Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis

Zhao, Xiao Ling; Psarianos, Pamela; Ghoraie, Laleh Soltan; Yip, Kenneth W.; Goldstein, David; Gilbert, Ralph W.; Witterick, Ian J.; Pang, Hilary; Hussain, Ali; Lee, Ju Hee; Williams, Joanna M.; Bratman, Scott V.; Ailles, Laurie; Haibe‐Kains, Benjamin; Liu, Feifei

doi:10.1038/s42255-018-0008-5

Cited by 162 publications

(149 citation statements)

References 33 publications

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“…Here, for the first time, we identified that type XI collagen in the tumor microenvironment can switch the metabolic preferences of ovarian cancer cells toward FAO. While type I collagen has been shown to upregulate glycolysis 48 , our data show that type I collagen does not upregulate FAO in ovarian cancer cells. In contrast, COL11A1 does not change glycolysis, yet preferentially upregulates fatty acid metabolism to promote cisplatin resistance in ovarian cancer cells.…”

Section: Discussioncontrasting

confidence: 56%

Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer

et al. 2020

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Collagen type XI alpha 1 (COL11A1) is a novel biomarker associated with cisplatin resistance in ovarian cancer. However, the mechanisms underlying how COL11A1 confers cisplatin resistance in ovarian cancer are poorly understood. We identified that fatty acid β-oxidation (FAO) is upregulated by COL11A1 in ovarian cancer cells and that COL11A1-driven cisplatin resistance can be abrogated by inhibition of FAO. Furthermore, our results demonstrate that COL11A1 also enhances the expression of proteins involved in fatty acid synthesis. Interestingly, COL11A1-induced upregulation of fatty acid synthesis and FAO is modulated by the same signaling molecules. We identified that binding of COL11A1 to its receptors, α1β1 integrin and discoidin domain receptor 2 (DDR2), activates Src-Akt-AMPK signaling to increase the expression of both fatty acid synthesis and oxidation enzymes, although DDR2 seems to be the predominant receptor. Inhibition of fatty acid synthesis downregulates FAO despite the presence of COL11A1, suggesting that fatty acid synthesis might be a driver of FAO in ovarian cancer cells. Taken together, our results suggest that COL11A1 upregulates fatty acid metabolism in ovarian cancer cells in a DDR2-Src-Akt-AMPK dependent manner. Therefore, we propose that blocking FAO might serve as a promising therapeutic target to treat ovarian cancer, particularly cisplatin-resistant recurrent ovarian cancers which typically express high levels of COL11A1.

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Section: Discussioncontrasting

confidence: 56%

Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer

et al. 2020

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“…The phagosome, the intracellular vacuolar compartment generated during phagocytosis, fuses with the regulated PPAR gene, which is involved in osteoclast differentiation processes, was recently shown to 529 induce a lysosome-controlled ECM catabolism [83]. In line with these results, matrix resorption in our 530 degraded tendon model might be accelerated by lysosomal proteases upon release from lysosomal 531 vesicles that fuse with the plasma membrane as cathepsins were found both in tissue proteome and 532 secretome [84].…”

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confidence: 67%

Tendon response to matrix unloading is determined by the patho-physiological niche

