Oxidative Stress in Skeletal Muscle Hinders Metastatic Colonization

Many cancer types display characteristic patterns of metastasis, preferentially developing metastases in certain organs more than others, but across all cancers, metastasis to skeletal muscle is extremely rare in contrast to more permissive sites of metastasis such as the lungs. To investigate whether skeletal muscle might uniquely suppress metastatic colonization of disseminated tumor cells (DTC), Crist and colleagues analyzed skeletal muscle samples from patients with metastatic breast cancer, as well as from a murine model of spontaneous breast cancer metastasis, revealing that DTCs localized to skeletal muscle with notable frequency without developing macrometastases. To mimic metastasis-permissive lung or metastasis-suppressive skeletal muscle microenvironments, human breast cancer cells were cultured on lung stroma or myotubes, and the significant growth suppression of cancer cells seeded on myotubes suggested that the muscle niche produced transient factors that prevent DTC outgrowth. Metabolomic comparison of lung metastases with rare skeletal muscle metastases highlighted glutathione metabolism as the primary metabolic adaptation specifically required for muscle colonization, which was further supported by high levels of reactive oxygen species within tumor cells grown in the skeletal muscle niche, indicating increased oxidative stress. Notably, sustained oxidative stress via consistent generation of hydrogen peroxide diminished tumor cell outgrowth in the typically permissive lung niche, whereas enhancement of antioxidant capacity of tumor cells via expression of catalase, an enzyme that degrades hydrogen peroxide, enabled metastatic colonization of skeletal muscle. In addition, enhancing the antioxidant capacity of skeletal muscle cells similarly increased metastatic colonization, demonstrating that the resolution of oxidative stress within the muscle niche or within DTCs was sufficient to overcome barriers to metastasis. In summary, this study describes a mechanism of metastatic suppression uniquely imposed on DTCs by the skeletal muscle niche, uncovering redox capacity as an important bottleneck for metastatic colonization that may be exploited to inhibit metastasis to more permissive tissues.

Crist SB, Nemkov T, Dumpit RF, Dai J, Tapscott SJ, True LD, et al. Unchecked oxidative stress in skeletal muscle prevents outgrowth of disseminated tumour cells. Nat Cell Biol 2022;24:538–53.

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