A neuronal network of mitochondrial dynamics regulates metastasis

Abstract

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.

The mitochondrial dynamics in cancer and immune-surveillance

“…Consistent with its role as an onco-suppressor, SNPH is downregulated in several malignancies, such as the epithelial and haematological ones [76]. On the contrary, levels of Miro2, which promotes mitochondria movement along microtubules, are upregulated in the same tumors [76]. Moreover, SNPH downregulation correlates also with poor survival prognosis in colon and lung adenocarcinoma patients [76].…”

“…Syntaphilin (SNPH), a protein first discovered in neurons for its ability to dock mitochondria to axon microtubules, similarly suppresses mitochondrial dynamic movements, and therefore cell motility, in tumor cells [76]. Consistent with its role as an onco-suppressor, SNPH is downregulated in several malignancies, such as the epithelial and haematological ones [76]. On the contrary, levels of Miro2, which promotes mitochondria movement along microtubules, are upregulated in the same tumors [76].…”

“…On the contrary, levels of Miro2, which promotes mitochondria movement along microtubules, are upregulated in the same tumors [76]. Moreover, SNPH downregulation correlates also with poor survival prognosis in colon and lung adenocarcinoma patients [76]. Recently, it has been shown that NF-κB-inducing kinase (NIK) localizes at OMM in both MEFs and cancer cell lines where it interacts with Drp1, by promoting its translocation and activation; this favours fragmented mitochondria redistribution to lamellipodia and sustains high-speed cell migration [77].…”

“…In addition, the inhibition of mitochondria transport along the microtubules, obtained by downregulation of the Miro1 dynein motor, also prevents epithelial cancer cell migration [73]. Syntaphilin (SNPH), a protein first discovered in neurons for its ability to dock mitochondria to axon microtubules, similarly suppresses mitochondrial dynamic movements, and therefore cell motility, in tumor cells [76]. Consistent with its role as an onco-suppressor, SNPH is downregulated in several malignancies, such as the epithelial and haematological ones [76].…”

Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer

“…Unexpectedly, a key regulator of this pathway was identified as syntaphilin (SNPH), a cytoskeletal protein known in neurons for arresting mitochondrial movement at sites of high energy demands (27,28). Instead, SNPH was found to be expressed in cancer, but downregulated in advanced disease settings, blocking mitochondrial trafficking to the cortical cytoskeleton and suppressing cell motility and invasion (29).…”