January 31, 2017

Story by Rebecca Hood, photo by Kristyna Wentz-Graff

The featured paper for January is entitled "MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment" and was published in Nature Communications. Sudarshan Anand, Ph.D., assistant professor of cell, developmental and cancer biology, OHSU School of Medicine, is the senior author on the paper, which included contributions from OHSU researchers RaeAnna Wilson, Cristina Espinosa-Diez, Ph.D., Nathan Kanner, Namita Chatterjee, Ph.D., Rebecca Ruhl, Christina Hipfinger, Sushil Kumar, and Lisa Coussens, Ph.D., professor and chair of cell, developmental and cancer biology, OHSU School of Medicine, and associate director of basic research, Knight Cancer Institute.

While it seems logical that tumor-fighting strategies would target the tumor itself, Dr. Anand and his team focused instead on the accessory cells surrounding tumors referred to as the tumor microenvironment. 

The tumor microenvironment contains a variety of different cell types, but Dr. Anand specifically studied the blood vessels that supply tumors and how those vessels can be targeted to potentially mediate tumor cell health. 

As Dr. Anand put it, "In my lab, we are now trying to understand how these blood vessels in the tumor can modulate responses to radiation or chemotherapy, interact with the immune cells, tumor cells and orchestrate the neighborhood to either protect the tumor cells or enhance their death."

Identifying the utility of microRNAs

In order to do this, Dr. Anand used small non-coding RNAs called microRNAs that are known to affect tumor blood vessels. During his postdoctoral work at U.C. San Diego, Dr. Anand studied how "microRNAs affect angiogenesis or the formation of new blood vessels in response to growth factors from the tumor." Now he has applied that knowledge to identify ways to manipulate blood vessel cells to affect tumor cells.

"In this paper, we discovered a specific group of microRNAs that regulate responses to DNA damaging agents in the tumor blood vessels," says Dr. Anand. 

Experiments show that microRNAs can be induced by radiation and cisplatin, a chemotherapeutic agent, in blood vessels from mouse tumors and in petri dishes containing the cells lining the inside of blood vessels, called endothelial cells. 

Dr. Anand states that his team showed that "one of these microRNAs (miR-103)" is capable of "decreasing tumor burden and metastasis in preclinical mouse models of brain, breast and colon cancer." 

He continued, " This microRNA not only behaves like a dose of radiation and induces DNA damage but also kills endothelial cells, induces inflammatory cytokines and increases the expression of death receptors in the tumors."

But wait, there's more!

Furthermore, he said, "We were able to show that the major target for this microRNA was a gene named TREX1 (three prime repair exonuclease 1)." 

TREX1 is an enzyme capable of degrading single-stranded DNA and potentially other types of nucleic acids. If the cells don't degrade single-stranded DNA due to mutations in TREX1, "DNA-sensing machinery suspects a viral invasion and triggers a potent inflammatory reaction," explained Dr. Anand. 

Notably, patients suffering from lupus have mutations in the TREX1 gene that cause activation of the cytosolic DNA-sensing machinery. While this can be deleterious in normal cells, "By decreasing the levels of this enzyme TREX1 in the tumor blood vessels, our microRNA triggered the same reaction, leading to better control of tumor growth."

"Our work demonstrates that it is possible to provoke tumor immune responses indirectly by targeting the tumor blood vessels," said Dr. Anand. "The tumor microenvironment, unlike the tumor cells, is mostly devoid of mutations, genomic instability, etc., and therefore is less prone to escape from therapies." 

Essentially, Dr. Anand and his group have been able to take advantage of the fact that the tumor microenvironment is easier to influence than tumor cells and have described a potential therapy that indirectly targets tumor cells through modification of the tumor microenvironment. 

As Dr. Coussens described it, "This is an exciting finding for the field as it introduces a novel strategy for modulating tumor microenvironments by disrupting DNA repair in tumor-associated endothelial cells."

This would be a new step forward in how scientists consider the role of RNA and how to best treat tumors. Mary Heinricher, Ph.D., associate dean for basic research, OHSU School of Medicine, said that she "was just blown away by the idea of non-coding RNAs influencing not so much the tumor, but the tumor microenvironment."

These findings also affect the current understanding of how radiation and chemotherapy can be beneficial. "Our work sets the stage to both understand how DNA-damaging therapies such as radiation alter transcription programs in cells and manipulate it for therapeutic gains," said Dr. Anand. "On a fundamental level, some of these pathways and their roles in endothelial survival have not been appreciated before, and our work illustrates how endothelial cells overall deal with DNA damage."

Next steps

This is just the beginning for Dr. Anand and his team. Dr. Coussens described their potential, "I look forward to seeing Sud and his group define and develop more of these pathways that will aid improved therapeutic options to pair with chemotherapy and radiation to combat cancer." 

Regarding his next steps, Dr. Anand said, "Our long-term goal is to develop RNA biomarkers that can predict treatment responses in cancer. For example, if we see our miR-103 levels increase and trex1 levels decrease in a tumor, does it augur well for radiotherapy responses?" 

His team is also developing other ways to target TREX1 by developing an assay to measure the potential of small molecules to alter TREX1 activity. "We hope to get pilot funding to screen more and try and get drug leads," he said. Finally, he said, "We also have other discovery efforts underway with a goal of understanding the function of some of the other microRNAs that came up in our screen. We are fortunate to have a wonderful group of generous collaborators here at OHSU so we can start to develop some of these projects."

Resources 

• Read the paper

More Published Papers

• Previous School of Medicine Papers of the Month
• Recent OHSU published papers

Pictured above, from left: postdoctoral researcher Cristina Espinosa, senior research assistant Rebecca Ruhl and Dr. Sudarshan Anand