Tumor Extracellular Vesicles Regulate Macrophage-Driven Metastasis through CCL5.

PURPOSE: To understand how tumor cells alter macrophage biology once they are recruited to triple-negative breast cancer (TNBC) tumors by CCL5. METHOD: Mouse bone marrow derived macrophage (BMDMs) were isolated and treated with recombinant CCL5 protein alone, with tumor cell conditioned media, or with tumor extracellular vesicles (EVs). Media from these tumor EV-educated macrophages (TEMs) was then used to determine how these macrophages affect TNBC invasion. To understand the mechanism, we assayed the cytokine secretion from these macrophages to determine how they impact tumor cell invasion. Tumor CCL5 expression was varied in tumors to determine its role in regulating macrophage biology through EVs. RESULTS: Tumor EVs are a necessary component for programming naïve macrophages toward a pro-metastatic phenotype. CCL5 expression in the tumor cells regulates both EV biogenesis/secretion/cargo and macrophage EV-education toward a pro-metastatic phenotype. Analysis of the tumor EV-educated macrophages (TEMs) showed secretion of a variety of factors including CXCL1, CTLA-4, IFNG, OPN, HGF, TGFB, and CCL19 capable of remodeling the surrounding tumor stroma and immune infiltrate. Injection of tumor cells with macrophages educated by metastatic tumor cell EVs into mice increased tumor metastasis to the lung. CONCLUSION: These results demonstrate that tumor-derived EVs are key mediators of macrophage education and likely play a more complex role in modulating tumor therapeutic response by regulating the tumor immune infiltrate.

Medical students' preference for returning to the clinical setting during the COVID-19 pandemic.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has led to widespread disruptions in the clinical education of medical students. In managing students' return to the clinical setting, medical schools face the challenge of balancing education, service and risk considerations. To compound this challenge, medical students may prefer not to re-enter during a period of great uncertainty, leading to substantive downstream sequelae on individual, institutional and national levels. Understanding students' views on resuming clinical experiences, therefore, is an important consideration. The purpose of this study was to assess medical students' preference for re-entering the clinical setting during the COVID-19 pandemic and to explore personal and environmental characteristics associated with that preference. METHODS: We conducted an electronic survey of currently enrolled medical students at the Duke-NUS Medical School, less than a month into the COVID-19 pandemic. Survey items were aligned with a conceptual framework related to medical students' preference for returning to the clinical setting. The framework consisted of three domains: (a) non-modifiable demographic information; (b) factors thought to be modifiable through the course of medical education, including burnout, tolerance for ambiguity, motivation and professionalism, and (c) students' perception of COVID-19 infection risk to self. RESULTS: Approximately one-third (n=63) of 179 students preferred not to return to the clinical setting. Results of a multivariable analysis indicated that compared to this group, the two-thirds (n=116) of students favouring return showed evidence of greater autonomous (or internal) motivation, a greater sense of professional responsibility and a lower self-perception of harbouring risk to patients. CONCLUSIONS: Students' preference on returning to the clinical environment stems from the interplay of several key factors, and is substantively associated with perceptions of professional responsibility and their own potential risk to the health care system. Mindfully considering and addressing these issues may help medical schools in their preparation for returning students to the clinical setting.

Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism.

Mitochondrial metabolism is an attractive target for cancer therapy1,2. Reprogramming metabolic pathways could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options, such as triple-negative breast cancer (TNBC)1,3. Here we show that BTB and CNC homology1 (BACH1)4, a haem-binding transcription factor that is increased in expression in tumours from patients with TNBC, targets mitochondrial metabolism. BACH1 decreases glucose utilization in the tricarboxylic acid cycle and negatively regulates transcription of electron transport chain (ETC) genes. BACH1 depletion by shRNA or degradation by hemin sensitizes cells to ETC inhibitors such as metformin5,6, suppressing growth of both cell line and patient-derived tumour xenografts. Expression of a haem-resistant BACH1 mutant in cells that express a short hairpin RNA for BACH1 rescues the BACH1 phenotype and restores metformin resistance in hemin-treated cells and tumours7. Finally, BACH1 gene expression inversely correlates with ETC gene expression in tumours from patients with breast cancer and in other tumour types, which highlights the clinical relevance of our findings. This study demonstrates that mitochondrial metabolism can be exploited by targeting BACH1 to sensitize breast cancer and potentially other tumour tissues to mitochondrial inhibitors.