Metastastic cancer remains incurable and invariably kills 90% of cancer patients. Despite significant progress in determining the molecular and biochemical determinants of the metastatic cascade, we still lack actionable targets for metastatic disease. Filling this gap, our lab focuses on understanding the importance of mitochondria biology in metastatic breast and prostate cancer.  Mitochondria are bioenergetic, biosynthetic, and signaling organelles that have been implicated in various aspects of tumorigenesis and therapy resistance.  Indeed, mitochondrial respiration has been linked to oncogene-dependent transformation, metabolic reprogramming, protein translation, tumor repopulation, cell motility and metastasis.  In this context, mitochondrial quality control mechanisms are emerging as drivers of metastasis and attractive therapeutic targets. 

Mitochondrial dynamics in cancer. A key mechanism by which tumors regulate mitochondrial functions are the collective processes of mitochondrial dynamics. Mitochondrial dynamics refers to spatiotemporal regulation of gross morphology, transport of organelles, inner membrane and cristae morphology, communication between adjacent mitochondria and contact with other organelles such as the endoplasmic reticulum. Tumor microenvironmental conditions (hypoxia, starvation and oxidative stress) exploit mitochondrial dynamics as adaptive mechanisms. In this context, the possibility that mitochondria trafficking might affect tumor biology is poorly studied. In a series of recent contributions, we show that tumor cells reposition mitochondria at subcellular sites of high energetic demands, thus powering up mechanisms of invasion and metastasis. Disparate stimuli, ranging from growth factor stimulation, to therapy resistance to hypoxic stress, led to the trafficking of energetically active mitochondria to the cortical cytoskeleton of tumor cells. In turn, regional energy production supported membrane lamellipodia dynamics and increased turnover of focal adhesion complexes. 

Deregulated mitochondrial trafficking fuels metastasis. The mitochondrial trafficking machinery had been previously studied in the context of neuronal cells, and many of the molecules were believed to be neuron-specific.  Recently, we identified the molecular motors and adaptors responsible for trafficking of mitochondria in tumor cells by a genome-wide shRNA screen. Syntaphilin (SNPH), the molecular brake anchoring mitochondria to microtubules, is broadly expressed in normal tissues and lost in most cancer types, including breast cancer. Higher levels of SNPH were associated with removal of mitochondria from the cortical cytoskeleton, impaired focal adhesion dynamics and inhibition of tumor cell invasion and metastasis. In patients, SNPH loss in tumors correlated with shortened patient survival. Conversely, positive regulators of mitochondrial trafficking, the mitochondrial Rho GTPases (Miro) 1 and 2, were overexpressed in patient cohorts and were associated with poorer prognosis. Our current goal are: (i) to  dissect the molecular mechanisms underlying mitochondrial trafficking in tumors, particularly in the context of hypoxic stress from the tumor microenvironment; (ii) to understand how rewiring of the mitochondrial network in tumors impacts cellular behaviors that drive progressive and lethal cancer; and (iii) to examine the contribution of the mitochondrial trafficking components (SNPH, Miro1/2 and Kinesin) to tumor cell invasion and metastatic dissemination. ​