The Essential Role Of Macrophages In Liver Tumor Initiating Cell Survival And Tumorigenesis

Immune system and inflammation play a critical role in different stages of tumor development.In established tumors,infiltrated inflammatory cells such as tumor-associated macrophages(TAMs)impact tumorigenesis by interacting with tumor cells and modulating microenvironment,which is the basis of cancer immunotherapy.Human liver cancer often arises from chronic inflammation.Hepatocellular carcinoma(HCC)is a huge threat to public health worldwide and in China.However,a reliable mouse genetic model of HCC is lacking.To study the impact of the immune system on early stage of liver tumorigenesis in vivo,especially that induced by deregulation of the Hippo pathway,I established a mouse model,which combines hydrodynamic tailvein injection with piggyBac transposon-mediated genomic integration.Using this model,I have found that activate the Hippo pathway effector YAP induces liver tumors within 4 months.Co-expression of VGLL4 protein strongly inhibits YAP-induced liver tumorigenesis.On the contrary,co-expression of miR-130a,which targets VGLL4,enhances YAP-induced tumorigenesis.The tumors induced by active YAP contain poorly differentiated tumor cells and a lot of infiltrated macrophages.We checked the macrophages recruitment at different time points and found that YAP expression strongly recruits macrophages from a single cell stage.Inactivation of endogenous Hippo pathway kinases Latsl/2 or Mstl/2 also recruits macrophages.YAP recruits macrophages via direct induction of chemokine CCL2 and also CSF1.Eradication of these tumor-initiating-cell-associated macrophages(TICAMs)via Ccl2 and Csf1 knockdown leads to clearance of TICs by immunosurveillance in a p53-dependent manner,and thus causes complete elimination of tumorigenesis.Importantly,YAP activation correlates with TICAM recruitment to murine hepatocytes in vivo upon activation of pathologically relevant oncogenes and in human liver precancerous lesions.v Those results revealed an unexpected non-cell-autonomous function of the Hippo pathway in liver tumorigenesis underscoring the essential role of macrophages in the survival of tumor initiating cells.This study suggests a new avenue for cancer immunoprevention by inhibiting YAP and blocking tumor initiating associated macrophages.