MYC and Twist1 cooperate to drive metastasis by eliciting crosstalk between cancer and innate immunity

Abstract

Metastasis is a major cause of cancer mortality. We generated an autochthonous transgenic mouse model whereby conditional expression of <i>MYC</i> and <i>Twist1</i> enables hepatocellular carcinoma (HCC) to metastasize in >90% of mice. <i>MYC</i> and <i>Twist1</i> cooperate and their sustained expression is required to elicit a transcriptional program associated with the activation of innate immunity, through secretion of a cytokinome that elicits recruitment and polarization of tumor associated macrophages (TAMs). Systemic treatment with Ccl2 and Il13 induced <i>MYC</i>-HCCs to metastasize; whereas, blockade of Ccl2 and Il13 abrogated <i>MYC</i>/<i>Twist1</i>-HCC metastasis. Further, in 33 human cancers (n = 9502) <i>MYC</i> and <i>TWIST1</i> predict poor survival (p=4.3×10^-10), CCL2/IL13 expression (p<10^-109) and TAM infiltration (p<10^-96). Finally, in the plasma of patients with HCC (n = 25) but not cirrhosis (n = 10), CCL2 and IL13 were increased and IL13 predicted invasive tumors. Therefore, <i>MYC</i> and <i>TWIST1</i> generally appear to cooperate in human cancer to elicit a cytokinome that enables metastasis through crosstalk between cancer and immune microenvironment.