CaMKK2 in myeloid cells is a key regulator of the immune suppressive microenvironment in breast cancer
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ABSTRACT:
PROVIDER: PRJNA416369 | ENA |
REPOSITORIES: ENA
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Project description:Tumor-associated myeloid cells play a pivotal role in the regulation of processes that control tumor growth and metastasis, and their accumulation in tumors is an established negative prognostic factor in breast cancer. Here, we show that inhibition of calcium/calmodulin-dependentkinase kinase 2 (CaMKK2) expression within myeloid cells inhibits tumor growth in mouse models of mammary cancer. This activity is associated with the accumulation of macrophages within the tumor microenvironment that express high levels of the major histocompatibility molecule class II molecule I-A (MHC II I-A), and granzyme positive CD8+T-cells. Treatment with specific CaMKK2 inhibitors block tumor growth, in a CD8+ T-cell dependent manner, and facilitates favorable reprogramming of the immune cell microenvironment. CaMKK2 protein expression was highest in the most aggressive subtypes of human breast cancer and, in the most malignant tumors, both tumor cells and tumor-associated macrophages express high levels of this enzyme. In aggregate, these findings implicate CaMKK2 as a macrophage-selective immune checkpoint, the inhibition of which may have utility in the immunotherapy of breast cancer.
2019-06-16 | GSE106357 | GEO
Project description:Macrophages play crucial roles in immunity and tissue homeostasis, exhibiting diverse phenotypes influenced by their microenvironment. While matrix stiffness is recognized as a key regulator of macrophage fate, the underlying mechanism remains elusive. Here, we investigate primary bone marrow-derived macrophages (BMDMs) in a physiologically relevant 3D environment using a dynamic stiffening collagen-based hydrogel system. We show that increasing matrix stiffness promotes BMDM polarization towards a pro-regenerative phenotype, characterized by elevated CD206 levels, and M2-like gene signature. Mechanistically, we identify the calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) as an important component of molecular machinery controlling BMDM response to stiff microenvironment. Surprisingly, the blocking of CaMKK2 does not interfere with the IL-4-induced pro-regenerative programs. On the contrary, the inhibition of this kinase abolishes phenotypic and transcriptional changes induced by stiffness, highlighting the specific function of the CaMKK2-STAT6 axis in macrophage mechanosensory signaling. Functionally, matrix stiffening promotes M2-like/pro-tumoral polarization of BMDM in a CaMKK2-dependent manner, confirming the critical role of this kinase in the tumor microenvironment and identifying a direct pro-tumoral effect mediated by Camkk2-signaling in macrophages. In a murine wound healing model, stiffened matrices drive immune cell recruitment and macrophage polarization towards a pro-regenerative phenotype, facilitating vascularization, while deletion of Camkk2 impairs this phenomenon. Our findings elucidate the mechanistic basis of matrix stiffness-mediated macrophage fate determination, identifying CaMKK2 as a druggable target to selectively modulate the mechanoresponsiveness of macrophages in malignant and injured tissues.
2025-04-30 | GSE273834 | GEO
Project description:Tumor-associated myeloid cells regulate tumor growth and metastasis, and their accumulation is a negative prognostic factor for breast cancer. Here we find calcium/calmodulin-dependent kinase kinase (CaMKK2) to be highly expressed within intratumoral myeloid cells in mouse models of breast cancer, and demonstrate that its inhibition within myeloid cells suppresses tumor growth by increasing intratumoral accumulation of effector CD8+ T cells and immune-stimulatory myeloid subsets. Tumor-associated macrophages (TAMs) isolated from Camkk2-/- mice expressed higher levels of chemokines involved in the recruitment of effector T cells compared to WT. Similarly, in vitro generated Camkk2-/- macrophages recruit more T cells, and have a reduced capability to suppress T cell proliferation, compared to WT. Treatment with CaMKK2 inhibitors blocks tumor growth in a CD8+ T cell-dependent manner, and facilitates a favorable reprogramming of the immune cell microenvironment. These data, credential CaMKK2 as a myeloid-selective checkpoint, the inhibition of which may have utility in the immunotherapy of breast cancer.
