The Disabled homolog 2 controls pro-metastatic activity of tumor-associated macrophages
Tumor-associated macrophages (TAMs) are regulators of extracellular matrix (ECM) remodeling and metastatic progression, the main cause of cancer-associated death. We found that disabled 2 mitogen-responsive phosphoprotein (DAB2) is highly expressed in tumor-infiltrating TAMs and its genetic ablation significantly impairs lung metastasis formation. DAB2-expressing TAMs, mainly localized along the tumor invasive front, participate in integrin recycling, ECM remodeling and directional migration in a tridimensional matrix. DAB2+ macrophages escort the invasive dissemination of cancer cells by a mechanosensing pathway requiring the transcription factor Yes-Associated Protein. In human lobular breast and gastric carcinomas, DAB2+ TAMs correlated with a poor clinical outcome, identifying DAB2 as potential prognostic biomarker for cancer patient stratification. DAB2 is therefore central for the pro-metastatic activity of TAMs. Overall design: Single cell transcrptome profiling of tumor-infiltrating myeloid cells from PyMT-WT and PyMT-Dab2 KO mice. Tumors pooled from 3 PyMT-WT and 3 PyMT-Dab2 KO mice were digested and myeloid cells were FACS sorted as CD45+lineage (CD3, CD19, NK1.1) negative cells. Sorted cell suspension was loaded on a GemCode Single Cell Instrument (10x Chromium System) to generate single cell GEMs. Single cell RNA-Seq libraries were prepared using GemCode Single Cell 3' Gel Bead and Library Kit v2 (10x Genomics).