microRNAs and oligometastasis

occur as a result of metastases – tumor cells derived from the primary tumor which colonize distant sites. Metastases widely differ in their behavior which contributes to the heterogeneity in clinical manifestations of metastatic disease. To highlight this heterogeneity the concept of " oligometastases " was introduced two decades ago (Hellman and Weichselbaum. The oligometastatic hypothesis posits the existence of a state of limited metastatic disease in contrast to the widely held notion that metastasis is a widespread disease (i.e. polymetastatic). Patients with oligo-metastatic cancers could potentially be cured with localized, metastasis-directed therapies, such as surgery and radiotherapy, while most metastatic patients are incurable even with systemic therapies. Two central questions arise: (1) are there molecular differences between oligometastases and polymetastases and (2) can we predict the behavior of metastatic disease in a given patient? The answers to these questions would advance our understanding of metastasis development and potentially lead to the discovery of biomarkers guiding the appropriate selection of therapeutic modalities for individual patients. Recently we collected clinical samples derived from cancer patients with oligo-or poly-metastatic disease based on the number of metastatic lesions and their rate of metastatic progression [1,2]. We profiled microRNAs (miRs) from patient-derived samples to examine their potential roles in gene regulation mediating the oligometastatic phenotype. We investigated two cohorts of patients. In the first cohort, patients were treated with stereotactic body radiotherapy (SBRT) to all sites of metastatic disease [1]. In the second cohort, patients underwent surgical removal of lung metastases from various primary tumors [2]. In both cohorts, oligometastatic patients demonstrated significantly longer overall and disease-free survival as compared to polymetastatic patients. Together, 112 samples from both cohorts were profiled to identify differences in miR expression. Among these, 35 miRs and 15 miRs were differentially expressed in surgically resected lung oligometastases and SBRT treated oligometastases, respectively. We designated these as " oligomiRs " [3]. This finding provided evidence that oligometastases are a specific clinical entity and prompted a detailed Editorial examination into the molecular underpinnings of the actions of these miRs for their potential use as prognostic and predictive markers for subtypes of metastatic disease. We mapped ~20,000 computer-predicted target genes to 101 specific KEGG pathways for the clinically identified oligomiRs. These pathways were enriched by cellular processes mediating adhesion, invasion and migration – the " AIM " phenotype [4]. We further found that ectopic expression of the oligomiRs 127-5p, 544a and 655-3p …