Dissertation
Paradoxical metastasis suppressor functions of the Abl family kinases in a model of androgen receptor-indifferent advanced prostate cancer
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2019
DOI: 10.17077/etd.005216
Abstract
Prostate cancer remains the second most lethal cancer in U.S. men, due to the emergence of advanced, metastatic castration-resistant prostate cancer (mCRPC). Although, castration-resistance may be driven by alterations to androgen receptor (AR) signaling, it may also occur through the development of phenotypically plastic states. In this manner, advanced mCRPC escapes hormone ablative therapies through the recruitment of alternative signaling pathways that can promote the growth and survival of AR-indifferent tumors in the absence of androgen signaling.
Previous research has implicated a paradoxical tumor suppressor function for the notoriously oncogenic Abl family kinases in a cell-based model of advanced, AR-indifferent, mCRPC that demonstrates phenotypic plasticity. Utilizing orthotopic implantation, we determined mCRPC cells depleted of the Abl family kinases exhibit enhanced in vivo tumor progression, as well as, localized, regional, and distant metastatic outgrowth. We also identified differences in the morphological and migratory properties of Abl family kinase-depleted mCRPC cells, which may account for the increased in vivo metastasis phenotypes we observed.
By applying, genetic, pharmacological, biochemical, and functional proteomic methods to mCRPC cells growing on 3D collagen I extracellular matrix, a condition that successfully recapitulates our in vivo phenotypes, we delineated a Caveolin-1-AXL-AKT signaling axis acting downstream of the Abl family kinases. Components of this signaling axis, in turn, go on to affect several downstream factors, including those involved in protein synthesis, survival, cell-cycling, and lipogenesis. Pharmacological intervention at multiple points within this signaling cascade successfully constrained the growth and activation of AKT signaling in Abl family kinase-depleted mCRPC cells growing in 3D.
Taken together, these data establish the Abl family kinases as tumor and metastasis suppressors in a model of AR-indifferent prostate cancer and identifies potential therapeutic targets for the treatment of advanced mCRPC.
Details
- Title: Subtitle
- Paradoxical metastasis suppressor functions of the Abl family kinases in a model of androgen receptor-indifferent advanced prostate cancer
- Creators
- Melissa Ann Marchal
- Contributors
- Christopher S. Stipp (Advisor)Aloysius J Klingelhutz (Committee Member)Tina Tootle (Committee Member)Kris A. DeMali (Committee Member)Chi-Lien Cheng (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Genetics
- Date degree season
- Autumn 2019
- DOI
- 10.17077/etd.005216
- Publisher
- University of Iowa
- Number of pages
- xii, 116 pages
- Copyright
- Copyright 2019 Melissa Ann Marchal
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 96-116).
- Public Abstract (ETD)
Despite continuous advances in early diagnosis and treatment, prostate cancer is the second most lethal cancer in U.S. men. Most prostate cancer-related deaths are due to advanced metastatic disease that is resistant to current therapeutic options. My research focuses on the Abl family kinases, signaling proteins that function inside cells to regulate cell proliferation, survival, and migration. The Abl family kinases were previously thought to have pro-tumor effects, but my research has revealed that they paradoxically act to suppress prostate tumor cell growth and metastasis in a model of advanced, metastatic, treatment-resistant prostate cancer. Utilizing this cell-based-model, in combination with genetic and pharmacological methods, I have identified signaling pathways that are dysregulated in the absence of the Abl family kinases. Importantly, drugs targeting these same signaling pathways are currently under investigation in clinical trials. Developing therapies that target signaling molecules that are dysregulated in Abl family kinase-depleted cells may provide novel treatment options for advanced, treatment-resistant prostate cancer.
- Academic Unit
- Interdisciplinary Graduate Program in Genetics
- Record Identifier
- 9983780000002771
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