Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance

Abstract

Most cancer deaths result from progression of therapy resistant disease, yet our understanding of this phenotype is limited. Cancer therapies generate stress signals that act upon mitochondria to initiate apoptotic programs. We isolated mitochondria from neuroblastoma cell lines obtained from children at diagnosis and after relapse following failed therapy, and profiled responses to tBid and Bim, death effectors activated by therapeutic stress. Mitochondria from post-relapse models had markedly attenuated cytochrome c release (surrogate for apoptotic commitment) in comparison with patient-matched diagnostic models. Mitochondrial DNA content, size, and shape did not differ consistently. However, we used electron microscopy to identify reduced endoplasmic reticulum-mitochondria contacts (ERMCs) as correlated with therapy resistance. ERMCs form microdomains for the transfer of Ca2+ to mitochondria. We confirmed reduced Ca2+ transfer in resistant cells, with restoration by re-opposing ERMCs via genetically-encoded linkers. However, reduced Ca2+ transfer was not present in all ERMC-reduced cancers with therapy resistance, supporting Ca2+-independent mechanisms. Genetically or biochemically reducing ERMCs in therapy sensitive tumors phenocopied resistance, validating these inter-organelle contacts as physiologic regulators of apoptosis. Our work confirms the importance of ERMCs in stress signaling and provides a previously unrecognized mechanism for cancer cell resistance that is not exclusive to other contributors.

Inhibiting mitochondrial translation overcomes multidrug resistance in MYC-driven neuroblastoma via OMA1-mediated integrated stress response

“…1f). This is in line with our previous findings demonstrating that CHLA-20 has diminished sensitivity to apoptosis induction directly at the level of isolated mitochondria [13]. Together, the CHLA-15/CHLA-20 pair represents a useful model of emergent therapy resistance and cancer stemness in neuroblastoma.…”

“…Previously, CHLA-20 cells were reported more resistant to diverse chemotherapeutics than CHLA-15 [13,22]. Validating this phenotype in our experimental settings, CHLA-20 cells exhibited broad resistance (1.6-fold to 44.5-fold difference vs. CHLA-15) to both DNA and non-DNA targeting drugs.…”

“…Among other functions, MYC oncogenic transcription factors induce expression of genes involved in mitochondrial biogenesis [6][7][8][9] and mitochondriadependent metabolism [10][11][12]. Importantly, we have recently demonstrated that mitochondria from therapy-resistant tumor cells often show attenuated apoptotic signaling, which largely contributes to neuroblastoma multidrug resistance [13]. Here, we therefore investigated potential mitochondrial dependencies, testing mitochondria as direct targets to overcome multidrug resistance in neuroblastoma.…”

Silver nanoparticle-induced alteration of mitochondrial and ER homeostasis affects human breast cancer cell fate

“…There are existing reports that establish the crosstalk between ER and mitochondria. According to Sassano et al, the first-ever inter-organelle contact site was discovered was the entanglement (mitochondria-associated membranes) between mitochondria and ER [30] , and they proposed that inter-organelle Ca +2 ion flow maintains their functionality [33] . Miscommunication between these organelles can lead to cellular bio-chemical dis-equilibrium shifting balance towards disorders [31] .…”

Get Closer to the World of Contact Sites: A Beginner's Guide to Proximity-Driven Fluorescent Probes

“…Since the dysregulation of inter-organelle communication seems to play a crucial role in the onset of pathological conditions, membrane contact sites could also become an interesting and appealing pharmacological target. For example, recently, Coku et al, 2022 demonstrated that reduced ER–mitochondria crosstalk promotes multidrug resistance in neuroblastoma cells. Thus, testing the effect of different chemotherapeutic agents in modulating the contact sites of interest could be insightful.…”