Editorial: Inter-Organelle Calcium Communication in Cancer

FONDECYT grant 
1160332 
CONICYT/FONDAP 
15150012 
Research Foundation-Flanders (FWO) 
G.0634.13N 
G.0C91.14N 
G.0A34.16N 
G.0901.18N 
Research Council-KU Leuven 
OT/14/101 
Italian Ministry of Education, University and Research 
Italian Ministry of Health 
Telethon 
GGP15219/B 
Italian Association for Cancer Research 
AIRC: IG-18624 
University of Ferrara


iNtrodUCtioN
Cancer is a leading cause of death worldwide, accounting for 8.2 million deaths (around 13% of all deaths) in 2012, with this number expected to rise to over 11 million by 2030 (1). The term "cancer" groups over 100 distinct diseases that share a series of "acquired capabilities, " which were first defined by Hanahan and Weinberg in 2000 consisting of six hallmark alterations in cell physiology that collectively dictate malignant growth: cell sufficiency in growth signals, insensitivity to growth inhibitory signals, evasion of programmed cell death, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis (2). In the last 25 years, the description and interpretation of genomic abnormalities in cancer cells have dominated cancer research (3). However, bioinformatic analyses suggest that cancer-related driver mutations affect a dozen or more core cell signaling pathways (4), suggesting that individual targets will not be fruitful candidates for therapeutic development, and instead, intervening with cellular processes will be more effective. In this regard, it has become increasingly clear that many key oncogenic signaling pathways that support tumor cell growth and survival converge at cell metabolism (5). In fact, the reprogramming of energy metabolism, which relies on mitochondrial function, is absolutely required for malignant transformation, and for this reason, it has recently been added as a hallmark of cancer (6). This research topic focuses on the role of the endoplasmic reticulum (ER)-to-mitochondria communication in the regulation of mitochondrial function, with special emphasis on Ca 2+ transfer, and its impact on cancer cell fate.

MitoCHoNdria-aSSoCiatEd Er MEMBraNES iN CaNCEr
It has been known since the 1950 that mitochondria and the ER, the main intracellular Ca 2+ store, interact with each other in response to changes in cellular metabolism (7). The ER-mitochondrial association can be physically isolated (8) as mitochondria-associated ER membranes that establish a specific microdomain with distinct signaling functions (9). These contact sites not only allow "quasi-synaptic" transfer of Ca 2+ from the ER to the mitochondria but also enables lipid synthesis and exchange, mitochondrial trafficking, cell death, bioenergetics, proteostasis, and autophagy, all processes often altered in oncogenesis and cancer, as has been reviewed in detail by Sassano et al. Consistent with the pivotal role of MAMs in these fundamental cellular processes, their function and thus composition ought to be fine-tuned. This is achieved by a growing list of proteins that impact cell survival and cell stress tolerance, of which, many are well-known oncogenes and oncosuppressors such as p53, AKT, PTEN, and PML (10,11 Ca 2+ is a ubiquitous signaling messenger that regulates various cellular processes ranging from muscle contraction to synaptic transmission and from cellular proliferation to cell death (12,13). This versatility is achieved by the interplay of the Ca 2+ -signaling toolkit (including channels, pumps, exchangers, and binding/ buffering proteins), generating specific spatiotemporal Ca 2+ signals (14). Alterations in the expression and/or function of these Ca 2+ -transport/binding systems have been implicated in oncogenesis and cancer progression (15,16). In this regard, Wolf and Guse contribute a comprehensive review focused on the generation, regulation, and function of Ca 2+ microdomains in T lymphocytes. Ca 2+ microdomains occur in cancer cells due to the spontaneous opening of a single or some small clusters of the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R), in the ER, which proves to be necessary to maintain the bioenergetic homeostasis of these cells (17)

MitoCHoNdrial Ca 2+ dYNaMiCS iN iNVaSioN aNd MEtaStaSiS
Mitochondria are highly dynamic organelles undergoing constant fusion and fission governed in part by the metabolic status of the cell (19). Cancer cells, which are characterized by alterations in their metabolism, also exhibit several changes regarding mitochondrial dynamics, morphology, and cellular positioning, as discussed in the review by Pendin et al. These alterations enable cancer cells to avoid apoptosis and to cope with the sustained energy demand, particularly during migration, invasion, and metastasis. White concisely reviews the key steps controlled by Ca 2+ during the invasion-metastasis cascade and reveals how changes in the Ca 2+ -handling components that reside in the MAMs might facilitate invasion and metastasis by impacting bioenergetics and reactive oxygen species generation. Along these lines, Hegedüs et al. provide experimental evidence that enhanced clearance of Ca 2+ by increased expression of the plasma membrane Ca 2+ ATPase 4b induced by histone deacetylase inhibitors, and reduces migration in a melanoma cell line.

PErSPECtiVES
Cancer has a multifactorial nature. Over the last decade, it has become increasingly clear that ER-to-mitochondria communication, in particular, through the flux of Ca 2+ ions, impacts a plethora of cancer hallmarks and plays a critical role in oncogenesis. The emerging insights at the molecular level in the dependence of cancer cells on ER-mitochondrial Ca 2+ signaling for their survival and migration will pave the path for new therapeutic strategies and tools (20), hopefully opening up new avenues for designing anticancer treatments that exploit these dependencies and vulnerabilities.
aUtHor CoNtriBUtioNS CC drafted the manuscript that was reviewed and edited by PP and GB. All authors co-edited the Research Topic.
aCKNoWlEdGMENtS CC wants to thank Alenka Lovy for her continuous support, creative power, and inspiring discussion. CC has been supported by FONDECYT grant #1160332 (CC) and CONICYT/ FONDAP #15150012 (CC). GB was supported by the Research