Altered Mitochondria Functionality Defines a Metastatic Cell State in Lung Cancer and Creates an Exploitable Vulnerability

Abstract

Lung cancer is a prevalent and lethal cancer type that leads to more deaths than the next four major cancer types combined. Metastatic cancer spread is responsible for most cancer-related deaths but the cellular changes that enable cancer cells to leave the primary tumor and establish inoperable and lethal metastases remain poorly understood. To uncover genes that are specifically required to sustain metastasis survival or growth, we performed a genome-scale pooled lentiviral-shRNA library screen in cells that represent nonmetastatic and metastatic states of lung adenocarcinoma. Mitochondrial ribosome and mitochondria-associated genes were identified as top gene sets associated with metastasis-specific lethality. Metastasis-derived cell lines in vitro and metastases analyzed ex vivo from an autochthonous lung cancer mouse model had lower mitochondrial membrane potential and reduced mitochondrial functionality than nonmetastatic primary tumors. Electron microscopy of metastases uncovered irregular mitochondria with bridging and loss of normal membrane structure. Consistent with these findings, compounds that inhibit mitochondrial translation or replication had a greater effect on the growth of metastasis-derived cells. Finally, mice with established tumors developed fewer metastases upon treatment with phenformin in vivo. These results suggest that the metastatic cell state in lung adenocarcinoma is associated with a specifically altered mitochondrial functionality that can be therapeutically exploited. Significance: This study characterizes altered mitochondria functionality of the metastatic cell state in lung cancer and opens new avenues for metastasis-specific therapeutic targeting.

The metabolism of cancer cells during metastasis

“…Functionally, expression of genes contributing to oxidative phosphorylation showed a negative corre-lation with EMT 32 . Accordingly, metastasis-derived cell lines in vitro and metastases analysed ex vivo from a lung cancer mouse model had reduced mitochondrial functionality compared with non-metastatic primary tumours 33 . Although these changes in mitochondrial metabolism will have multiple effects, they may indi-cate a shift towards glycolytic energy production that requires lactate synthesis.…”

Unraveling Tumor Heterogeneity by Using DNA Barcoding Technologies to Develop Personalized Treatment Strategies in Advanced-Stage PDAC

“…Phenformin demonstrates a more rapid entrance to the cell and mitochondria without transporters, resulting in an enhanced anti-neoplastic effect in OXPHOS high pancreatic cancer as well as other cancer entities [43][44][45][46][47][48] (Table 1). Consistent with these findings, Chuang et al recently demonstrated a cell autonomous effect of phenformin on metastatic ability in murine lung cancer cells by specifically targeting dysfunctional mitochondria [49]. Other studies focused on inhibiting mitochondrial uptake of glutamine by targeting glutaminase 1 (GLS), which showed anti-proliferative effects in vitro but only minor effects on tumor growth in preclinical cancer models due to the metabolic adaptability of PDAC [50][51][52].…”

Redox Regulation in Cancer Cells during Metastasis

“…However, flow cytometric measurements of mitochondrial membrane potential do not always correlate with mitochondrial or electron chain function (135). Lung cancer cell lines with metastatic potential have lower mitochondrial membrane potential and reduced mitochondrial function as compared with nonmetastatic lung cancer cell lines (136). PGC1α, a transcription factor that promotes mitochondrial biogenesis, seems to promote invasion and metastasis in some contexts (76) while inhibiting metastasis in others, including in melanoma (84,137).…”

“…Asparagine is synthesized from aspartate, and aspartate synthesis depends on electron transport chain function (139)(140)(141). This raises the possibility that asparagine is limiting in metastasizing cancer cells because mitochondrial function is limited in an effort to manage oxidative stress (136).…”