Abstract
Metastasis is a major cause of cancer mortality. We generated an autochthonous transgenic mouse model whereby conditional expression of MYC and Twist1 enables hepatocellular carcinoma (HCC) to metastasize in >90% of mice. MYC and Twist1 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 MYC-HCCs to metastasize; whereas, blockade of Ccl2 and Il13 abrogated MYC/Twist1-HCC metastasis. Further, in 33 human cancers (n = 9502) MYC and TWIST1 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, MYC and TWIST1 generally appear to cooperate in human cancer to elicit a cytokinome that enables metastasis through crosstalk between cancer and immune microenvironment.
Highlights
Tumorigenesis is caused by specific oncogenes but tumor progression often involves the acquisition of metastasis (Chaffer and Weinberg, 2011)
Twist1 transgenic mice (LAP-transactivator protein (tTA)/tetracycline responsive element (TRE)-Twist1/Luc) exhibited no disease nor gross or microscopic pathology for as long as 18 months of observation demonstrating that Twist1 did not play a role in autochthonous tumorigenesis when overexpressed in the liver (Figure 1—figure supplement 1a)
We considered that Twist1 could be influencing MYC expression levels, but MYC levels were similar between the two tumor models, while Twist1 was only overexpressed in the MYC/Twist1-hepatocellular carcinoma (HCC) (Figure 1—figure supplement 1c-d)
Summary
Tumorigenesis is caused by specific oncogenes but tumor progression often involves the acquisition of metastasis (Chaffer and Weinberg, 2011). The experiments showed that these two proteins work together to reprogram mouse cancer cells to release signal molecules known as cytokines These molecules convert immune cells known as macrophages to a tumor-friendly state that allows cancers cells to spread around the body. Further experiments analyzed tumor samples from around 10,000 human patients with 33 different cancers This revealed that patients that had higher levels of MYC and TWIST1 proteins in their tumors had increased levels of CCL2 and IL13, more activated macrophages and were less likely to recover from their cancer. The findings of Dhanasekaran, Baylot et al suggest that MYC and TWIST1 may instigate metastasis in many human cancers, and therapies targeting specific cytokines may prevent these cancers from spreading around the body. Our results are broadly generalizable to 33 different human cancers and predict invasive cancer in a pilot clinical study
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