Mitochondria, known for more than a century as the energy powerhouse of a cell, represent key intracellular signaling hub that are emerging as important determinants of several aspects of cancer development and progression, including metabolic reprogramming, acquisition of metastatic capability, and response to chemotherapeutic drugs. The majority of cancer cells harbors somatic mutations in the mitochondrial genome (mtDNA) and/or alterations in the mtDNA content, leading to mitochondrial dysfunction. Decreased mtDNA content is also detected in tumor-initiating cells, a subpopulation of cancer cells that are believed to play an integral role in cancer recurrence following chemotherapy. Although mutations in mitochondrial genes are common in cancer cells, they do not shut down completely the mitochondrial energy metabolism and functionality. Instead, they promote rewiring of the bioenergetics and biosynthetic profile of a cancer cell through a mitochondria-to-nucleus signaling activated by "dysfunctional" mitochondria that results in changes in transcription and/or activity of cancer-related genes and signaling pathways. Different cancer cell types may undergo different bioenergetic changes, some to more glycolytic and some to more oxidative. These different metabolic signatures may coexist within the same tumor mass (intra-tumor heterogeneity). In this review we describe the current understanding of mitochondrial dysfunction in the context of cancer chemoresistance with special attention to the role of mtDNA alterations. We put emphasis on potential therapeutic strategies targeting different metabolic events specific to cancer cells, including glycolysis, glutaminolysis, oxidative phosphorylation, and the retrograde signaling, to prevent chemoresistance. We also highlight novel genome-editing strategies aimed at "correcting" mtDNA defects in cancer cells. We conclude on the importance of considering intratumor metabolic heterogeneity to develop effective metabolism-based cancer therapy that can overcome chemoresistance. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.

Osteoclasts are essential cells for bone erosion in inflammatory arthritis and are derived from cells in the myeloid lineage. Recently, we reported that tumor necrosis factor-␣ (TNF␣) increases the blood osteoclast precursor (OCP) numbers in arthritic patients and animals, which are reduced by anti-TNF therapy, implying that circulating OCPs may have an important role in the pathogenesis of erosive arthritis. The aim of this study is to investigate the mechanism by which TNF␣ induces this increase in OCP frequency. We found that TNF␣ stimulated cell division and conversion of CD11b

Neoplastic transformation of prostate epithelium involves aberrant activation of anti-apoptotic and pro-invasive pathways triggered by multiple poorly understood genetic events. We demonstrated earlier that depletion of mitochondrial DNA (mtDNA) induces prostate cancer progression. Here, using normal prostate epithelial PNT1A cells we demonstrate that mtDNA depletion prevents detachment-induced apoptosis (anoikis) and promotes migratory capabilities onto basement membrane proteins through upregulation of p85 and p110 phosphatidylinositol 3-kinase (PI3K) subunits, which results in Akt2 activation and phosphorylation of downstream substrates GSK3b, c-Myc, MMP-9, Mdm2, and p53. Pharmacological or genetic PI3K inhibition, siRNA-mediated Akt2 depletion, as well as mtDNA reconstitution were sufficient to restore sensitivity to anoikis and curtail cell migration. Moreover, Akt2 activation induced glucose transporter 1 (GLUT1) expression, glucose uptake, and lactate production, common phenotypic changes seen in neoplastic cells. In keeping with these findings, several prostate carcinoma cell lines displayed reduced mtDNA content and increased PI3K/Akt2 levels when compared to normal PNT1A cells, and Akt2 downregulation prevented their survival, migration and glycolytic metabolism. On a tissue microarray, we also found a statistically significant decrease in mtDNA-encoded cytochrome oxidase I in prostate carcinomas. Taken together, these results provide novel mechanistic evidence supporting the notion that mtDNA mutations may confer survival and migratory advantage to prostate cancer cells through Akt2 signaling.

Smoldering myeloma (SMM) is associated with a high-risk of progression to myeloma (MM). We report the results of a study of 82 patients with both targeted sequencing that included a capture of the immunoglobulin and MYC regions. By comparing these results to newly diagnosed myeloma (MM) we show fewer NRAS and FAM46C mutations together with fewer adverse translocations, del(1p), del(14q), del(16q), and del(17p) in SMM consistent with their role as drivers of the transition to MM. KRAS mutations are associated with a shorter time to progression (HR 3.5 (1.5–8.1), p = 0.001). In an analysis of change in clonal structure over time we studied 53 samples from nine patients at multiple time points. Branching evolutionary patterns, novel mutations, biallelic hits in crucial tumour suppressor genes, and segmental copy number changes are key mechanisms underlying the transition to MM, which can precede progression and be used to guide early intervention strategies.

IFNg, a potent cytokine known to modulate tumor immunity and tumoricidal effects, is highly elevated in patients with prostate cancer after radiation. In this study, we demonstrate that IFNg can induce epithelial-to-mesenchymal transition (EMT) in prostate cancer cells via the JAK-STAT signaling pathway, leading to the transcription of IFN-stimulated genes (ISG) such as IFN-induced tetratricopeptide repeat 5 (IFIT5). We unveil a new function of IFIT5 complex in degrading precursor miRNAs (pre-miRNA) that includes pre-miR-363 from the miR-106a-363 cluster as well as pre-miR-101 and pre-miR-128, who share a similar 5 0 -end structure with pre-miR-363. These suppressive miRNAs exerted a similar function by targeting EMT transcription factors in prostate cancer cells. Depletion of IFIT5 decreased IFNg-induced cell invasiveness in vitro and lung metastasis in vivo. IFIT5 was highly elevated in high-grade prostate cancer and its expression inversely correlated with these suppressive miRNAs. Altogether, this study unveils a prometastatic role of the IFNg pathway via a new mechanism of action, which raises concerns about its clinical application.Significance: A unique IFIT5-XRN1 complex involved in the turnover of specific tumor suppressive microRNAs is the underlying mechanism of IFNg-induced epithelial-tomesenchymal transition in prostate cancer.See related commentary by Liu and Gao, p. 1032