Method to visualize the intratumor distribution and impact of gemcitabine in pancreatic ductal adenocarcinoma by multimodal imaging

Strittmatter, N. et al. (2022) Method to visualize the intratumor distribution and impact of gemcitabine in pancreatic ductal adenocarcinoma by multimodal imaging. Analytical Chemistry, 94(3), pp. 1795-1803. (doi: 10.1021/acs.analchem.1c04579) (PMID:35005896)

Abstract

Gemcitabine (dFdC) is a common treatment for pancreatic cancer; however, it is thought that treatment may fail because tumor stroma prevents drug distribution to tumor cells. Gemcitabine is a pro-drug with active metabolites generated intracellularly; therefore, visualizing the distribution of parent drug as well as its metabolites is important. A multimodal imaging approach was developed using spatially coregistered mass spectrometry imaging (MSI), imaging mass cytometry (IMC), multiplex immunofluorescence microscopy (mIF), and hematoxylin and eosin (H&E) staining to assess the local distribution and metabolism of gemcitabine in tumors from a genetically engineered mouse model of pancreatic cancer (KPC) allowing for comparisons between effects in the tumor tissue and its microenvironment. Mass spectrometry imaging (MSI) enabled the visualization of the distribution of gemcitabine (100 mg/kg), its phosphorylated metabolites dFdCMP, dFdCDP and dFdCTP, and the inactive metabolite dFdU. Distribution was compared to small-molecule ATR inhibitor AZD6738 (25 mg/kg), which was codosed. Gemcitabine metabolites showed heterogeneous distribution within the tumor, which was different from the parent compound. The highest abundance of dFdCMP, dFdCDP, and dFdCTP correlated with distribution of endogenous AMP, ADP, and ATP in viable tumor cell regions, showing that gemcitabine active metabolites are reaching the tumor cell compartment, while AZD6738 was located to nonviable tumor regions. The method revealed that the generation of active, phosphorylated dFdC metabolites as well as treatment-induced DNA damage primarily correlated with sites of high proliferation in KPC PDAC tumor tissue, rather than sites of high parent drug abundance.

• Item Type: Articles
• Additional Information: The authors thank the CRUK Cambridge Institute (CI) Preclinical Genome Editing Core Facility, in particular, Lisa Young, Steven Kupczak, Yi Cheng, Maureen Cronshaw, and Naomi Vranas. We thank the CRUK CI BRU staff for technical support, Sandra Bernaldo de Quirós Fernández for cell line maintenance, and CRUK CI Cell Services core for cell line authentication. All CRUK CI authors received research funding from Cancer Research UK (Nos. C14303/A17197 and C9545/A29580). P.E.A. acknowledges funding from the Swedish Research Council (No. 2018-03320), the Swedish Foundation for Strategic Research (No. RIF14-0078) and the Science for Life Laboratory. The authors would furthermore like to acknowledge the CRUK Grand Challenge Rosetta Consortium (No. C59824/A25044) for scientific discussions relating to this research. O.J.S. acknowledges CRUK core funding to the CRUK Beatson Institute A17196 and CRUK core funding to O.J.S. (No. A21139).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Goodwin, Dr Richard and Sansom, Professor Owen
• Authors: Strittmatter, N., Richards, F. M., Race, A. M., Ling, S., Sutton, D., Nilsson, A., Wallez, Y., Barnes, J., Maglennon, G., Gopinathan, A., Brais, R., Wong, E., Serra, M. P., Atkinson, J., Smith, A., Wilson, J., Hamm, G., Johnson, T. I., Dunlop, C. R., Kaistha, B. P., Bunch, J., Sansom, O. J., Takats, Z., Andrén, P. E., Lau, A., Barry, S. T., Goodwin, R. J.A., and Jodrell, D. I.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Analytical Chemistry
• Publisher: American Chemical Society
• ISSN: 0003-2700
• ISSN (Online): 1520-6882
• Published Online: 10 January 2022