Related Experiment Video
Updated: Jul 26, 2025
12:14
CAM-Delam Assay to Score Metastatic Properties by Quantifying Delamination and Invasion Capacity of Cancer Cells
Published on: June 2, 2022
2.7K
Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis
Debarati Mukherjee1, Rebecca A Previs2, Corinne Haines1
1Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
Cancer Research
|June 19, 2023
Summary
Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) drives invasion in triple-negative breast cancer and ovarian cancer. Inhibiting CaMKK2 blocks metastasis by targeting the PDE1A-PKG1-VASP pathway, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC) are aggressive subtypes with poor prognoses.
- Early-stage metastasis and distant recurrence are significant challenges in TNBC and HGSOC treatment.
- Identifying novel therapeutic targets is crucial for improving patient survival outcomes.
Purpose of the Study:
- To investigate the role of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) in TNBC and HGSOC metastasis.
- To elucidate the molecular mechanisms by which CaMKK2 promotes tumor invasiveness.
- To evaluate CaMKK2 inhibition as a potential therapeutic strategy against metastatic breast and ovarian cancers.
Main Methods:
- Analysis of CaMKK2 expression correlation with tumor invasiveness.
- Utilizing murine xenograft models of TNBC and HGSOC to assess the impact of CaMKK2 inhibition on metastasis.
- Investigating the downstream signaling pathway involving phosphodiesterase 1A (PDE1A), protein kinase G1 (PKG1), and vasodilator-stimulated phosphoprotein (VASP).
Main Results:
- Elevated CaMKK2 expression strongly correlates with tumor invasiveness in TNBC.
- Genetic or pharmacological inhibition of CaMKK2 significantly reduced spontaneous metastatic outgrowth in TNBC and HGSOC xenograft models.
- CaMKK2 upregulates PDE1A, which decreases cyclic guanosine monophosphate (cGMP) levels, inhibiting protein kinase G1 (PKG1) activity and promoting actin cytoskeleton dynamics essential for cell motility.
Conclusions:
- CaMKK2 is a key regulator of cancer cell motility and metastasis by modulating the actin cytoskeleton through the PDE1A-PKG1-VASP pathway.
- CaMKK2 inhibition represents a promising therapeutic strategy to impede tumor invasiveness and metastasis in early-stage TNBC and localized HGSOC.
- Targeting CaMKK2 offers a novel approach to improve treatment outcomes for patients with these aggressive cancer types.
Related Concept Videos
02:34Inhibition of Cdk Activity
4.8K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.8K
01:35Cancer Cell Migration through Invadopodia
2.3K
Invadosome is a broad category of cell surface structures with proteolytic activity that degrades the extracellular matrix (ECM). Invadosomes are present in normal cell types, including macrophages, endothelial cells, and neurons, as well as tumor cells. Although the macrophage podosomes and tumor cell invadopodia are classified as invadosomes, they have different structures, molecular pathways, and functions. Podosomes are short structures that last for a few minutes. However,...
2.3K
02:57Targeted Cancer Therapies
7.7K
The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
There are several types of targeted therapies against...
7.7K
03:03mTOR Signaling and Cancer Progression
3.8K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.8K
01:15Drugs that Stabilize Microtubules
2.1K
Microtubules are dynamic structures that undergo cycles of catastrophe and rescue. The microtubules play a central role in cell division by forming the spindle apparatus for segregating the chromosomes. This makes them ideal targets for regulating dividing cells in tumors and malignant cancer cells. Microtubule stabilizing drugs help stabilize the microtubule formation and promote its polymerization. Paclitaxel was the first microtubule stabilizing agent used as anticancer drug in chemotherapy...
2.1K
01:10Drugs that Destabilize Microtubules
2.0K
Microtubules are dynamic structures and can be regulated by microtubule targeting agents (MTAs). Microtubule destabilizing drugs are a class of MTAs that destabilize and prevent microtubules' polymerization. Both natural and synthetic chemicals can be found under this class of drugs. Vincristine and vinblastine, two vinca alkaloids, and colchicine were among the first to be discovered. These drugs can affect cells in various ways, either by inducing a change in cell morphology, preventing...
2.0K