Rac2 controls tumor growth, metastasis and M1-M2 macrophage differentiation in vivo.
Although it is well-established that the macrophage M1 to M2 transition plays a role in tumor progression, the molecular basis for this process remains incompletely understood. Herein, we demonstrate that the small GTPase, Rac2 controls macrophage M1 to M2 differentiation and the metastatic phenotype in vivo. Using a genetic approach, combined with syngeneic and orthotopic tumor models we demonstrate that Rac2-/- mice display a marked defect in tumor growth, angiogenesis and metastasis. Microarray, RT-PCR and metabolomic analysis on bone marrow derived macrophages isolated from the Rac2-/- mice identify an important role for Rac2 in M2 macrophage differentiation. Furthermore, we define a novel molecular mechanism by which signals transmitted from the extracellular matrix via the α4β1 integrin and MCSF receptor lead to the activation of Rac2 and potentially regulate macrophage M2 differentiation. Collectively, our findings demonstrate a macrophage autonomous process by which the Rac2 GTPase is activated downstream of the α4β1 integrin and the MCSF receptor to control tumor growth, metastasis and macrophage differentiation into the M2 phenotype. Finally, using gene expression and metabolomic data from our Rac2-/- model, and information related to M1-M2 macrophage differentiation curated from the literature we executed a systems biologic analysis of hierarchical protein-protein interaction networks in an effort to develop an iterative interactome map which will predict additional mechanisms by which Rac2 may coordinately control macrophage M1 to M2 differentiation and metastasis.
UCSD Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
Shweta
S
Joshi
UCSD Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
Alok R
AR
Singh
UCSD Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
Muamera
M
Zulcic
UCSD Department of Biostatistics, Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
Lei
L
Bao
UCSD Department of Biostatistics, Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
Karen
K
Messer
Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
Trey
T
Ideker
Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
Janusz
J
Dutkowski
UCSD Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America; Department of Pediatrics and Rady Children's Hospital, San Diego, La Jolla, California, United States of America.
Donald L
DL
Durden
D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D039041:Integrin alpha4beta1 / Q000378:metabolism; D008175:Lung Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000556:secondary; D008264:Macrophages / Q000502:physiology*; D008546:Melanoma, Experimental / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden; D020744:rac GTP-Binding Proteins / Q000502:physiology*; D000097766:RAC2 GTP-Binding Protein
D039041:Integrin alpha4beta1; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016186:Receptor, Macrophage Colony-Stimulating Factor; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein