Calpain-2 regulates hypoxia/HIF-induced plasticity toward amoeboid cancer cell migration and metastasis

Boekhorst, Veronika te; Jiang, Liying; Mählen, Marius; Meerlo, Maaike; Dunkel, Gina; Durst, Franziska C.; Yang, Yanjun; Levine, Herbert; Burgering, Boudewijn M.T.; Friedl, Peter

doi:10.1016/j.cub.2021.11.040

Cited by 26 publications

(22 citation statements)

References 82 publications

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“…Hypoxia has been reported to promote rounded-amoeboid migration in cancer cells 40 and cancer cells under hypoxic conditions display fragmented and less active mitochondria 41 . Altogether, these observations suggest that rounded-amoeboid migration may be an e cient and energetically parsimonious mode of dissemination both in normoxia and under low oxygen conditions 42 . We open up the exciting possibility that mitochondria orchestrate mechano-responsiveness via AMPK-mediated ATP/AMP sensing.…”

Section: Discussionmentioning

confidence: 80%

AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin II dependent cell migration

Sanz-Moreno

Crosas‐Molist

Maiques³

et al. 2022

Preprint

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Cell migration are crucial for development, immunity and cancer dissemination. We find that AMPK controls cell migration by acting as an adhesion sensing molecular hub. In 3-dimensional (3D) matrices, fast migrating amoeboid cancer cells exert low adhesion/low traction linked to lower energy levels; while their low ATP/AMP ratio leads to AMPK activation. In turn, AMPK plays a dual role controlling both mitochondrial dynamics and cytoskeletal remodelling. High AMPK in low adhering migratory cells, induces mitochondrial fission via MFF phosphorylation, resulting in lower OXPHOS and lower mitochondrial ATP. At the same time, AMPK phosphorylates and inactivates MYPT1, increasing Myosin II dependent amoeboid migration. Reducing adhesion, inducing AMPK activity or inhibiting mitochondrial fusion result in profound cytoskeletal remodelling and efficient rounded-amoeboid 3D migration and invasion. Moreover, AMPK inhibition suppresses in vivo metastatic potential of amoeboid cancer cells. We measure a mitochondrial/AMPK-driven switch in regions of human tumours where amoeboid cells are actively disseminating. We unveil how mitochondrial dynamics control cell migration and suggest that AMPK is a master “mechano-metabolic sensor” at the crossroads between energetics and the actomyosin cytoskeleton.

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Section: Discussionmentioning

confidence: 80%

AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin II dependent cell migration

Sanz-Moreno

Crosas‐Molist

Maiques³

et al. 2022

Preprint

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“…To achieve this goal, we used a validated method of invalidation of LRP-1 in FTC-133 thyroid carcinoma cells by siRNA ( 36 ) leading to a 70% decrease of its gene expression as evaluated by RT-qPCR ( Figure 1A ) , and to a 66% decrease of its protein expression measured by western blot ( Figure 1B ) . Calpains constitute a family of intracellular calcium-dependent cysteine-proteases which exert crucial actions on focal adhesion dynamics, and are able to cleave cytoskeleton components to mediate turnover and disassembly of focal complexes as well as the activation and clustering of extracellular matrix receptors ( 41 , 48 , 49 ). We tested the consequences of LRP-1 invalidation on calpain activity in FTC133 cells during the phase of attachment by performing a biochemical assay based on calpain substrate II cleavage ( Figure 1C ) .…”

Section: Resultsmentioning

confidence: 99%

“…The regulation of calpain activity is complex dynamic and still lacking in mechanistic insights, especially in the field of cancer ( 41 , 49 , 60 , 61 ). In this study, we evidenced that calpain activity are dampened by LRP-1 in thyroid carcinoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, under hypoxic conditions, induction of calpain-2 switched the collective mode of migration of breast and head and neck cancer cells to an amoeboid metastatic behavior. This transition relied on talin cleavage and decreased strength of β1 integrin-mediated attachments, and was reverted by pharmacological challenge of calpain activity ( 49 ).…”

