Fascin Controls Metastatic Colonization and Mitochondrial Oxidative Phosphorylation by Remodeling Mitochondrial Actin Filaments

Abstract

SUMMARYThe deregulation of the actin cytoskeleton has been extensively studied in metastatic dissemination. However, the post-dissemination role of the actin cytoskeleton dysregulation is poorly understood. Here, we report that fascin, an actin-bundling protein, promotes lung cancer metastatic colonization by augmenting metabolic stress resistance and mitochondrial oxidative phosphorylation (OXPHOS). Fascin is directly recruited to mitochondria under metabolic stress to stabilize mitochondrial actin filaments (mtF-actin). Using unbiased metabolomics and proteomics approaches, we discovered that fascin-mediated mtF-actin remodeling promotes mitochondrial OXPHOS by increasing the biogenesis of respiratory Complex I. Mechanistically, fascin and mtF-actin control the homeostasis of mtDNA to promote mitochondrial OXPHOS. The disruption of mtF-actin abrogates fascin-mediated lung cancer metastasis. Conversely, restoration of mitochondrial respiration by using yeast NDI1 in fascin-depleted cancer cells is able to rescue lung metastasis. Our findings indicate that the dysregulated actin cytoskeleton in metastatic lung cancer could be targeted to rewire mitochondrial metabolism and to prevent metastatic recurrence.

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

“…Recently it was shown that OXPHOS is regulated by fascin, an actin-bundling protein that promotes lung cancer metastatic colonization by augmenting metabolic stress resistance by remodeling mitochondrial actin filaments (72).…”

How does fascin promote cancer metastasis?

“…Since many cancer patients may develop metastatic recurrence from previously disseminated cells or occult micrometastases at the time of diagnosis, prevention of metastatic expansion might be the only feasible way to prevent metastatic recurrence [2]. Inhibition or knockout of fascin in extravasated Lewis lung carcinoma cells (LLC) (with inducible CRISPR/Cas9 and pharmacological fascin inhibitor) was able to robustly block metastatic expansion in the lung, suggesting that fascin promotes metastatic expansion independent of its role in cell motility [109].…”

“…Fascin is critical for metastasis to the lung but not the bone [114]. Intriguingly, metabolomics and mass spectrometry screening implicate a role for fascin in augmenting mitochondrial oxidative phosphorylation (OXPHOS) in lung adenocarcinoma [109]. The mitochondrial regulation by fascin is dependent on inverted formin 2‐CAAX (INF2‐CAAX), a ER membrane actin nucleator responsible for the polymerization of mitochondrial actin filaments [115,116].…”

“…The mitochondrial regulation by fascin is dependent on inverted formin 2‐CAAX (INF2‐CAAX), a ER membrane actin nucleator responsible for the polymerization of mitochondrial actin filaments [115,116]. Metabolic stress induced the recruitment of fascin to mitochondria, which was essential for mtF‐actin accumulation in stressed lung cancer cells [109]. Interestingly, although fascin overexpression or depletion does not affect cell proliferation or survival under conventional cell culture condition, fascin overexpression confers resistance to metabolic stress such as glucose limitation or biguanide treatment [109].…”

The miR-143/145 Cluster, a Novel Diagnostic Biomarker in Chondrosarcoma, Acts as a Tumor Suppressor and Directly Inhibits Fascin-1

“…Additionally, FSCN1 has been implicated in oncogenesis, chemoresistance, anoikis resistance, and cancer cell stemness via multiple signaling pathways . A recent report provided evidence that FSCN1 promotes metabolic stress resistance and thereby controls metastatic colonization in lung cancer . In contrast to epithelial cancers, only a few studies have addressed the role FSCN1 in sarcomas .…”