The long range objective of our laboratory is to understand the cellular and molecular mechanisms by which signaling pathways and downstream transcription factors coordinate the specification of adrenocortical cells within the adrenal gland in health and disease. Our strategy for this proposal is to focus on the mechanism and consequences of Wnt-mediated activation of gene expression in adrenal cancer. Based on our preliminary data, we hypothesize that dysregulated Wnt/?-catenin signaling in adrenocortical subcapsular cells induces aberrant target gene activation by the nuclear receptor, steroidogenic factor 1 (SF1), and ultimate oncogenic transformation of cells within this population.
Our specific aims are therefore directed towards a systematic characterization of the mechanisms by which Wnt/?-catenin target genes control the normal and dysregulated growth and differentiation of the adrenal cortex. To that end we propose to determine whole genome targets of Wnt-mediated SF1 transcription in adrenocortical carcinoma (ACC) in both human patients and mice and to define the role of a subset of these target genes in adrenal cortical growth maintenance and cancer in vitro and in vivo. We believe that the studies proposed here will provide the framework for understanding the role of Wnt/?-catenin signaling in adrenocortical growth maintenance and cancer and lay the groundwork for future targeted therapy.

Public Health Relevance

Adrenal cancer is an incredibly rare and routinely fatal disease with few effective treatments. Understanding the cellular and genetic basis for the disease is predicted to provide novel cellular and molecular targets for therapeutic intervention. This proposal aims to elucidate the mechanism and consequences of Wnt-mediated activation of gene expression in adrenal cancer. Using cellular systems and mouse models together with genomic approaches in mouse and human adrenocortical carcinoma samples, we aim to characterize the mechanisms by which Wnt/?-catenin signaling participates in normal adrenal growth maintenance and cancer. Specifically, in these studies we will determine whole genome targets of Wnt-mediated Sf1 transcription in adrenocortical carcinoma (ACC) in human patients and mice and to define the role of a subset of these target genes in both normal growth and cancer of the adrenal cortex. Future efforts are predicted to focus on therapies that target this pathway and downstream genes that are found in the course of these studies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134606-05
Application #
8585037
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Woodhouse, Elizabeth
Project Start
2009-12-01
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2014
Total Cost
$262,874
Indirect Cost
$81,726
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Else, Tobias; Kim, Alex C; Sabolch, Aaron et al. (2014) Adrenocortical carcinoma. Endocr Rev 35:282-326
Walczak, Elisabeth M; Kuick, Rork; Finco, Isabella et al. (2014) Wnt signaling inhibits adrenal steroidogenesis by cell-autonomous and non-cell-autonomous mechanisms. Mol Endocrinol 28:1471-86
Lerario, Antonio M; Moraitis, Andreas; Hammer, Gary D (2014) Genetics and epigenetics of adrenocortical tumors. Mol Cell Endocrinol 386:67-84
Franca, Monica Malheiros; Ferraz-de-Souza, Bruno; Santos, Mariza Gerdulo et al. (2013) POD-1 binding to the E-box sequence inhibits SF-1 and StAR expression in human adrenocortical tumor cells. Mol Cell Endocrinol 371:140-7
Wood, Michelle A; Acharya, Asha; Finco, Isabella et al. (2013) Fetal adrenal capsular cells serve as progenitor cells for steroidogenic and stromal adrenocortical cell lineages in M. musculus. Development 140:4522-32
Simon, Derek P; Giordano, Thomas J; Hammer, Gary D (2012) Upregulated JAG1 enhances cell proliferation in adrenocortical carcinoma. Clin Cancer Res 18:2452-64
Simon, Derek P; Hammer, Gary D (2012) Adrenocortical stem and progenitor cells: implications for adrenocortical carcinoma. Mol Cell Endocrinol 351:2-11
Kelly, Victoria R; Hammer, Gary D (2011) LRH-1 and Nanog regulate Dax1 transcription in mouse embryonic stem cells. Mol Cell Endocrinol 332:116-24
Wood, Michelle A; Hammer, Gary D (2011) Adrenocortical stem and progenitor cells: unifying model of two proposed origins. Mol Cell Endocrinol 336:206-12
Xu, Bin; Yang, Wei-Hsiung; Gerin, Isabelle et al. (2009) Dax-1 and steroid receptor RNA activator (SRA) function as transcriptional coactivators for steroidogenic factor 1 in steroidogenesis. Mol Cell Biol 29:1719-34

Showing the most recent 10 out of 12 publications