Deficiency in fibroblast PPARβ/δ reduces nonmelanoma skin cancers in mice

Tan, Mark Wei Yi; Sng, Ming Keat; Cheng, Hong Sheng; Low, Zun Siong; Leong, Benjamin Jia Juin; Chua, Damien; Tan, Eddie Han Pin; Chan, Jeremy Soon Kiat; Yip, Yun Sheng; Lee, Yin Hao; Pal, Mintu; Wahli, Walter; Tan, Nguan Soon

doi:10.1038/s41418-020-0535-y

Cited by 11 publications

(14 citation statements)

References 40 publications

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“…Our finding is in line with another recent study that demonstrated that c-MET activation triggered the nuclear localization of Nrf2 and its downstream effector, heme oxygenase-1, to resolve drug-induced oxidative stress in renal tumors 56 . Coincidentally, PI3K/Akt pathway also acts as an activator of Nrf2 transcription and nuclear translocation to modulate redox homeostasis and enhance cancer survival during carcinogenesis 57 , 58 . Hence, cancer cells can actuate c-MET-PI3K-Nrf2 signaling cascade upon hypoxia exposure to mitigate the imminent threat from oxidative stress buildup while more complex defense machineries (i.e., angiogenesis and epithelial-to-mesenchymal transition) take effect to preserve their long-term survival.…”

Section: Discussionmentioning

confidence: 99%

Kinomic profile in patient-derived glioma cells during hypoxia reveals c-MET-PI3K dependency for adaptation

Cheng¹,

Marvalim²,

Zhu³

et al. 2021

Theranostics

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Hypoxic microenvironment is a hallmark of solid tumors, especially glioblastoma. The strong reliance of glioma-propagating cells (GPCs) on hypoxia-induced survival advantages is potentially exploitable for drug development. Methods: To identify key signaling pathways for hypoxia adaptation by patient-derived GPCs, we performed a kinase inhibitor profiling by screening 188 small molecule inhibitors against 130 different kinases in normoxia and hypoxia. Potential kinase candidates were prioritized for in vitro and in vivo investigations using a ranking algorithm that integrated information from the kinome connectivity network and estimated patients' survival based on expression status. Results: Hypoxic drug screen highlighted extensive modifications of kinomic landscape and a crucial functionality of c-MET-PI3K. c-MET inhibitors diminished phosphorylation of c-MET and PI3K in GPCs subjected to hypoxia, suggesting its role in the hypoxic adaptation of GPCs. Mechanistically, the inhibition of c-MET and PI3K impaired antioxidant defense, leading to oxidative catastrophe and apoptosis. Repurposed c-MET inhibitors PF04217903 and tivantinib exhibited hypoxic-dependent drug synergism with temozolomide, resulting in reduced tumor load and growth of GPC xenografts. Detailed analysis of bulk and single-cell glioblastoma transcriptomes associates the cellular subpopulation over-expressing c-MET with inflamed, hypoxic, metastatic, and stem-like phenotypes. Conclusions: Thus, our “bench to bedside (the use of patient-derived GPCs and xenografts for basic research) and back (validation with independent glioblastoma transcriptome databases)” analysis unravels the novel therapeutic indications of c-MET and PI3K/Akt inhibitors for the treatment of glioblastoma, and potentially other cancers, in the hypoxic tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

Kinomic profile in patient-derived glioma cells during hypoxia reveals c-MET-PI3K dependency for adaptation

Cheng¹,

Marvalim²,

Zhu³

et al. 2021

Theranostics

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“…CAFs can disrupt the local ECM and deliver proliferative paracrine signals to support tumorigenic events. Interestingly, mice with fibroblast-selective PPARβ/δ deletion developed fewer and smaller skin tumors than wild-type mice exposed to topical carcinogens [ 85 ]. Similar results were recapitulated using chemically and genetically induced intestinal carcinogenesis in these mutant mice [ 86 ], indicating that PPARβ/δ activity in stromal fibroblasts promotes tumor initiation.…”

Section: The Roles Of Ppars In Stromal Cells In the Tumor Microenviromentioning

confidence: 99%

“…Mechanistically, PPARβ/δ-knockout fibroblasts markedly increase the Nox4-derived H 2 O 2 production in the adjacent epidermis, subsequently triggering an RAF/MEK-mediated NRF2 activation that elicits a strong antioxidant and cytoprotective response [ 85 ]. By reducing the phosphorylation of many tumor suppressors and oncogenes, NRF2 also increases the tumor suppressor activity of PTEN and reduces the oncogenic activity of Src and Akt, leading to delayed tumor growth [ 85 ]. Hence, reducing the expression and activity of PPARβ/δ in CAFs may provide a new therapeutic option to disrupt cancer susceptibility in the neighboring tumor epidermis.…”

