Due to its ability to inhibit prometastatic matrix metalloproteinases, tissue inhibitor of metalloproteinases (TIMP)‐1 has been thought to suppress tumor metastasis. However, elevated systemic levels of TIMP‐1 correlate with poor prognosis in cancer patients, suggesting a metastasis‐stimulating role of TIMP‐1. In colorectal cancer patients, tumor as well as plasma TIMP‐1 levels were correlated with synchronous liver metastasis or distant metastasis‐associated disease relapse. In mice, high systemic TIMP‐1 levels increased the liver susceptibility towards metastasis by triggering the formation of a premetastatic niche. This promoted hepatic metastasis independent of origin or intrinsic metastatic potential of tumor cells. High systemic TIMP‐1 led to increased hepatic SDF‐1 levels, which in turn promoted recruitment of neutrophils to the liver. Both inhibition of SDF‐1‐mediated neutrophil recruitment and systemic depletion of neutrophils reduced TIMP‐1‐induced increased liver susceptibility towards metastasis. This indicates a crucial functional role of neutrophils in the TIMP‐1‐induced premetastatic niche. Conclusion: Our results identify TIMP‐1 as an essential promoter of hepatic premetastatic niche formation. (Hepatology 2015;61:238–248)

R-loops are three-stranded DNA/RNA hybrids that form by the annealing of the mRNA transcript to its coding template while displacing the non-coding strand. While R-loop formation regulates physiological genomic and mitochondrial transcription and DNA damage response, imbalanced R-loop formation can be a threat to the genomic integrity of the cell. As such, R-loop formation is a double-edged sword in cancer progression, and perturbed R-loop homeostasis is observed across various malignancies. Here, we discuss the interplay between R-loops and tumor suppressors and oncogenes, with a focus on BRCA1/2 and ATR. R-loop imbalances contribute to cancer propagation and the development of chemotherapy drug resistance. We explore how R-loop formation can cause cancer cell death in response to chemotherapeutics and be used to circumvent drug resistance. As R-loop formation is tightly linked to mRNA transcription, their formation is unavoidable in cancer cells and can thus be explored in novel cancer therapeutics.