Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function

Area of Science:

• Oncology
• Cancer Metabolism
• Mitochondrial Biology

Background:

• The Warburg effect (aerobic glycolysis) is characteristic of cancer cells in vitro.
• The roles of glycolysis versus respiratory metabolism in supporting in vivo tumor growth, dissemination, and metastasis are not fully understood.
• Understanding these metabolic dependencies is crucial for developing targeted cancer therapies.

Purpose of the Study:

• To investigate the in vivo metabolic requirements of lung cancer cells, focusing on the roles of mitochondrial respiratory genes.
• To compare the metabolic demands of primary tumor growth versus metastatic growth.
• To elucidate how perturbations in mitochondrial respiration affect tumor behavior in different anatomical contexts.

Main Methods:

• Utilized a CRISPRi mini-library targeting mitochondrial ribosomal protein and respiratory chain genes in human lung cancer cell lines.
• Analyzed in vivo metabolic requirements using xenograft tumor models in distinct anatomical locations (flank and orthotopic lung).
• Employed RNA-Seq and metabolomics to assess gene expression and metabolic profiles of tumor cells with modified respiratory function.

Main Results:

• Knockdown of mitochondrial ribosomal protein and respiratory chain genes minimally affected cancer cell growth in vitro.
• In vivo, tumor cells heavily depended on these mitochondrial genes for flank and primary orthotopic lung tumor xenograft growth.
• Mitochondrial respiratory function was dispensable for metastatic tumor growth.
• Primary tumor cells with perturbed respiratory function down-regulated glycolytic mechanisms in vivo, unlike their in vitro behavior.

Conclusions:

• Mitochondrial respiratory chain function is critical for in vivo primary tumor growth but not for metastatic growth.
• Cancer cell metabolism is context-specific, with distinct requirements for primary versus metastatic tumors.
• Targeting mitochondrial respiration may offer context-dependent therapeutic strategies for lung cancer.