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ccr-23-0131_supplementary_figure_s2_suppsf2.pdf (8.17 MB)

Supplementary Figure S2 from Dual-Hit Strategy for Therapeutic Targeting of Pancreatic Cancer in Patient-Derived Xenograft Tumors

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posted on 2024-04-01, 07:24 authored by Tista Roy Chaudhuri, Qingxiang Lin, Ewa K. Stachowiak, Spencer R. Rosario, Joseph A. Spernyak, Wen Wee Ma, Michal K. Stachowiak, Michelle K. Greene, Gerard P. Quinn, Simon S. McDade, Martin Clynes, Christopher J. Scott, Robert M. Straubinger

Supplementary Figure S2. SHHi-treatment decreases tumor collagen and enhances SSL-DiI permeability and deposition

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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National Center for Advancing Translational Sciences (NCATS)

United States Department of Health and Human Services

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New York State Stem Cell Science (NYSTEM)

Center for Protein Therapeutics, University at Buffalo (CPT)

Division of Chemical, Bioengineering, Environmental, and Transport Systems (CBET)

Roswell Park Comprehensive Cancer Center (RPCI)

Science Foundation Ireland (SFI)

Health and Social Care Northern Ireland (HSC)

Medical Research Council (MRC)

Cancer Research UK (CRUK)

History

ARTICLE ABSTRACT

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. 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. 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. 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.