Wunderli

Blache

Piccoli

et al. 2019

Preprint

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1Aberrant matrix turnover with elevated matrix proteolysis is a hallmark of tendon pathology. While 2 tendon disease mechanisms remain obscure, mechanical cues are central regulators. Unloading of 3 tendon explants in standard culture conditions provokes rapid cell-mediated tissue breakdown. Here we 4 show that biological response to tissue unloading depends on the mimicked physiological context. Our 5 experiments reveal that explanted tendon tissues remain functionally stable in a simulated avascular 6 niche of low temperature and oxygen, regardless of the presence of serum. This hyperthermic and 7 hyperoxic niche-dependent catabolic switch was shown by whole transcriptome analysis (RNA-seq) to 8 be a strong pathological driver of an immune-modulatory phenotype, with a stress response to reactive 9 oxygen species (ROS) and associated activation of catabolic extracellular matrix proteolysis that 10 involved lysosomal activation and transcription of a range of proteolytic enzymes. Secretomic and 11 degradomic analysis through terminal amine isotopic labeling of substrates (TAILS) confirmed that 12 proteolytic activity in unloaded tissues was strongly niche dependent. Through targeted 13 pharmacological inhibition we isolated ROS mediated oxidative stress as a major checkpoint for matrix 14 proteolysis. We conclude from these data that the tendon stromal compartment responds to traumatic 15 mechanical unloading in a manner that is highly dependent on the extrinsic niche, with oxidative stress 16 response gating the proteolytic breakdown of the functional collagen backbone. tendon fibroblasts in a collagen-rich extracellular matrix (ECM). The fact that tendons bear 20 physiologically extreme mechanical stresses is reflected by its tightly packed and highly structured 21 ECM. The load bearing tendon core is comprised by hierarchically organized type-I collagen fibrils, 22 fibres and fascicles (or fibre bundles) [1], with fascicles representing the basic functional load-bearing 23 unit of stromal tissue [2,3]. Physiological mechanical signals are understood to regulate the lifelong 24 adaption of the tissue to individual functional demands [4][5][6][7][8], with a narrow gap between beneficial and 25 detrimental mechanical loads [9][10][11][12]. This threshold is often exceeded, with tendon disorders 26 accounting for 30 -50% of all musculoskeletal clinical complaints associated with pain [13]. 27Our basic knowledge of the molecular and cellular mechanisms behind tendon physiology and 28 pathology is limited [14][15][16], yet damage and inadequate repair are considered to be central to tendon 29 disease onset and progression [17][18][19]. The stimuli that trigger tissue healing responses remain unclear, 30 potentially being a direct effect of cellular activation by overloading or by unloading after isolated fibre 31 rupture with subsequently altered cell-matrix interaction [20]. However, the mechanisms of 32 overloading and underloading may not be mutually exclusive, with tissue damage resulting in localized 33 regions...

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“…The skin is the largest organ in the human body and provides a protective barrier against microorganisms, injuries and water loss [1]. Approximately 70% of its dry weight is formed by the extracellular matrix (ECM) [2]. The synthesis, deposition and remodelling of the ECM is critical for the maintenance of tissue homoeostasis under physiological conditions.…”

Section: Introductionmentioning

confidence: 99%

Activin A-Mediated Regulation of XT-I in Human Skin Fibroblasts

Plümers

Fischer

et al. 2020

Biomolecules

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Fibrosis is a fundamental feature of systemic sclerosis (SSc) and is characterized by excessive accumulation of extracellular matrix components like proteoglycans (PG) or collagens in skin and internal organs. Serum analysis from SSc patients showed an increase in the enzyme activity of xylosyltransferase (XT), the initial enzyme in PG biosynthesis. There are two distinct XT isoforms—XT-I and XT-II—in humans, but until now only XT-I is associated with fibrotic remodelling for an unknown reason. The aim of this study was to identify new XT mediators and clarify the underlying mechanisms, in view of developing putative therapeutic anti-fibrotic interventions in the future. Therefore, we used different cytokines and growth factors, small molecule inhibitors as well as small interfering RNAs, and assessed the cellular XT activity and XYLT1 expression in primary human dermal fibroblasts by radiochemical activity assays and qRT-PCR. We identified a new function of activin A as a regulator of XYLT1 mRNA expression and XT activity. While the activin A-induced XT-I increase was found to be mediated by activin A receptor type 1B, MAPK and Smad pathways, the activin A treatment did not alter the XYLT2 expression. Furthermore, we observed a reciprocal regulation of XYLT1 and XYLT2 transcription after inhibition of the activin A pathway components. These results improve the understanding of the differential expression regulation of XYLT isoforms under pathological fibroproliferative conditions.

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Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis

Cited by 162 publications

References 33 publications

Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer

Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer

Tendon response to matrix unloading is determined by the patho-physiological niche

Activin A-Mediated Regulation of XT-I in Human Skin Fibroblasts

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