Dual-hit strategy for therapeutic targeting of pancreatic cancer in patient-derived xenograft tumors
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ABSTRACT:
PROVIDER: PRJNA668382 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12804163.fastq.gz | Fastqsanger.gz | |||
| SRR12804164.fastq.gz | Fastqsanger.gz | |||
| SRR12804165.fastq.gz | Fastqsanger.gz | |||
| SRR12804166.fastq.gz | Fastqsanger.gz | |||
| SRR12804167.fastq.gz | Fastqsanger.gz |
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Project description:Paracrine activation of pro-fibrotic sonic hedgehog (sHH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of sHH-mediated tumor-stroma crosstalk with smoothened inhibitors transiently increases tumor permeability and macromolecule delivery. Using diffusion-weighted magnetic resonance (DW-MR) imaging, we demonstrate in multiple patient-derived xenografts (PDX) that responders to short-term sHH inhibitor exposure show increased permeability with proportionate increases in tumor diffusivity. However, a subset of PDXs fails to respond. Responders show co-induction of epithelial-mesenchymal transition (EMT), elevated FGF drive, and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1). A pan-FGFR inhibitor (NVP-BGJ398) reverses EMT and nuclear FGFR1 accumulation without compromising the tumor priming effect. This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical requirement for patient stratification
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Project description:PurposeParacrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) "primes" PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial-mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on clinically-quantifiable parameters.Experimental designAnimals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intratumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key "nodes" responsible for EMT induction.ResultsMultiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Nonresponding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect.ConclusionsThis dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical-translational requirement for patient stratification.
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