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Project description:CaMKK2 promotes a more pro-tumor and checkpoint blockade-resistance associated immune tumor microenvironment in glioblastoma.
2022-08-30 | GSE197879 | GEO
Project description:Jun is a key Regulator of Prostate Cancer Progression and Immune Microenvironment Dynamics
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Project description:The calcium-calmodulin (Ca2+-CaM) dependent protein kinase kinase-2 (CaMKK2) is activated by increases in intracellular Ca2+ and is a key regulator of cellular and wholebody energy metabolism. CaMKK2 inhibition protects against prostate cancer, hepatocellular carcinoma and metabolic derangements induced by a high-fat diet, therefore elucidating the intracellular mechanisms that inactivate CaMKK2 has important therapeutic implications. Here we show that stimulation of cyclic AMP (cAMP)-dependent protein kinase (PKA) signaling in cells inactivates CaMKK2 by phosphorylation of three conserved serine residues. PKA-dependent phosphorylation of Ser495 directly impairs Ca2+-CaM activation, whereas phosphorylation of Ser100 and Ser511 mediate recruitment of 14-3-3 adaptor proteins that hold CaMKK2 in the inactivated state by preventing dephosphorylation of phospho-Ser495. We also report the crystal structure of 14-3-3z bound to a synthetic diphosphorylated peptide that reveals how the canonical (Ser511) and non-canonical (Ser100) 14-3-3 consensus sites on CaMKK2 co-operate to bind 14-3-3 proteins. Our findings provide a detailed mechanistic insight into how cAMP-PKA signaling inactivates CaMKK2 and reveals a pathway to inhibit CaMKK2 with potential for treating human diseases.
2020-11-06 | PXD020133 | Pride
Project description:To determine the function of Camkk2 in HSC we performed a microarray analysis on isolated KSL from WT and Camkk2 null mice. Using a threshold of 0.05 for statistical significance (p-value) and a log fold change of expression with absolute value of at least 0.6, 1831 differentially expressed genes (DEGs) were identified out of a total of 29352 genes with measured expression. When compared to WT KSL, 1289 genes were significantly downregulated and 533 genes were upregulated in Camkk2 null HSC. The genes downregulated in Camkk2 null KSL were strongly enriched in HSC, early progenitors and lymphoid-myeloid-affiliated genes (s-myly) primed in HSC. Of note, HSC-affiliated genes found downregulated in Camkk2 KSL included Hlf, Meis1, Pbx-1 and Prdm5 which are 4 of the 8 genes capable to reprogram committed murine blood cells into HSC. The GSEA analysis also showed that genes affiliated with the late progenitor signature and erythroid genes primed in HSC and GMP specific genes (d-my) were significantly upregulated in Camkk2 null KSL. These findings indicate Camkk2 controls crucial transcriptional programs involved in the mechanism of HSC differentiation and lineage commitment.
2018-02-13 | GSE95733 | GEO
Project description:Cysteine dioxygenase type 1 (Cdo1) is a key enzyme for cysteine catabolism that is enriched in liver, whose role in NAFLD remains poorly understood. Here, we show that exercise induces the expression of hepatic Cdo1 via the cAMP/PKA/CREB signaling pathway. Hepatocyte-specific knockout of Cdo1 (Cdo1LKO) impairs the effect of exercise against NAFLD, whereas hepatocyte-specific overexpression of Cdo1 (Cdo1LTG) and exercise synergistically ameliorates NAFLD in male mice. Mechanistically, Cdo1 facilitates the binding between AMPK and kinase active Camkk2, which activates AMPK signaling. This promotes fatty acid oxidation and mitochondrial biogenesis in hepatocytes to attenuate hepatosteatosis. Therefore, by promoting hepatic Camkk2-AMPK signaling pathway, Cdo1 acts as an important downstream effector of exercise to combat against NAFLD
2023-08-07 | GSE239729 | GEO
Project description:CaMKK2 regulates mechanically-induced macrophage fate
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Project description:Immune suppressive landscape in a human esophageal squamous cell carcinoma microenvironment
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