Section: Discussionmentioning

confidence: 99%

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LRP-1-dependent control of calpain expression and activity: A new mechanism regulating thyroid carcinoma cell adhesion

et al. 2022

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The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor mediating the clearance of various molecules from the extracellular matrix. LRP1 also regulates cell surface expression of matrix receptors by modulating both extracellular and intracellular signals, though current knowledge of the underlying mechanisms remains partial in the frame of cancer cells interaction with matricellular substrates. In this study we identified that LRP1 downregulates calpain activity and calpain 2 transcriptional expression in an invasive thyroid carcinoma cell model. LRP1-dependent alleviation of calpain activity limits cell-matrix attachment strength and contributes to FTC133 cells invasive abilities in a modified Boyden chamber assays. In addition, using enzymatic assays and co-immunoprecipitation experiments, we demonstrated that LRP1 exerts post-translational inhibition of calpain activity through PKA-dependent phosphorylation of calpain-2. This LRP-1 dual mode of control of calpain activity fine-tunes carcinoma cell spreading. We showed that LRP1-mediated calpain inhibition participates in talin-positive focal adhesions dissolution and limits β1-integrin expression at carcinoma cell surface. In conclusion, we identified an additional and innovative intracellular mechanism which demonstrates LRP-1 pro-motile action in thyroid cancer cells. LRP-1 ability to specifically control calpain-2 expression and activity highlights a novel facet of its de-adhesion receptor status.

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“…The occurrence of side effects in the case of anti-angiogenic drugs can be explained primarily by increased hypoxia ( Pennacchietti et al, 2003 ) caused by the lack of blood supply in the tumor ( Büchler et al, 2004 ; Ebos et al, 2009 ; Loges et al, 2009 ; Pàez-Ribes et al, 2009 ). It was shown in many works that hypoxia activates EMT ( Imai et al, 2003 ; Yang et al, 2008 ) and thus can stimulate metastasis through the mesenchymal motility mode ( Brahimi-Horn et al, 2007 ; Sullivan and Graham, 2007 ; Yang et al, 2008 ), but it can also stimulate the transition to amoeboid movement, which is characterized by faster cell dissemination and lack of dependence on the activity of MMPs, which in turn further enhances the metastatic potential of tumors ( Te Boekhorst et al, 2022 ). In particular, hypoxia has been shown to strengthen the migration of mouse breast CCs by enhancing the EMT and/or MAT of some cells.…”

Section: Enhancement Of Metastasis As a Side-effect Of Widely Used An...mentioning

confidence: 99%

How does plasticity of migration help tumor cells to avoid treatment: Cytoskeletal regulators and potential markers

Alexandrova¹,

Lomakina²

2022

Front. Pharmacol.

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Tumor shrinkage as a result of antitumor therapy is not the only and sufficient indicator of treatment success. Cancer progression leads to dissemination of tumor cells and formation of metastases - secondary tumor lesions in distant organs. Metastasis is associated with acquisition of mobile phenotype by tumor cells as a result of epithelial-to-mesenchymal transition and further cell migration based on cytoskeleton reorganization. The main mechanisms of individual cell migration are either mesenchymal, which depends on the activity of small GTPase Rac, actin polymerization, formation of adhesions with extracellular matrix and activity of proteolytic enzymes or amoeboid, which is based on the increase in intracellular pressure caused by the enhancement of actin cortex contractility regulated by Rho-ROCK-MLCKII pathway, and does not depend on the formation of adhesive structures with the matrix, nor on the activity of proteases. The ability of tumor cells to switch from one motility mode to another depending on cell context and environmental conditions, termed migratory plasticity, contributes to the efficiency of dissemination and often allows the cells to avoid the applied treatment. The search for new therapeutic targets among cytoskeletal proteins offers an opportunity to directly influence cell migration. For successful treatment it is important to assess the likelihood of migratory plasticity in a particular tumor. Therefore, the search for specific markers that can indicate a high probability of migratory plasticity is very important.

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Calpain-2 regulates hypoxia/HIF-induced plasticity toward amoeboid cancer cell migration and metastasis

Cited by 26 publications

References 82 publications

AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin II dependent cell migration

AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin II dependent cell migration

LRP-1-dependent control of calpain expression and activity: A new mechanism regulating thyroid carcinoma cell adhesion

How does plasticity of migration help tumor cells to avoid treatment: Cytoskeletal regulators and potential markers

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