Inactivation of Autophagy in Keratinocytes Reduces Tumor Growth in Mouse Models of Epithelial Skin Cancer

Barresi, Caterina; Rossiter, Heidemarie; Buchberger, Maria; Pammer, Johannes; Sukseree, Supawadee; Sibilia, Maria; Tschachler, Erwin; Eckhart, Leopold

doi:10.3390/cells11223691

Cited by 6 publications

(3 citation statements)

References 51 publications

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“…In agreement, we show that ATG16L1-deficiency in keratinocytes promotes epidermal inflammation upon treatment with a topical inflammatory agent. As the molecular mechanisms underlying inflammatory responses in the skin also partly mediate tumor formation [ 4 ], Δ Ker atg16l1 mice are also shown to be sensitized to inflammation-driven carcinogenesis induced by DMBA/TPA treatment, in agreement with previous studies in Δ Ker atg7 mice [ 39 ]. However, we observed a higher number of tumors per mouse in Δ Ker atg16l1 relative to control skin, which is opposite to what has been described in Δ Ker atg7 skin.…”

Section: Discussionsupporting

confidence: 84%

Autophagy critically controls skin inflammation and apoptosis-induced stem cell activation

Van Hove,

Toniolo,

Ghiasloo

et al. 2023

Autophagy

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Macroautophagy/autophagy is a cellular recycling program regulating cell survival and controlling inflammatory responses in a context-dependent manner. Here, we demonstrate that keratinocyte-selective ablation of Atg16l1 , an essential autophagy mediator, results in exacerbated inflammatory and neoplastic skin responses. In addition, mice lacking keratinocyte autophagy exhibit precocious onset of hair follicle growth, indicating altered activation kinetics of hair follicle stem cells (HFSCs). These HFSCs also exhibit expanded potencies in an autophagy-deficient context as shown by de novo hair follicle formation and improved healing of abrasion wounds. ATG16L1-deficient keratinocytes are markedly sensitized to apoptosis. Compound deletion of RIPK3-dependent necroptotic and CASP8-dependent apoptotic responses or of TNFRSF1A/TNFR1 reveals that the enhanced sensitivity of autophagy-deficient keratinocytes to TNF-dependent cell death is driving altered activation of HFSCs. Together, our data demonstrate that keratinocyte autophagy dampens skin inflammation and tumorigenesis but curtails HFSC activation by restraining apoptotic responses. Abbreviations: ATG16L1: autophagy related 16 like 1; DMBA: 2,4-dimethoxybenzaldehyde; DP: dermal papilla; EpdSCs: epidermal stem cells; Gas6: growth arrest specific 6; HF: hair follicle; HFSC: hair follicle stem cell; IFE: interfollicular epidermis; KRT5: keratin 5; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; PMK: primary mouse keratinocyte; RIPK3: receptor-interacting serine-threonine kinase 3; scRNAseq: single-cell RNA-sequencing; SG: sebaceous gland; TEWL: transepidermal water loss; TPA: 12-O-tetradecanoylphorbol-13-acetate; TNF: tumor necrosis factor; TNFRSF1A/TNFR1: tumor necrosis factor receptor superfamily, member 1a; UMAP: uniform manifold approximation and projection

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Section: Discussionsupporting

confidence: 84%

Autophagy critically controls skin inflammation and apoptosis-induced stem cell activation

Van Hove,

Toniolo,

Ghiasloo

et al. 2023

Autophagy

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“…Note that 48 h after photosensitization with AO, there is a large accumulation of acid vacuoles (AVOs, Figure 2E To better correlate lysosome damage with the status of the autophagy flux, we chose to use HaCaT cells, since their basal autophagic levels are always active [44]. Modulation of the autophagy flux is a novel approach for targeting cancer cells [41,45]. Thus, understanding AO's impact on the autophagy levels is of paramount importance.…”

