains unexplored.The efficacy of LIFR small molecule inhibitor, EC359 was evaluated in combination with standard-of-care using human and mouse cell lines, tumoroids, KPC (KrasG12D; TP53R172H; Pdx1-Cre), and orthotopically co-implanted murine models. The impact of LIFR targeting on PDAC was analyzed by RNA-sequencing, immunohistochemistry, western blot, and immune profiles by flow cytometry.In co-implantation murine models, EC359 (5mg/kg body weight), in combination with gemcitabine (Gem, 25mg/kg body weight), reduced the tumor burdens up to 90% compared to the untreated controls (p<0.001) and by 55% compared to Gem alone. The RNA-seq analysis of treated tumors showed significant alterations in stemness markers, extracellular matrix modulation, microtubule structure assembly, and adaptive immune response, suggesting the simultaneous targeting of cell-intrinsic and TME-mediated mechanisms by EC359. The EC359 in autochthonous KPC tumors improved the efficacy of Gem and nab-paclitaxel targeting, increased the dendritic cells, but reduced regulatory T-cells, systemically. Mechanistically, EC359 reduces the PDAC cell stemness, stabilizes the microtubule assembly, and reduces the immunosuppressive microenvironment, contributing to improved efficacy of standard of care in PDAC.

ORGANISM(S): Mus musculus

PROVIDER: GSE300401 | GEO | 2025/08/27

REPOSITORIES: GEO

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Project description:Ferroptosis is a form of regulated cell death characterized by iron-dependent overaccumulation of lipid peroxides. It can be prevented by cellular mechanisms such as GPX4-mediated elimination of the lipid peroxides at the cost of glutathione (GSH). Since originally being discovered as a property of RAS-mutant cancer cells, ferroptosis has been shown to be regulated by several important oncogenes and tumor suppressors. In particular, LIFR, the receptor of the pleiotropic cytokine LIF, has recently been shown to be required for ferroptosis, as loss of Lifr in mouse liver tumor confers the cells resistance to ferroptosis. In this study, however, we found that the LIFR-targeting drugs, EC330 and EC359, are potent inducers of ferroptosis, thus reflecting an interesting “gain-of-function” effect of EC330/EC359 on LIFR-associated ferroptosis. Treatment of various types of cells with EC330/EC359 causes a rapid nonapoptotic cell death with characteristic morphology of ferroptosis, which can be inhibited by iron chelator (DFO) and lipid ROS scavenger (Fer-1), but not pan-caspase inhibitor (z-VAD-fmk). Consistent with previous observations, the efficiency of EC330/EC359 appears to be correlated with the expression levels of LIF and LIFR. RNA-seq analysis showed that the EC330/EC359 treatment leads to (i) a gene expression profile highly resembling that of RSL3, the GPX4-targeting ferroptosis inducer, and (ii) a specific decrease of expression of a few gene encoding membrane-located proteins, especially those located on the mitochondria (e.g., TOMM6 and COX14), implying defects in cellular/mitochondrial membrane functions. Indeed, transmission electron microscopy imaging of the EC330/EC359-treated cells shows shrunken mitochondria and loss of mitochondrial cristae. EC330/EC359 also decreases the activity of GPX4 in the cells to the level comparable with RSL3; meanwhile, the intracellular level of GSH is also decreased, and thus GPX4 inactivation and GSH depletion may jointly disable the cells to eliminate the toxic lipid peroxides. Lastly, although the STAT3 and AKT signaling pathways downstream of LIFR are inhibited by EC330/EC359, inhibition of these pathways per se can only induce non-ferroptotic cell death, suggesting that the EC330/EC359-induced ferroptosis is independent of these downstream pathways; the LIFR-NFkB-LCN2 axis discovered recently in mouse liver tumor cells might not explain the EC330/EC359-induced ferroptosis either, because LCN2 is not detectable in the herein used cell lines. Taken together, these results reveal an unexpected role of the LIFR-targeting drugs EC330/EC359 as potent inducer of ferroptosis and, in combination with previous studies, suggest that there could be either unknown mechanism for the LIFR-associated ferroptosis or unknown target for EC330/EC359 to effect the ferroptosis induction.

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Targeting cancer-associated fibroblast-mediated LIF/LIFR axis improves the therapeutic efficacy of gemcitabine and nab-paclitaxel in pancreatic cancer

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