PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion

Abstract

Molecular therapies are hallmarks of "personalized" medicine, but how tumors adapt to these agents is not well-understood. Here we show that small-molecule inhibitors of phosphatidylinositol 3-kinase (PI3K) currently in the clinic induce global transcriptional reprogramming in tumors, with activation of growth factor receptors, (re)phosphorylation of Akt and mammalian target of rapamycin (mTOR), and increased tumor cell motility and invasion. This response involves redistribution of energetically active mitochondria to the cortical cytoskeleton, where they support membrane dynamics, turnover of focal adhesion complexes, and random cell motility. Blocking oxidative phosphorylation prevents adaptive mitochondrial trafficking, impairs membrane dynamics, and suppresses tumor cell invasion. Therefore, "spatiotemporal" mitochondrial respiration adaptively induced by PI3K therapy fuels tumor cell invasion, and may provide an important antimetastatic target. mitochondria | molecular therapy | cytoskeleton | PI3K | cell invasion

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

“…Unexpectedly, a similar pathway was recently uncovered in cancer (29), where SNPH prevented the repositioning of mitochondria to the cortical cytoskeleton, a process that fuels chemotaxis and cell invasion (25,26), thus suppressing tumor cell movements (29). Here, we uncovered a mechanistic underpinning of the SNPH pathway in cancer, centered on the expression of a previously unrecognized, alternatively spliced SNPH isoform, characterized…”

“…Low levels of ROS may contribute to tumorigenesis via increased DNA damage and activation of oncogene signaling (44), whereas higher generation of ROS may trigger cytotoxicity and suppress metastasis (45). Here, the heightened production of mitochondrial superoxide in response to SNPH depletion triggered a dual phenotype of inhibition of tumor cell proliferation via G 2 /M arrest and stimulation of cell motility by increasing mitochondrial trafficking to the cortical cytoskeleton (25). This is consistent with a long-held tenet that ROS mediate cell motility (46), contributing to the acquisition of an EMT phenotype (47) and metastatic competence (21).…”

“…dynamics (22); and horizontal transfer of respiration-competent mitochondria from stromal cells (23,24). Recently, an additional mechanism of active mitochondrial trafficking to the cortical cytoskeleton has been linked to greater tumor cell invasion and metastasis (25,26), potentially by providing a concentrated, "regional" energy source to fuel membrane dynamics of chemotaxis and tumor cell movements. 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).…”

The mitochondrial dynamics in cancer and immune-surveillance

“…Differently from what has been elucidated so far, Caino and colleagues reported that mitochondria accumulation at the leading-edge of migrating glioma cells is Mfn-1-dependent and requires PI3K inhibition to promote focal adhesion turnover and tumor invasiveness. Interestingly, OXPHOS inhibition prevents such mitochondria redistribution, this indicating that ATP production and oxidative metabolism may play an important role during cell migration [79]. Of note, this study may suggest that in cancer cell migration the relative contribution of mitochondrial fission/ fusion equilibrium is highly context-dependent.…”

“…Moreover, increased Drp1 expression in OVCA420 cells impairs HIF-1α upregulation upon hypoxia, thus rendering these cells unable to cope with the stress [102]. Nevertheless, as previously stated, optimal OXPHOS activity has been suggested to play a role in supporting tumor cell invasiveness [79], thus highlighting the metabolic plasticity of cancer cells in different conditions. Despite the numerous examples here reported, correlating an altered cellular metabolism with a modification of the mitochondrial morphology in cancer cells, it is not clear yet whether modulation of the mitochondrial network in cancer cells is a priming event or just a consequence of the OXPHOS-glycolysis metabolic shift.…”