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Cancer cells display metabolic plasticity to survive metabolic and energetic stresses in the tumor microenvironment, prompting the need for tools to target tumor metabolism. Cellular adaptation to energetic stress is coordinated in part by signaling through the Liver Kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Reducing LKB1-AMPK signaling exposes metabolic vulnerabilities in tumor cells with potential for therapeutic targeting. Here we describe that miRNA-mediated silencing of LKB1 (mediated by the oncogenic miRNA clustermiR-17∼92) confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides. Using both classic (phenformin) and novel (IM156) biguanides, we demonstrate thatMyc+lymphoma cells with elevatedmiR-17∼92expression display increased sensitivity to biguanide treatment both in cell viability assaysin vitroand tumor growth assaysin vivo. This increased biguanide sensitivity is driven bymiR-17-dependent silencing of LKB1, which results in reduced AMPK activation in response to bioenergetic stress. Mechanistically, biguanide treatment inhibits TCA cycle metabolism and mitochondrial respiration inmiR-17∼92-expressing tumor cells, targeting their metabolic vulnerability. Finally, we demonstrate a direct correlation betweenmiR-17∼92expression and biguanide sensitivity in human cancer cells. Our results identifymiR-17∼92expression as a potential biomarker for biguanide sensitivity in hematological malignancies and solid tumors.One Sentence SummarymiR-17∼92 expression inMyc+tumors sensitizes cancer cells to biguanide treatment by disrupting bioenergetic stability in lymphoma cells.

Summary Cancer cells display metabolic plasticity to survive stresses in the tumor microenvironment. Cellular adaptation to energetic stress is coordinated in part by signaling through the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Here, we demonstrate that miRNA-mediated silencing of LKB1 confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides. Using both classic (phenformin) and newly developed (IM156) biguanides, we demonstrate that elevated miR-17∼92 expression in Myc+ lymphoma cells promotes increased apoptosis to biguanide treatment in vitro and in vivo. This effect is driven by the miR-17-dependent silencing of LKB1, which reduces AMPK activation in response to complex I inhibition. Mechanistically, biguanide treatment induces metabolic stress in Myc+ lymphoma cells by inhibiting TCA cycle metabolism and mitochondrial respiration, exposing metabolic vulnerability. Finally, we demonstrate a direct correlation between miR-17∼92 expression and biguanide sensitivity in human cancer cells. Our results identify miR-17∼92 expression as a potential biomarker for biguanide sensitivity in malignancies., Graphical Abstract, Highlights IM156 is a newly developed biguanide with more potency than phenformin IM156 inhibits mitochondrial respiration to cause bioenergetic stress in lymphoma miR-17-dependent silencing of LKB1 reduces adaptation to bioenergetic stress miR-17∼92 expression correlates with biguanide sensitivity in human cancer cells, Izreig et al. show that miR-17∼92 expression in cancer cells sensitizes them to biguanide treatment by disrupting bioenergetic stability. These data implicate miR-17∼92 expression as a potential biomarker for biguanide sensitivity in hematological malignancies and possibly solid tumors.

The microRNAs encoded by the miR-17∼92 polycistron are commonly overexpressed in cancer and orchestrate a wide range of oncogenic functions. Here, we identify a mechanism for miR-17∼92 oncogenic function through the disruption of endogenous microRNA (miRNA) processing. We show that, upon oncogenic overexpression of the miR-17∼92 primary transcript (pri-miR-17∼92), the microprocessor complex remains associated with partially processed intermediates that aberrantly accumulate. These intermediates reflect a series of hierarchical and conserved steps in the early processing of the pri-miR-17∼92 transcript. Encumbrance of the microprocessor by miR-17∼92 intermediates leads to the broad but selective downregulation of co-expressed polycistronic miRNAs, including miRNAs derived from tumor-suppressive miR-34b/c and from the Dlk1-Dio3 polycistrons. We propose that the identified steps of polycistronic miR-17∼92 biogenesis contribute to the oncogenic re-wiring of gene regulation networks. Our results reveal previously unappreciated functional paradigms for polycistronic miRNAs in cancer.