Section: Resultsmentioning

confidence: 99%

Photodynamic Activity of Acridine Orange in Keratinocytes under Blue Light Irradiation

et al. 2023

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Acridine orange (AO) is a metachromatic fluorescent dye that stains various cellular compartments, specifically accumulating in acidic vacuoles (AVOs). AO is frequently used for cell and tissue staining (in vivo and in vitro), mainly because it marks different cellular compartments with different colors. However, AO also forms triplet excited states and its role as a photosensitizer is not yet completely understood. Human immortalized keratinocytes (HaCaT) were incubated for either 10 or 60 min with various concentrations (nanomolar range) of AO that were significantly lower than those typically used in staining protocols (micromolar). After incubation, the cells were irradiated with a 490 nm LED. As expected, cell viability (measured by MTT, NRU and crystal violet staining) decreased with the increase in AO concentration. Interestingly, at the same AO concentration, altering the incubation time with HaCaT substantially decreased the 50% lethal dose (LD50) from 300 to 150 nM. The photoinduced cell death correlated primarily with lysosomal disfunction, and the correlation was stronger for the 60 min AO incubation results. Furthermore, the longer incubation time favored monomers of AO and a distribution of the dye to intracellular sites other than lysosomes. Studies with mimetic systems indicated that monomers, which have higher yields of fluorescence emission and singlet oxygen generation, are favored in acidic environments, consistent with the more intense emission from cells submitted to the longer AO incubation period. Our results indicate that AO is an efficient PDT photosensitizer, with a photodynamic efficiency that is enhanced in acidic environments when multiple intracellular locations are targeted. Consequently, when using AO as a probe for live cell tracking and tissue staining, care must be taken to avoid excessive exposure to light to avoid undesirable photosensitized oxidation reactions in the tissue or cell under investigation.

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“…In addition, K5-Son of sevenless (SOS) EGFR wa2/wa2 mice, in which wounding induces tumors, were used. In mouse tumors generated by chemical treatment, there was no significant change resulting from the deletion of Atg7, but the deletion of Atg7 in tumors caused by HRas mutation markedly suppressed tumor progression based on the size of the tumor and the survival rate of the mice [37].…”

Section: Dual Roles Of Autophagy In Cancermentioning

confidence: 96%

Unraveling the Intricacies of Autophagy and Mitophagy: Implications in Cancer Biology

Lee,

Son,

Lee

et al. 2023

Cells

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Autophagy is an essential lysosome-mediated degradation pathway that maintains cellular homeostasis and viability in response to various intra- and extracellular stresses. Mitophagy is a type of autophagy that is involved in the intricate removal of dysfunctional mitochondria during conditions of metabolic stress. In this review, we describe the multifaceted roles of autophagy and mitophagy in normal physiology and the field of cancer biology. Autophagy and mitophagy exhibit dual context-dependent roles in cancer development, acting as tumor suppressors and promoters. We also discuss the important role of autophagy and mitophagy within the cancer microenvironment and how autophagy and mitophagy influence tumor host–cell interactions to overcome metabolic deficiencies and sustain the activity of cancer-associated fibroblasts (CAFs) in a stromal environment. Finally, we explore the dynamic interplay between autophagy and the immune response in tumors, indicating their potential as immunomodulatory targets in cancer therapy. As the field of autophagy and mitophagy continues to evolve, this comprehensive review provides insights into their important roles in cancer and cancer microenvironment.

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Inactivation of Autophagy in Keratinocytes Reduces Tumor Growth in Mouse Models of Epithelial Skin Cancer

Cited by 6 publications

References 51 publications

Autophagy critically controls skin inflammation and apoptosis-induced stem cell activation

Autophagy critically controls skin inflammation and apoptosis-induced stem cell activation

Photodynamic Activity of Acridine Orange in Keratinocytes under Blue Light Irradiation

Unraveling the Intricacies of Autophagy and Mitophagy: Implications in Cancer Biology

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