The role of mitochondria in cancer is controversial. Using a genome-wide shRNA screen, we now show that tumours reprogram a network of mitochondrial dynamics operative in neurons, including syntaphilin (SNPH), kinesin KIF5B and GTPase Miro1/2 to localize mitochondria to the cortical cytoskeleton and power the membrane machinery of cell movements. When expressed in tumours, SNPH inhibits the speed and distance travelled by individual mitochondria, suppresses organelle dynamics, and blocks chemotaxis and metastasis, in vivo. Tumour progression in humans is associated with downregulation or loss of SNPH, which correlates with shortened patient survival, increased mitochondrial trafficking to the cortical cytoskeleton, greater membrane dynamics and heightened cell invasion. Therefore, a SNPH network regulates metastatic competence and may provide a therapeutic target in cancer.

Significance: Exploitation of mitochondrial functions promotes tumor traits, including metastasis, which is responsible for >90% of all cancer deaths. In this study, we investigated how mitochondrial fitness impacts tumor behavior. We found that acutely damaged, de-energized, and reactive oxygen species-producing mitochondria not only persist in cancer but are also key enablers of metastasis. These “ghost” mitochondria originate from the heterogeneous and often reduced expression of Mic60, an essential scaffold of organelle structure, in certain human cancers. The compensatory activation of gene expression programs as well as GCN2/Akt kinase signaling enables the survival of Mic60-low tumors but also provides a new therapeutic target in advanced and hard-to-treat malignancies.

Parathyroid tumors deregulate microRNAs belonging to the two clusters on the chromosome 19, the C19MC and miR-371-373 clusters. Here, we report that the embryonic miR-372 is aberrantly expressed in half of parathyroid adenomas, (PAds) in most of atypical adenomas and carcinomas (n=15). Through in situ hybridization we identified that miR-372-positive parathyroid tumor cells were scattered throughout the tumor parenchyma. In PAds-derived cells, ectopic miR-372 inhibited the expression of its targets CDKN1A/p21 and LATS2 at both mRNA and protein levels. Although the viability of parathyroid cells was not affected by miR-372 overexpression, the miRNA blunted camptothecin-induced apoptosis in primary PAds-derived cultures. MiR-372 overexpression in parathyroid tumor cells increased parathormone (PTH) mRNA levels and it positively correlated in vivo with circulating PTH levels. Conversely, the parathyroid-specific genes TBX1 and GCM2 were not affected by miR-372 mimic transfection. Finally, miR-372 dampened the Wnt pathway in parathyroid tumor cells through DKK1 upregulation. In conclusion, miR-372 is a novel mechanism exploited by a subset of parathyroid tumor cells to partially decrease sensitivity to apoptosis, to increase PTH synthesis and to deregulate Wnt signaling.

Tumors of the parathyroid glands are the second most common endocrine neoplasia. Epigenetic studies revealed an embryonic signature involved in parathyroid tumorigenesis. Here, we investigated the expression of the stem core genes SOX2, POU5F1/OCT4, and NANOG. Rare cells within normal parathyroid glands expressed POU5F1/OCT4 and NANOG, while SOX2 was undetectable. Nuclear SOX2 expression was detectable in 18% of parathyroid adenomas (PAds, n = 34) involving 5–30% of cells, while OCT4 and NANOG were expressed at the nuclear level in a more consistent subset of PAds involving 15–40% of cells. Most parathyroid carcinomas expressed the core stem genes. SOX2-expressing cells co-expressed parathormone (PTH). In PAds-derived primary cultures, silencing of the tumor suppressor gene MEN1 induced the expression of SOX2, likely through a MEN1/HAR1B/SOX2 axis, while calcium-sensing receptor activation increased SOX2 mRNA levels through YAP1 activation. In addition, inducing nuclear β-catenin accumulation in PAds-derived primary cultures by short-term incubation with lithium chloride (LiCl), SOX2 and POU5F1/OCT4 expression levels increased, while NANOG transcripts were reduced, and LiCl long-term incubation induced an opposite pattern of gene expression. In conclusion, detection of the core stem genes in parathyroid tumors supports their embryogenic signature, which is modulated by crucial genes involved in parathyroid tumorigenesis.

A role for long non‐coding RNAs (lncRNAs) in endocrine cancer pathogenesis is emerging. However, knowledge regarding their expression pattern, correlation with known genetic defects, and clinical implications in parathyroid tumors is still unclear. Here, we profiled 90 known lncRNAs in a first series of normal (PaN=2), adenomatous (PAds=12), and carcinomatous (PCa=4) parathyroid glands and we confirmed deregulation of 11 lncRNAs using an independent cohort of patients (PaN=4; PAd=26; PCa=9). LncRNAs expression was correlated with cytogenetic aberrations, Multiple Endocrine Neoplasia 1 (MEN1), and Cell Division Cycle 73 (CDC73) genes status or clinical features. Globally, lncRNAs discriminate according to tissue histology. BC200 consistently identifies parathyroid cancers from adenomas and atypical adenomas. Loss‐of‐heterozygosis (LOH) at chromosomes 1, 11, 15, 21, and 22 significantly impacts on lncRNAs expression in PAds. Silencing of the key parathyroid gene MEN1 modulates 6 lncRNAs expression in primary PAds‐derived cultures. Analogous lncRNAs levels are measured in PAds with the mutation in the MEN1 gene compared with PAds with wild‐type MEN1. Similarly, carcinomas with mutated CDC73 differ from PCas with wild‐type protein in terms of lncRNAs expression. PCas harboring CDC73 mutations overexpress BC200 compared to wild‐type carcinomas. Overall, these findings shed light on lncRNAs deregulation in human parathyroid tumors and propose that circuits between lncRNAs and the oncosuppressors MEN1 or CDC73 may have a role in parathyroid tumorigenesis as epigenetic modulators.