UA researcher and doctoral student reconcile scientific battle in colon cancer research

When two studies to identify new methods of colon cancer treatment yielded different results, a researcher from the University of Arizona Cancer Center was asked to help solve the problem. 39; uncertainty.

Curtis Thorne, Ph.D., an badistant professor in cellular and molecular medicine, accepted the challenge and enlisted one of her PhD students, Carly R. Cabel, to badist in the project.

The goal was simple: to determine whether the therapeutic targeting of a specific protein – LRP6 – was an appropriate treatment strategy for colon cancer. If so, it will challenge current scientific dogma and approaches to patient care.

The National Cancer Institute ranked colorectal cancer (cancer of the colon or rectum) as the fourth most cancers diagnosed in the United States. More than 145,000 new cases are expected in 2019.

A potential breakthrough in the therapeutic targeting of colon cancer begins with the biology of cancer cells. Previously accepted research has identified a protein called adenomatous polyposis (APC) as a tumor suppressor in the colon. When it works properly, APC protein prevents cells from growing and dividing too quickly or uncontrollably.

However, when APC is mutated and loses its function, the effects can be harmful. One result is the abnormal activation of signaling pathways (the way cells communicate with each other) that can lead to cancer.

"In colon cancer, the Wnt (" disappeared ") pathway is used to control the proliferation of cells lining the colon," said Dr. Thorne. "This path is activated inappropriately where it signals too much, which leads to colon cancer."

In healthy intestinal cells, the Wnt pathway consists of an antenna-like cell surface receptor, called LRP6, which "listens" to signals in the tissue environment to tell cells when to develop or at what time moment to stop growing. In cases where an APC mutation occurs, the Wnt pathway is activated inside the cell rather than on the surface. When this occurs, it is believed that the APC mutant cells completely ignore the signals from the LRP6 receptor. Scientists have generally felt that there is little point in targeting LRP6 with therapeutic agents because of the "downstream" pathway triggered by APC.

It was common thought until a team of researchers led by Ethan Lee, MD, Ph.D., of Vanderbilt University and Yashi Ahmed, MD, Ph.D., of Dartmouth College, discovered that Wnt receptors such as LRP6 can further promote growth, even when the pathway is mutated downstream to APC.

The researchers concluded that the therapeutic targeting of this protein could be a treatment strategy to consider to block the progression of colon cancer. Their findings were published in the March 2018 edition of Developmental cell, a journal of great interest covering the fields of cell biology and developmental biology.

After the report was published, Harvard Medical Center researchers, led by Xi He, Ph.D., attempted to repeat the results. However, the Harvard team, using a slightly different experimental approach, was not able to do it. This apparent conflict prompted Dr. Lee, from the original study, to contact Dr. Thorne at the UA Cancer Center in late 2018 to further explore the results. Dr. Thorne's lab presented an opportunity for a new technique not used in the first two studies: single-cell profiling. This was done using colon tissue derived from the patient, including healthy and cancerous cells, grown in the laboratory.

Holder of a Bachelor's degree in Molecular and Cell Biology from the AU and recipient of the John and Betty Anderson Memorial Fellowship, Cabel has been responsible for the majority of the project's work. The scholarship supports first-year graduate students who have chosen to pursue careers in cancer research. For his experiments, Cabel's relied on a high-throughput microscope called Operetta CLS, a state-of-the-art technology available via the functional genomic nucleus of DU, to take thousands of images of cancerous cells. colon. She then badyzed millions of cells captured in the images with the help of custom software developed by Elaheh Alizadeh, Ph.D., a postdoctoral research badociate at Thorne's lab at the AU.

"I think what we brought to the table is this colon cell resource with specific and definite mutations," said Cabel. "I measured Wnt channel activity in each cell individually and compared it before and after LRP6 inhibition."

When the project was completed in the spring of 2019, Thorne and Cabel were able to repeat the results of the first research teams in Vanderbilt and Dartmouth. Cabel was the first author of a letter of June 2019 published in Developmental cell detailing the results. This publication was published in conjunction with a letter from the Harvard Group detailing its difficulties in repeating the findings of the original study.

As the principal investigator of the study, Dr. Thorne said, "These types of conflicts are more common than we would all like to believe in biomedical research." I congratulate the developers of Development Cell for providing a open discussion forum on conflicting results research groups.We need more of this open dialogue in the scientific publication, not less. "

Dr. Thorne believes that this research has validated an important target to consider in therapeutic treatments for colon cancer.

"I'm thinking of colon cancer and other types of cancer," said Dr. Thorne. "We should not ignore LRP6 and it should be at the top of the list of drug targets in the Wnt pathway."

For Cabel, his first published work is a rewarding step in pursuing a PhD. and a career in cancer research.

"I think the most important concept to remember is the concept of collaboration," said Cabel. "The best groups are going to have a lot of researchers working on a common goal, especially in the case of cancer.We want to get the best science and the best research possible to get the best care because that is what is the most important."