Metastasis accounts for the overwhelming majority of cancer deaths. In prostate cancer and many other solid tumors, progression to metastasis is associated with drastically reduced survival outcomes, yet the mechanisms behind this progression remain largely unknown. ATAD2 (ATPase family AAA domain containing 2) is an epigenetic reader of acetylated histones that is overexpressed in multiple cancer types and usually associated with poor patient outcomes. However, the functional role of ATAD2 in cancer progression and metastasis has been relatively understudied. Here we employ genetically engineered mouse models of prostate cancer bone metastasis, as well as multiple independent human cohorts, to show that ATAD2 is highly enriched in bone metastasis compared to primary tumors and significantly associated with the development of metastasis. We show that ATAD2 expression is associated with MYC pathway activation in patient datasets and that, at least in a subset of tumors, MYC and ATAD2 can regulate each other's expression. Using functional studies on mouse bone metastatic cell lines and innovative organ-on-a-chip bone invasion assays, we establish a functional role for ATAD2 inhibition in diminishing prostate cancer metastasis and growth in bone. Implications: Our study highlights ATAD2 as a driver of prostate cancer progression and metastasis and suggests it may constitute a promising novel therapeutic target.
Molecular cancer research : MCR. 2025 Feb 05 [Epub ahead of print]
Anindita Dutta, Antonio Rodriguez-Calero, Kacey Ronaldson-Bouchard, Anne Offermann, Daoud Rahman, Twinkle Bapuji Vhatkar, Dan Hasson, Mohammed Alshalalfa, Elai Davicioni, R Jeffrey Karnes, Mark A Rubin, Gordana Vunjak-Novakovic, Cory Abate-Shen, Juan Martin Arriaga
Icahn School of Medicine at Mount Sinai, New York, New York, United States., University of Bern, Bern, Switzerland., Columbia University, United States., University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany., Icahn School of Medicine at Mount Sinai, New York, United States., University of California, San Francisco, Vancouver, Canada., Veracyte (United States), San Diego, California, United States., Mayo Clinic, Rochester, MN, United States., University of Bern, Bern, Bern, Switzerland., Columbia College - South Carolina., Columbia University Irving Medical Center, New York, NY, United States.