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Updated: Jul 5, 2025
Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma
Published on: November 19, 2019
Dual-Hit Strategy for Therapeutic Targeting of Pancreatic Cancer in Patient-Derived Xenograft Tumors
Tista Roy Chaudhuri1, Qingxiang Lin2, Ewa K Stachowiak3
1Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York.
Purpose:
Paracrine 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 Design:
Animals 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.
Results:
Multiple 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.
Conclusions:
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-translational requirement for patient stratification.
Insights
Pancreatic cancer drug delivery improves with combined SMO and FGFR inhibition, reversing tumor resistance. Diffusion-weighted MRI can identify responsive patients for this dual-therapy approach.
Area of Science:
- Oncology
- Cancer Biology
- Tumor Microenvironment
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits stromal amplification driven by hedgehog (HH) signaling, hindering drug delivery and patient outcomes.
- Smoothened (SMO) inhibitors (SHHi) transiently improve vascular permeability in PDAC, but tumor responsiveness varies, with responders showing epithelial-mesenchymal transition (EMT).
Purpose of the Study:
- Identify signaling pathways causing EMT in SHHi-responsive PDAC tumors.
- Develop strategies to reverse EMT and stratify patients noninvasively using clinical parameters.
Main Methods:
- Diffusion-weighted magnetic resonance (DW-MR) imaging to assess intratumor diffusivity.
- Quantification of nanoparticle probe deposition to measure vascular permeability.
- Transcriptomic and bioinformatic analyses to identify key signaling nodes in SHHi-induced EMT.
Main Results:
- SHHi treatment increased vascular patency and tumor diffusivity in responsive PDAC isolates.
- SHHi-treated tumors exhibited elevated FGF signaling and nuclear FGFR1 accumulation in EMT-polarized cells.
- Pan-FGFR inhibitor (Infigratinib) reversed SHHi-induced EMT and nuclear FGFR1 without affecting enhanced permeability.
Conclusions:
- A dual-hit strategy combining SMO and FGFR inhibition offers a clinically translatable method to overcome PDAC tumor impermeability.
- DW-MR imaging presents a viable tool for patient stratification in clinical settings.
