Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis.
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2023-09
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Abstract
Triple-negative breast cancers (TNBC) tend to become invasive and metastatic at early stages in their development. Despite some treatment successes in early-stage localized TNBC, the rate of distant recurrence remains high, and long-term survival outcomes remain poor. In a search for new therapeutic targets for this disease, we observed that elevated expression of the serine/threonine kinase calcium/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) is highly correlated with tumor invasiveness. In validation studies, genetic disruption of CaMKK2 expression or inhibition of its activity with small molecule inhibitors disrupted spontaneous metastatic outgrowth from primary tumors in murine xenograft models of TNBC. High-grade serous ovarian cancer (HGSOC), a high-risk, poor prognosis ovarian cancer subtype, shares many features with TNBC, and CaMKK2 inhibition effectively blocked metastatic progression in a validated xenograft model of this disease. Mechanistically, CaMKK2 increased the expression of the phosphodiesterase PDE1A, which hydrolyzed cyclic guanosine monophosphate (cGMP) to decrease the cGMP-dependent activity of protein kinase G1 (PKG1). Inhibition of PKG1 resulted in decreased phosphorylation of vasodilator-stimulated phosphoprotein (VASP), which in its hypophosphorylated state binds to and regulates F-actin assembly to facilitate cell movement. Together, these findings establish a targetable CaMKK2-PDE1A-PKG1-VASP signaling pathway that controls cancer cell motility and metastasis by impacting the actin cytoskeleton. Furthermore, it identifies CaMKK2 as a potential therapeutic target that can be exploited to restrict tumor invasiveness in patients diagnosed with early-stage TNBC or localized HGSOC.
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CaMKK2 regulates actin cytoskeletal dynamics to promote tumor invasiveness and can be inhibited to suppress metastasis of breast and ovarian cancer, indicating CaMKK2 inhibition as a therapeutic strategy to arrest disease progression.Type
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Mukherjee, Debarati, Rebecca A Previs, Corinne Haines, Muthana Al Abo, Patrick K Juras, Kyle C Strickland, Binita Chakraborty, Sandeep Artham, et al. (2023). Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis. Cancer research, 83(17). pp. 2889–2907. 10.1158/0008-5472.can-22-1622 Retrieved from https://hdl.handle.net/10161/33095.
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Scholars@Duke
Rebecca A Previs
Kyle C. Strickland
Dr. Strickland specializes in cytopathology and women's and perinatal surgical pathology. His areas of interest include epithelial and mesenchymal gynecologic neoplasia and fine needle aspiration cytology.
Binita Chakraborty
Steven Patierno
Patierno's current translational research interests are focused on the genomics molecular biology of cancer disparities, cancer biology, molecular pharmacology and targeted experimental therapeutics to control prostate, breast and lung tumor aggressiveness. He is an internationally recognized expert in cancer control, cancer causation and molecular carcinogenesis, which includes a broad spectrum of laboratory and population level research. Patierno is also actively engaged in cancer health disparities and healthcare delivery research focused on patient navigation, survivorship, community-based interventions, mHealth, implementation sciences, cancer care economics, and policy.
Jennifer Freedman
Ching-yi Chang
The main focus of my research has been to define the roles of nuclear hormone receptors (NHRs) in the pathogenesis of disease, with a focus on hormone-related cancers.
During earlier stages of my research career, definition of the structural and molecular determinants of NHR receptor biology and pharmacology was the main focus. Information obtained from these studies was used to guide the development of receptor modulators for therapeutic interventions and to gain insights into the pharmacology of estrogen and androgen receptor ligands. More recently, my research has shifted to define receptor-mediated signaling pathways relevant to the pathogenesis of breast and prostate cancers. One example of this is the definition of signaling pathways downstream of the orphan nuclear receptor, estrogen-related receptor alpha (ERRα) in breast cancer. Using gene expression signature defined in breast cancer cells we demonstrated that the activity of ERRα tracks with poor prognosis in all breast cancer subtypes. We confirmed a causal role for ERRα in breast cancer growth in both cellular and xenograft models of breast cancer. More recently, we further defined the role(s) of this receptor in tumor metabolism and validated its utility as a therapeutic target in triple negative breast cancer (TNBC). In addition to the cancer cell intrinsic effects of ERRα, this receptor is also expressed in T cells and in macrophages. We are currently evaluating the impact of modulating ERRα activity in these immune cells and how that influences tumor biology.
Donald Patrick McDonnell
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The research in our group is focused on the development and application of mechanism based approaches to identify novel therapeutics for use in the treatment and prevention of hormonally responsive cancers. Specifically we are interested in the pharmaceutical exploitation of the estrogen and androgen receptors as therapeutic targets in breast and prostate cancers and in defining how these receptors influence the pathogenesis of these diseases. These efforts have led to the discovery of several drugs that are currently being evaluated in the clinic as cancer therapeutics, and to the identification of potential biomarkers and predictors of response that can help to target the use of these new drugs. Most recently we have explored approaches to treat triple negative breast cancer and have identified an important pathway that links obesity/dyslipidemia and cancer risk.
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