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Efficient blockade of locally reciprocated tumor-macrophage signaling using a TAM-avid nanotherapy.

ABSTRACT: Interpreting how multicellular interactions in the tumor affect resistance pathways to BRAF and MEK1/2 MAPK inhibitors (MAPKi) remains a challenge. To investigate this, we profiled global ligand-receptor interactions among tumor and stromal/immune cells from biopsies of MAPK-driven disease. MAPKi increased tumor-associated macrophages (TAMs) in some patients, which correlated with poor clinical response, and MAPKi coamplified bidirectional tumor-TAM signaling via receptor tyrosine kinases (RTKs) including AXL, MERTK, and their ligand GAS6. In xenograft tumors, intravital microscopy simultaneously monitored in situ single-cell activities of multiple kinases downstream of RTKs, revealing MAPKi increased TAMs and enhanced bypass signaling in TAM-proximal tumor cells. As a proof-of-principle strategy to block this signaling, we developed a multi-RTK kinase inhibitor nanoformulation that accumulated in TAMs and delayed disease progression. Thus, bypass signaling can reciprocally amplify across nearby cell types, offering new opportunities for therapeutic design.

SUBMITTER: Wang SJ

PROVIDER: S-EPMC7244320 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Progress in tumor-associated macrophage (TAM)-targeted therapeutics.

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microRNA expression during tumor-associated macrophage (TAM) differentiation

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microRNA expression during tumor-associated macrophage (TAM) differentiation

2015-03-31 | GSE67408 | GEO

Fumagillin prodrug nanotherapy suppresses macrophage inflammatory response via endothelial nitric oxide.

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Targeting Gas6/TAM in cancer cells and tumor microenvironment.

Project description:Growth arrest-specific 6, also known as Gas6, is a human gene encoding the Gas6 protein, which was originally found to be upregulated in growth-arrested fibroblasts. Gas6 is a member of the vitamin K-dependent family of proteins expressed in many human tissues and regulates several biological processes in cells, including proliferation, survival and migration, by binding to its receptors Tyro3, Axl and Mer (TAM). In recent years, the roles of Gas6/TAM signalling in cancer cells and the tumour microenvironment have been studied, and some progress has made in targeted therapy, providing new potential directions for future investigations of cancer treatment. In this review, we introduce the Gas6 and TAM receptors and describe their involvement in different cancers and discuss the roles of Gas6 in cancer cells, the tumour microenvironment and metastasis. Finally, we introduce recent studies on Gas6/TAM targeting in cancer therapy, which will assist in the experimental design of future analyses and increase the potential use of Gas6 as a therapeutic target for cancer.

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Expression data from vehicle tumor associated macrophages (TAM) VS PLX3397 treated-TAM.

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2017-02-28 | GSE95406 | GEO

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