AFM Analysis Enables Differentiation between Apoptosis, Necroptosis, and Ferroptosis in Murine Cancer Cells

Meeren, Louis Van der; Verduijn, Joost; Krysko, Dmitri V.; Skirtach, André G.

doi:10.1016/j.isci.2020.101816

Cited by 45 publications

(65 citation statements)

References 54 publications

(34 reference statements)

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“…To investigate FcR-mediated phagocytosis, DAAMPs were functionalized with BSA and anti-BSA IgG, as well as AF647-Cadaverine for visualization ( Vorselen et al, 2020b ; Figure 1b ). RAW macrophages were fed DAAMPs with a diameter of 9 µm and a Young’s modulus of 1.4 or 6.5 kPa, which is in the same range as healthy tissue cells and physiological targets of macrophages like apoptotic cells ( Cross et al, 2007 ; Van der Meeren et al, 2020 ). RAW macrophages typically formed a chalice-shaped phagocytic cup and completed phagocytosis in a similar timeframe (~3 min) as previously reported for much stiffer (2–3 GPa) polystyrene particles ( Horsthemke et al, 2017 ; Figure 1a , Video 1 , Figure 1—figure supplement 1 ).…”

Section: Resultsmentioning

confidence: 99%

Phagocytic ‘teeth’ and myosin-II ‘jaw’ power target constriction during phagocytosis

Vorselen

Barger

Wang

et al. 2021

eLife

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Phagocytosis requires rapid actin reorganization and spatially controlled force generation to ingest targets ranging from pathogens to apoptotic cells. How actomyosin activity directs membrane extensions to engulf such diverse targets remains unclear. Here, we combine lattice light-sheet microscopy (LLSM) with microparticle traction force microscopy (MP-TFM) to quantify actin dynamics and subcellular forces during macrophage phagocytosis. We show that spatially localized forces leading to target constriction are prominent during phagocytosis of antibody-opsonized targets. This constriction is largely driven by Arp2/3-mediated assembly of discrete actin protrusions containing myosin 1e and 1f (‘teeth’) that appear to be interconnected in a ring-like organization. Contractile myosin-II activity contributes to late-stage phagocytic force generation and progression, supporting a specific role in phagocytic cup closure. Observations of partial target eating attempts and sudden target release via a popping mechanism suggest that constriction may be critical for resolving complex in vivo target encounters. Overall, our findings present a phagocytic cup shaping mechanism that is distinct from cytoskeletal remodeling in 2D cell motility and may contribute to mechanosensing and phagocytic plasticity.

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Section: Resultsmentioning

confidence: 99%

Phagocytic ‘teeth’ and myosin-II ‘jaw’ power target constriction during phagocytosis

Vorselen

Barger

Wang

et al. 2021

eLife

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“…Among various mechanisms of cell death, apoptosis is a programmed process consisting of a succession of controlled events which lead to cell shrinkage and membrane blebbing as well as internal alterations such as DNA condensation. Evasion of apoptosis is considered one of the hallmarks of cancer [ 36 ]. Numerous cancer therapies aim to trigger apoptosis, but the cell type and specific molecular aberration strongly influence cell death mechanisms [ 37 ].…”

Section: Resultsmentioning

confidence: 99%

3-Pyridinylidene Derivatives of Chemically Modified Lupane and Ursane Triterpenes as Promising Anticancer Agents by Targeting Apoptosis

Казакова

Èoica

Бабаев

et al. 2021

IJMS

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Cancer persists as a global challenge due to the extent to which conventional anticancer therapies pose high risks counterbalanced with their therapeutic benefit. Naturally occurring substances stand as an important safer alternative source for anticancer drug development. In the current study, a series of modified lupane and ursane derivatives was subjected to in vitro screening on the NCI-60 cancer cell line panel. Compounds 6 and 7 have been identified as highly active with GI50 values ranging from 0.03 µM to 5.9 µM (compound 6) and 0.18–1.53 µM (compound 7). Thus, these two compounds were further assessed in detail in order to identify a possible antiproliferative mechanism of action. DAPI (4′,6-diamidino-2-phenylindole) staining revealed that both compounds induced nuclei condensation and overall cell morphological changes consistent with apoptotic cell death. rtPCR analysis showed that both compounds induced upregulation of proapoptotic Bak and Bad genes while downregulating Bcl-XL and Bcl-2 antiapoptotic genes. Molecular docking analysis revealed that both compounds exhibited high scores for Bcl-XL inhibition, while compound 7 showed higher in silico Bcl-XL inhibition potential as compared to the native inhibitor ATB-737, suggesting that compounds may induce apoptotic cell death through targeted antiapoptotic protein inhibition, as well.

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“… 17–19 Ferroptosis is also morphologically different from necroptosis, which is characterized by swelling of the cells and intracellular organelles, and membrane rupture. 18 20 21 …”

Section: Characteristics Of Ferroptosismentioning

confidence: 99%

Immunogenic ferroptosis and where to find it?

Demuynck

Efimova

Naessens

et al. 2021

J Immunother Cancer

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Ferroptosis is a recently discovered form of regulated cell death that is morphologically, genetically, and biochemically distinct from apoptosis and necroptosis, and its potential use in anticancer therapy is emerging. The strong immunogenicity of (early) ferroptotic cancer cells broadens the current concept of immunogenic cell death and opens up new possibilities for cancer treatment. In particular, induction of immunogenic ferroptosis could be beneficial for patients with cancers resistant to apoptosis and necroptosis. However, ferroptotic cancer cells may be a rich source of oxidized lipids, which contribute to decreased phagocytosis and antigen cross-presentation by dendritic cells and thus may favor tumor evasion. This could explain the non-immunogenicity of late ferroptotic cells. Besides the presence of lactate in the tumor microenvironment, acidification and hypoxia are essential factors promoting ferroptosis resistance and affecting its immunogenicity. Here, we critically discuss the crucial mediators controlling the immunogenicity of ferroptosis that modulate the induction of antitumor immunity. We emphasize that it will be necessary to also identify the tolerogenic (ie, immunosuppressive) nature of ferroptosis, which can lead to tumor evasion.

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AFM Analysis Enables Differentiation between Apoptosis, Necroptosis, and Ferroptosis in Murine Cancer Cells

Cited by 45 publications

References 54 publications

Phagocytic ‘teeth’ and myosin-II ‘jaw’ power target constriction during phagocytosis

Phagocytic ‘teeth’ and myosin-II ‘jaw’ power target constriction during phagocytosis

3-Pyridinylidene Derivatives of Chemically Modified Lupane and Ursane Triterpenes as Promising Anticancer Agents by Targeting Apoptosis

Immunogenic ferroptosis and where to find it?

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