Project Name: Mechanistic and Therapeutic Studies of ZNRF3 Loss in Cancer

 

Cancer is fundamentally a problem of uncontrolled cell growth where there are either too many new cells being born or not enough old cells dying. Normally, networks of proteins known as ‘signaling pathways’ coordinate the proper balance between cell growth and cell death to prevent cancer from forming. However, many cancers disrupt this equilibrium by mutating genes that encode critical proteins required for these pathways to function.

 

To better understand the origins of cancer and design more effective therapeutic strategies, recent studies have focused on identifying all genes that are altered in each type of human cancer. The Cancer Genome Atlas Project led many of these multi-institutional efforts and implicated several new genes in cancer, including ZNRF3 and RNF43. These two highly related genes are inactivated, either by mutation or deletion, in a wide range of human cancers, including prostate, colon, ovarian, pancreatic and adrenal cancer. Previous studies have linked ZNRF3/RNF43 to a cellular pathway called Wnt signaling that is known to help control normal cell growth. However, the Wnt pathway splits into several different branches that each requires a specific type of cancer drug. Since ZNRF3/RNF43 are thought to function near the top of the pathway, it is unclear which branch of Wnt signaling is affected by ZNRF3/RNF43 loss.

 

To investigate the consequences of ZNRF3/RNF43 loss, I developed a genetically engineered mouse model that lacks ZNRF3 in the adrenal gland, one tissue where this gene is frequently altered in human tumors. Using the model, I aim to:

 

1) Determine how the loss of ZNRF3/RNF43 disrupts Wnt signaling
2) Test the efficacy of newly developed drugs predicted to target tumors lacking these genes

 

Ultimately, the long-term goal of my studies is to provide the framework necessary to develop new strategies for the treatment of a range of human cancers.

 

Summer 2019 Update from Dr. Katie Basham: In February 2019, Dr. Basham published a paper describing the mouse model of ZNFR3 loss that she generated. The ZNFR3 gene is frequently deleted in human adrenal tumors, and her work examines the effect this has on normal tissue homeostasis. Dr. Basham also presented on this topic at a conference in Munich, Germany in June 2018 where she received the New Investigator Award. Additionally, Dr. Basham was invited to present her work at a symposium during the Endocrine Society meeting in New Orleans in March 2019. She is currently using the mouse model to examine potential therapeutic strategies for the treatment of ZNFR3-altered tumors.

Dr. Basham has enjoyed becoming more involved with the American Cancer Society. Over the past year , she participated in her first Relay For Life event where she was a speaker during the opening ceremonies, and she joined the Michigan ResearcHERS campaign as an ambassador to help raise support for other women cancer researchers.