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Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis.

Publication ,  Journal Article
Mukherjee, D; Previs, RA; Haines, C; Al Abo, M; Juras, PK; Strickland, KC; Chakraborty, B; Artham, S; Whitaker, RS; Hebert, K; Fontenot, J ...
Published in: Cancer Res
September 1, 2023

UNLABELLED: 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. SIGNIFICANCE: 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.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

September 1, 2023

Volume

83

Issue

17

Start / End Page

2889 / 2907

Location

United States

Related Subject Headings

  • Triple Negative Breast Neoplasms
  • Protein Kinases
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Mice
  • Humans
  • Female
  • Cell Movement
  • Animals
  • Actins
 

Citation

APA
Chicago
ICMJE
MLA
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Mukherjee, D., Previs, R. A., Haines, C., Al Abo, M., Juras, P. K., Strickland, K. C., … McDonnell, D. P. (2023). Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis. Cancer Res, 83(17), 2889–2907. https://doi.org/10.1158/0008-5472.CAN-22-1622
Mukherjee, Debarati, Rebecca A. Previs, Corinne Haines, Muthana Al Abo, Patrick K. Juras, Kyle C. Strickland, Binita Chakraborty, et al. “Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis.Cancer Res 83, no. 17 (September 1, 2023): 2889–2907. https://doi.org/10.1158/0008-5472.CAN-22-1622.
Mukherjee D, Previs RA, Haines C, Al Abo M, Juras PK, Strickland KC, et al. Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis. Cancer Res. 2023 Sep 1;83(17):2889–907.
Mukherjee, Debarati, et al. “Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis.Cancer Res, vol. 83, no. 17, Sept. 2023, pp. 2889–907. Pubmed, doi:10.1158/0008-5472.CAN-22-1622.
Mukherjee D, Previs RA, Haines C, Al Abo M, Juras PK, Strickland KC, Chakraborty B, Artham S, Whitaker RS, Hebert K, Fontenot J, Patierno SR, Freedman JA, Lau FH, Burow ME, Chang C-Y, McDonnell DP. Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis. Cancer Res. 2023 Sep 1;83(17):2889–2907.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

September 1, 2023

Volume

83

Issue

17

Start / End Page

2889 / 2907

Location

United States

Related Subject Headings

  • Triple Negative Breast Neoplasms
  • Protein Kinases
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Mice
  • Humans
  • Female
  • Cell Movement
  • Animals
  • Actins