Michigan Cancer Research Fund                                                                                            American Cancer Society
   
test tube  
   

Research Project Description and Objectives from Kaitlin Basham, PhD, MCRF 2017 Fellow

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.