Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma

Abstract

The recent success of immune checkpoint blockade in melanoma and lung adenocarcinoma has galvanized the field of immuno-oncology as well as revealed the limitations of current treatments, as the majority of patients do not respond to immunotherapy. Development of accurate preclinical models to quickly identify novel and effective therapeutic combinations are critical to address this unmet clinical need. Pancreatic ductal adenocarcinoma (PDA) is a canonical example of an immune checkpoint blockade resistant tumor with only 2% of patients responding to immunotherapy. The genetically engineered Kras G12D+/-;Trp53 R172H+/-;Pdx-1 Cre (KPC) mouse model of PDA recapitulates human disease and is a valuable tool for assessing therapies for immunotherapy resistant in the preclinical setting, but time to tumor onset is highly variable. Surgical orthotopic tumor implantation models of PDA maintain the immunobiological hallmarks of the KPC tissue-specific tumor microenvironment (TME) but require a time-intensive procedure and introduce aberrant inflammation. Here, we use an ultrasound-guided orthotopic tumor implantation model (UG-OTIM) to non-invasively inject KPC-derived PDA cell lines directly into the mouse pancreas. UG-OTIM tumors grow in the endogenous tissue site, faithfully recapitulate histological features of the PDA TME, and reach enrollment-sized tumors for preclinical studies by four weeks after injection with minimal seeding on the peritoneal wall. The UG-OTIM system described here is a rapid and reproducible tumor model that may allow for high throughput analysis of novel therapeutic combinations in the murine PDA TME.

Ultrasound Guided Surgery as a Refinement Tool in Oncology Research

“…There is no limitation on the volume injected in the pancreas due to the minimum stiffness of the tissue, but in most of the publications, the injected volume range goes from 20 to 50 microliters [ 32 , 33 , 34 ].…”

Modeling pancreatic cancer in mice for experimental therapeutics

“…Several studies have used Matrigel based implantation method for testing various therapeutic modalities and reported that matrigel provides more consistent and proliferative tumors [118][119][120][121]. Alternative to surgical implantation method that is time-intensive and cause aberrant inflammation, a non-invasive method has been developed to implant the cells in the pancreas of the mouse with the help of USG imaging (Figure 1B; panel 2) [122]. Technically, as the transducer comes closer to the abdomen, pancreas can be visualized and the allowing a needle to be guided for the orthotopic implantation of the tumor cells.…”

Lipid nanoparticles delivering constitutively active STING mRNA as a novel anti-cancer therapeutic approach

“…Few effective treatments are available for patients with advanced pancreatic cancer [5]. Nearly 98% of pancreatic cancer patients are also resistant to PD-1/PD-L1 immune checkpoint blockade therapies [6][7][8][9]. Thus, there is a significant unmet need for developing more effective therapies targeting this highly lethal cancer.…”