PMID- 37131673
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230503
DP  - 2023 Apr 18
TI  - Ca (2+) /Calmodulin Dependent Protein Kinase Kinase-2 (CaMKK2) promotes Protein 
      Kinase G (PKG)-dependent actin cytoskeletal assembly to increase tumor 
      metastasis.
LID - 2023.04.17.536051 [pii]
LID - 10.1101/2023.04.17.536051 [doi]
AB  - Triple-negative breast cancers (TNBCs) tend to become highly invasive early 
      during cancer development. Despite some successes in the initial treatment of 
      patients diagnosed with early-stage localized TNBC, the rate of metastatic 
      recurrence remains high with poor long-term survival outcomes. Here we show that 
      elevated expression of the serine/threonine-kinase, Calcium/Calmodulin 
      (CaM)-dependent protein kinase kinase-2 (CaMKK2), is highly correlated with tumor 
      invasiveness. We determined that genetic disruption of CaMKK2 expression, or 
      inhibition of its activity, 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 
      genetic features with TNBC, and importantly, CaMKK2 inhibition effectively 
      blocked metastatic progression in a validated xenograft model of this disease. 
      Probing the mechanistic links between CaMKK2 and metastasis we defined the 
      elements of a new signaling pathway that impacts actin cytoskeletal dynamics in a 
      manner which increases cell migration/invasion and metastasis. Notably, CaMKK2 
      increases the expression of the phosphodiesterase PDE1A which decreases the 
      cGMP-dependent activity of protein kinase G1 (PKG1). This inhibition of PKG1 
      results in decreased phosphorylation of Vasodilator-Stimulated Phosphoprotein 
      (VASP), which in its hypophosphorylated state binds to and regulates F-actin 
      assembly to facilitate contraction/cell movement. Together, these data establish 
      a targetable CaMKK2-PDE1A-PKG1-VASP signaling pathway that controls cancer cell 
      motility and metastasis. Further, it credentials CaMKK2 as a therapeutic target 
      that can be exploited in the discovery of agents for use in the 
      neoadjuvant/adjuvant setting to restrict tumor invasiveness in patients diagnosed 
      with early-stage TNBC or localized HGSOC.
FAU - Mukherjee, Debarati
AU  - Mukherjee D
FAU - Previs, Rebecca A
AU  - Previs RA
FAU - Haines, Corinne N
AU  - Haines CN
FAU - Abo, Muthana Al
AU  - Abo MA
FAU - Juras, Patrick K
AU  - Juras PK
FAU - Strickland, Kyle C
AU  - Strickland KC
FAU - Chakraborty, Binita
AU  - Chakraborty B
FAU - Artham, Sandeep
AU  - Artham S
FAU - Whitaker, Regina
AU  - Whitaker R
FAU - Hebert, Katherine L
AU  - Hebert KL
FAU - Fontenot, Jake
AU  - Fontenot J
FAU - Patierno, Steven R
AU  - Patierno SR
FAU - Freedman, Jennifer A
AU  - Freedman JA
FAU - Lau, Frank H
AU  - Lau FH
FAU - Burow, Matthew
AU  - Burow M
FAU - Chang, Ching-Yi
AU  - Chang CY
FAU - McDonnell, Donald P
AU  - McDonnell DP
LA  - eng
PT  - Preprint
DEP - 20230418
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
PMC - PMC10153149
EDAT- 2023/05/03 06:42
MHDA- 2023/05/03 06:43
PMCR- 2023/05/02
CRDT- 2023/05/03 01:58
PHST- 2023/05/03 06:43 [medline]
PHST- 2023/05/03 06:42 [pubmed]
PHST- 2023/05/03 01:58 [entrez]
PHST- 2023/05/02 00:00 [pmc-release]
AID - 2023.04.17.536051 [pii]
AID - 10.1101/2023.04.17.536051 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2023 Apr 18:2023.04.17.536051. doi: 
      10.1101/2023.04.17.536051.