Extracellular Matrix Signals as Drivers of Mitochondrial Bioenergetics and Metabolic Plasticity of Cancer Cells During Metastasis.

Félix A Urra,Sebastián Fuentes-Retamal,Charlotte Palominos,Yarcely A Rodríguez-Lucart,Ramiro Araya-Maturana,Camila López-Torres

doi:10.3389/fcell.2021.751301

Félix A Urra, Sebastián Fuentes-Retamal + Show 4 more

Open Access

https://doi.org/10.3389/fcell.2021.751301

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Abstract

The role of metabolism in tumor growth and chemoresistance has received considerable attention, however, the contribution of mitochondrial bioenergetics in migration, invasion, and metastasis is recently being understood. Migrating cancer cells adapt their energy needs to fluctuating changes in the microenvironment, exhibiting high metabolic plasticity. This occurs due to dynamic changes in the contributions of metabolic pathways to promote localized ATP production in lamellipodia and control signaling mediated by mitochondrial reactive oxygen species. Recent evidence has shown that metabolic shifts toward a mitochondrial metabolism based on the reductive carboxylation, glutaminolysis, and phosphocreatine-creatine kinase pathways promote resistance to anoikis, migration, and invasion in cancer cells. The PGC1a-driven metabolic adaptations with increased electron transport chain activity and superoxide levels are essential for metastasis in several cancer models. Notably, these metabolic changes can be determined by the composition and density of the extracellular matrix (ECM). ECM stiffness, integrins, and small Rho GTPases promote mitochondrial fragmentation, mitochondrial localization in focal adhesion complexes, and metabolic plasticity, supporting enhanced migration and metastasis. Here, we discuss the role of ECM in regulating mitochondrial metabolism during migration and metastasis, highlighting the therapeutic potential of compounds affecting mitochondrial function and selectively block cancer cell migration.

Highlights

It is known that the activation of oncogenes such as c-Myc, Oct, and K-Ras (Jose et al, 2011; Hu et al, 2012; Sancho et al, 2015) and cellular sensors such as mTOR, AMPK, and HIF1α participate in the metabolic adaptations that support the primary tumor growth (Massagué and Obenauf, 2016; Valcarcel-Jimenez et al, 2017; Desbats et al, 2020; extracellular matrix (ECM) and Mitochondria in MetastasisMoldogazieva et al, 2020); how the cancer metabolism changes during metastasis remain less well known
Concomitantly occurs the activation of a signaling by β1-integrin/PINCH-1, a focal adhesion protein whose level is increased in response to ECM stiffening, decreasing DRP1 GTPase expression and mitochondrial fission (Chen et al, 2021)
Mechanical regulation of cytoskeletal remodeling during spreading and migration involves a metabolic shift toward increased OXPHOS, which is necessary for membrane ruffling in breast cancer cells (Wu et al, 2021)

Summary

Introduction

It is known that the activation of oncogenes such as c-Myc, Oct, and K-Ras (Jose et al, 2011; Hu et al, 2012; Sancho et al, 2015) and cellular sensors such as mTOR, AMPK, and HIF1α participate in the metabolic adaptations that support the primary tumor growth (Massagué and Obenauf, 2016; Valcarcel-Jimenez et al, 2017; Desbats et al, 2020; ECM and Mitochondria in MetastasisMoldogazieva et al, 2020); how the cancer metabolism changes during metastasis remain less well known. Different mitochondria-dependent metabolic adaptations occur during migration, invasion, and colonization; they all converge to supply mitochondrial ATP production, revealing an essential role of bioenergetics in metastasis. Activation of integrin signaling controls the metabolism, promoting metabolic shifts that support migration and metastasis (Figure 1C).

Results

Conclusion