Multidrug resistant tumors have reduced connections between mitochondria and endoplasmic reticulum (ER), causing signaling dysfunction that makes tumors resistant to therapy-induced stressors, according to a new study by researchers at Children’s Hospital of Philadelphia (CHOP). The study, published in The EMBO Journal, provides a new framework for understanding therapy resistance and could lead to improved cancer care.
“Even though most cancer deaths result from the progression of therapy-resistant disease, we still do not fully understand how this resistance occurs,” said senior author Michael D. Hogarty, MD, an attending physician in the Division of Oncology at Children's Hospital of Philadelphia. “In work led by Dr. Jorida Çoku, we were able to identify a unique mechanism involving a loss of contacts between the endoplasmic reticulum and mitochondria that occurs in resistant cancer cells and makes them less sensitive to diverse treatments. This provides opportunities to enhance cancer care by potentially restoring the communication across these membranes.”
To study therapy resistance, the researchers studied neuroblastoma, given that approximately half of patients diagnosed with the common high-risk version of this tumor relapse with multidrug-resistant disease. The research team established multiple tumor cell lines from the same neuroblastoma patients – one at the time of diagnosis and another at the time of relapse during or after treatment.
Knowing that mitochondria integrate cellular stress and survival signals, the researchers hypothesized that mitochondria might offer clues as to why some tumors become less sensitive to therapy. To test this theory, they exposed cancer mitochondria isolated from these tumors to the same proteins activated by cancer drugs to trigger cell death. They found that mitochondria from treatment-resistant tumors do not activate this death signaling pathway and do not open their outer membranes to initiate cell death. In contrast, this response was intact in the treatment-sensitive tumors from the time of diagnosis.
Assessing these mitochondria by electron microscopy allowed them to identify that resistant cancer cells had reduced numbers of specialized contacts they make with another organelle, the endoplasmic reticulum. These contact sites consist of many ER-mitochondria protein bridges that assist with signaling and communication, and when reduced, the cells are unable to appropriately transfer sphingolipids to the mitochondria, leading to their dysfunction and multidrug resistance.
“We hope our findings facilitate the development of tools that can more easily measure ER–mitochondria contacts for clinical use to predict therapy resistance, and provide a novel framework for testing interventions to restore mitochondrial competence to resistant cancers, or prevent resistance from emerging in the first place,” Dr. Hogarty said.
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Multidrug resistant tumors have reduced connections between mitochondria and endoplasmic reticulum (ER), causing signaling dysfunction that makes tumors resistant to therapy-induced stressors, according to a new study by researchers at Children’s Hospital of Philadelphia (CHOP). The study, published in The EMBO Journal, provides a new framework for understanding therapy resistance and could lead to improved cancer care.
“Even though most cancer deaths result from the progression of therapy-resistant disease, we still do not fully understand how this resistance occurs,” said senior author Michael D. Hogarty, MD, an attending physician in the Division of Oncology at Children's Hospital of Philadelphia. “In work led by Dr. Jorida Çoku, we were able to identify a unique mechanism involving a loss of contacts between the endoplasmic reticulum and mitochondria that occurs in resistant cancer cells and makes them less sensitive to diverse treatments. This provides opportunities to enhance cancer care by potentially restoring the communication across these membranes.”
To study therapy resistance, the researchers studied neuroblastoma, given that approximately half of patients diagnosed with the common high-risk version of this tumor relapse with multidrug-resistant disease. The research team established multiple tumor cell lines from the same neuroblastoma patients – one at the time of diagnosis and another at the time of relapse during or after treatment.
Knowing that mitochondria integrate cellular stress and survival signals, the researchers hypothesized that mitochondria might offer clues as to why some tumors become less sensitive to therapy. To test this theory, they exposed cancer mitochondria isolated from these tumors to the same proteins activated by cancer drugs to trigger cell death. They found that mitochondria from treatment-resistant tumors do not activate this death signaling pathway and do not open their outer membranes to initiate cell death. In contrast, this response was intact in the treatment-sensitive tumors from the time of diagnosis.
Assessing these mitochondria by electron microscopy allowed them to identify that resistant cancer cells had reduced numbers of specialized contacts they make with another organelle, the endoplasmic reticulum. These contact sites consist of many ER-mitochondria protein bridges that assist with signaling and communication, and when reduced, the cells are unable to appropriately transfer sphingolipids to the mitochondria, leading to their dysfunction and multidrug resistance.
“We hope our findings facilitate the development of tools that can more easily measure ER–mitochondria contacts for clinical use to predict therapy resistance, and provide a novel framework for testing interventions to restore mitochondrial competence to resistant cancers, or prevent resistance from emerging in the first place,” Dr. Hogarty said.
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