title: Tumor-infiltrating myeloid cells activate Dll4/Notch/TGF-β signaling to drive malignant progression.
abstract: Myeloid cells that orchestrate malignant progression in the tumor microenvironment offer targets for a generalized strategy to attack solid tumors. Through an analysis of tumor microenvironments, we explored an experimental model of lung cancer that uncovered a network of Dll4/Notch/TGF-β1 signals that links myeloid cells to cancer progression. Myeloid cells attracted to the tumor microenvironment by the tumor-derived cytokines CCL2 and M-CSF expressed increased levels of the Notch ligand Dll4, thereby activating Notch signaling in the tumor cells and amplifying tumor-intrinsic Notch activation. Heightened Dll4/Notch signaling in tumor cells magnified TGF-β-induced pSMAD2/3 signaling and was required to sustain TGF-β-induced tumor cell growth. Conversely, Notch blockade reduced TGF-β signaling and limited lung carcinoma tumor progression. Corroborating these findings, by interrogating RNAseq results from tumor and adjacent normal tissue in clinical specimens of human head and neck squamous carcinoma, we found evidence that TGF-β/Notch crosstalk contributed to progression. In summary, the myeloid cell-carcinoma signaling network we describe uncovers novel mechanistic links between the tumor microenvironment and tumor growth, highlighting new opportunities to target tumors where this network is active.
authors: Authors' Affiliations: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, NIH; Department of Intramural Research National Institutes of Neurological Disorders and Stroke, NIH, Bethesda, Maryland; and W2Motif, LLC, San Diego, California.
authors: Hidetaka
authors: H
authors: Ohnuki
authors: Kan
authors: K
authors: Jiang
authors: Dunrui
authors: D
authors: Wang
authors: Ombretta
authors: O
authors: Salvucci
authors: Hyeongil
authors: H
authors: Kwak
authors: David
authors: D
authors: Sánchez-Martín
authors: Dragan
authors: D
authors: Maric
authors: Giovanna
authors: G
authors: Tosato
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D022423:Myeloid Cells / Q000473:pathology*; D009374:Neoplasms, Experimental / Q000473:pathology*; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D059016:Tumor Microenvironment
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D016212:Transforming Growth Factor beta