University of Minnesota Medical School and Masonic Cancer Center researchers have partnered with geneticists from Genentech, Inc., to discover how some proteins may cause the development of some forms of colon cancers.
The proteins – part of R-spondin family – normally help activate cell proliferation during embryonic development. Now, University of Minnesota researchers have discovered that when two types of R-spondins – RSPO2 and RSPO 3 – are reactivated in adults through certain gene mutations, they can signal cells to restart the cell proliferation process, which can lead to tumor growth in the colon.
The discovery, which involved multiple researchers from the University’s Masonic Cancer Center, could lead the way to more personalized colon cancer therapy designed around the genetics of a patient’s specific cancer. The results are available online now, in the journal Nature.
“These results suggest there is a potential for personalized therapies based on knowing a tumor’s specific genetics,” said David Largaespada, Ph.D., associate director of Basic Sciences and professor in the Department of Genetics, Cell Biology and Development. “And because these R-spondins are related to embryonic growth, and seem to not have major roles in the adult, targeting them would likely be low in side effects.”
To arrive at the results, researchers analyzed more than 70 pairs of human colon tumors and a mouse model engineered using the Sleeping Beauty transposon by Largaespada. Through a series of investigations, researchers identified 36 rearrangements that result in gene fusions, including two recurrent ones involving R-spondin family members RSPO2 and RSPO3.
While the results could generate more personalized approaches to the treatment of colon cancer, researchers stress more research is needed before these results can be applied to actual patient care.
“What we’re finding is that tumors may look the same, but they’re fundamentally different,” said Conboy. “Diagnosis may be less about the tissue where the tumor is found, like the breast or colon, but the drivers of the tumor’s growth.”
Conboy is beginning work on a study that will help determine if a blocking agent could be useful in treating tumors driven by R-spondin production. If this project is successful, it could help create new therapeutic approaches useful in certain patients after a tumor genetic test is done.
Also making major contributions was Timothy Starr, Ph.D., assistant professor in the Division of Gynecologic Oncology and principal investigator in the Starr Lab at the University of Minnesota. Work in Largaespada lab was supported by National Institutes of Health grants R01-CA134759 and R01-CA113636.
Background on the Sleeping Beauty Method:
In 1997, University of Minnesota researchers created the Sleeping Beauty Transposon System. This system combines a transposase, which is a DNA binding and cutting enzyme, and a transposon, or a transposable DNA sequence able to change position within the genome. The system allows researchers to cut and move DNA molecules to another spot in the same or different DNA molecule or genome, making it possible to introduce new traits or discover new genes and their functions.
For nearly a decade, this method has been applied to research into the genomics of cancer. The University of Minnesota has been applying the system to research on a number cancer types, most notably colorectal cancer, brain tumors, sarcoma, and hepatocellular cancer, the most common type of liver cancer.
University of Minnesota Academic Health Center