Protein identified for detecting and targeting pancreatic adenocarcinoma [PreClinical]

1. Fluorescent reporters for the protein Muashi (Msi) were used for live imaging in mice, and showed that cancer cells that highly expressed Msi were tumorigenic and drug-resistant.

2. In a xenograft mouse model of pancreatic cancer, inhibition of Msi either before or after tumor implantation led to a decrease in tumor growth.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Pancreatic cancer typically does not begin to show symptoms until it has already metastasized. In addition, it is highly drug resistant, making it a difficult cancer to treat. As a result, current research is focused on both tracking and halting the progression of this cancer. This study first identified that the RNA binding proteins Msi1 and 2 are expressed in primary pancreatic tumors, with an increase in expression during progression. This initial finding led researchers to determine the potential of Msi1 and 2 as indicators and therapeutic targets for tumorigenesis.

Fluorescent reporters were created to detect the expression of Msi1 and 2, allowing for live imaging of cancer growth and spread in a mouse genetic model of pancreatic cancer. Tumor cells expressing Msi1 and 2 were more tumorigenic in vitro and in vivo. These cells were also highly resistant to gemcitabine, a chemotherapeutic currently used for the treatment of pancreatic adenocarcinoma. Next, Msi1 and 2 were inhibited in a xenograft mouse model. When protein expression was silenced with short hairpin RNAs (shRNAs) before implantation, a very small subset of cells progressed to adenocarcinoma. When Msi1 and 2 were directly targeted by antisense oligonucleotides (ASOs) after implantation, cancer growth was inhibited.

Although the ASOs developed in this study require further safety and efficacy testing, this study demonstrates the importance of Msi in pancreatic cancer cell development. These data show the possibilities of using Msi as both a therapeutic target and a way to visualize drug-resistant tumor development.

Click to read the study in Nature

Relevant Reading: Musashi signaling in stem cells and cancer

In-Depth [animal study]: Through immunohistochemistry, human pancreatic primary tumor samples were found to express both Msi1 and 2, with an increase in expression corresponding to tumor progression. This finding led the researchers to determine whether Msi directly impacted tumor cell growth. Msi1 and 2 genetic knock-in fluorescent reporters were introduced into a genetic mouse model of pancreatic cancer to allow for the real-time visualization of tumor growth and spread. Compared to cells that did not express the Msi reporters, cells that expressed the reporters were more tumorigenic, as measured by sphere-forming ability in vitro (p<0.05) and the survival of separate animals transplanted with the cells. Cells positive for Msi2 were then exposed to 500 mg/kg gemcitabine, which had no effect on cell survival, signifying that these cells were drug-resistant.

Before human primary pancreatic cancer cells were xenografted into mice, Msi1 expression was silenced using shRNA constructs delivered through a lentiviral vector. MRI imaging was used to detect tumor volume, and a 5-fold decrease in tumor size was noted in cells lacking Msi1 expression. Analogous results were obtained with the selective silencing of Msi2, with a tumor mass decreased around 6-fold decrease of tumor mass when Msi2 was silenced.

Finally, ASOs were developed to directly target Msi1 and 2 in established xenografts. This therapy led to a significant reduction in tumor volume and growth rate, demonstrating targeting these proteins could effectively suppress tumor development.

Image: PD

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