Section: The Roles Of Ppars In Stromal Cells In the Tumor Microenviromentioning

confidence: 99%

“…PPARβ/δ in fibroblasts upregulates the expression of LRG1, which blunts the epidermal response to TGFβ1 [ 87 ]. Furthermore, exogenous LRG1 can also ablate the influence of TGFβ1 on ROS generation and NRF2 activity [ 85 ]. In colorectal carcinoma and pancreatic ductal adenocarcinoma patients, the level of LRG1 in the TME and bloodstream is significantly higher than in healthy individuals and correlates positively with a more advanced cancer stage and poorer prognosis [ 88 , 89 , 90 ].…”

Section: The Roles Of Ppars In Stromal Cells In the Tumor Microenviromentioning

confidence: 99%

“…Hence, PPAR-independent activities on the carcinogenesis caused by the non-specificity of the PPAR modulators cannot be eliminated. However, many functional studies of PPAR in the TME were also reinforced by results from genetically knockout models [ 85 , 111 , 127 , 128 ]. Therefore, the pharmacodynamic and pharmacokinetic variations of synthetic PPAR ligands may not fully account for the observed discrepancies.…”

Section: Knowledge Gaps and Prospects Of Targeting Ppars In Tumor Stromamentioning

confidence: 99%

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PPARs and Tumor Microenvironment: The Emerging Roles of the Metabolic Master Regulators in Tumor Stromal–Epithelial Crosstalk and Carcinogenesis

Cheng

Yip

Lim

et al. 2021

Cancers

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Peroxisome proliferator-activated receptors (PPARs) have been extensively studied for more than three decades. Consisting of three isotypes, PPARα, γ, and β/δ, these nuclear receptors are regarded as the master metabolic regulators which govern many aspects of the body energy homeostasis and cell fate. Their roles in malignancy are also increasingly recognized. With the growing interest in crosstalk between tumor stroma and epithelium, this review aims to highlight the current knowledge on the implications of PPARs in the tumor microenvironment. PPARγ plays a crucial role in the metabolic reprogramming of cancer-associated fibroblasts and adipocytes, coercing the two stromal cells to become substrate donors for cancer growth. Fibroblast PPARβ/δ can modify the risk of tumor initiation and cancer susceptibility. In endothelial cells, PPARβ/δ and PPARα are pro- and anti-angiogenic, respectively. Although the angiogenic role of PPARγ remains ambiguous, it is a crucial regulator in autocrine and paracrine signaling of cancer-associated fibroblasts and tumor-associated macrophages/immune cells. Of note, angiopoietin-like 4 (ANGPTL4), a secretory protein encoded by a target gene of PPARs, triggers critical oncogenic processes such as inflammatory signaling, extracellular matrix derangement, anoikis resistance and metastasis, making it a potential drug target for cancer treatment. To conclude, PPARs in the tumor microenvironment exhibit oncogenic activities which are highly controversial and dependent on many factors such as stromal cell types, cancer types, and oncogenesis stages. Thus, the success of PPAR-based anticancer treatment potentially relies on innovative strategies to modulate PPAR activity in a cell type-specific manner.

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Signaling pathways in cancer‐associated fibroblasts: recent advances and future perspectives

Fang

Meng

et al. 2022

Cancer Communications

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As a critical component of the tumor microenvironment (TME), cancer‐associated fibroblasts (CAFs) play important roles in cancer initiation and progression. Well‐known signaling pathways, including the transforming growth factor‐β (TGF‐β), Hedgehog (Hh), Notch, Wnt, Hippo, nuclear factor kappa‐B (NF‐κB), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen‐activated protein kinase (MAPK), and phosphoinositide 3‐kinase (PI3K)/AKT pathways, as well as transcription factors, including hypoxia‐inducible factor (HIF), heat shock transcription factor 1 (HSF1), P53, Snail, and Twist, constitute complex regulatory networks in the TME to modulate the formation, activation, heterogeneity, metabolic characteristics and malignant phenotype of CAFs. Activated CAFs remodel the TME and influence the malignant biological processes of cancer cells by altering the transcriptional and secretory characteristics, and this modulation partially depends on the regulation of signaling cascades. The results of preclinical and clinical trials indicated that therapies targeting signaling pathways in CAFs demonstrated promising efficacy but were also accompanied by some failures (e.g., NCT01130142 and NCT01064622). Hence, a comprehensive understanding of the signaling cascades in CAFs might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the development of more efficient and safer stroma‐targeted cancer therapies. Here, we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.

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Deficiency in fibroblast PPARβ/δ reduces nonmelanoma skin cancers in mice

Cited by 11 publications

References 40 publications

Kinomic profile in patient-derived glioma cells during hypoxia reveals c-MET-PI3K dependency for adaptation

Kinomic profile in patient-derived glioma cells during hypoxia reveals c-MET-PI3K dependency for adaptation

PPARs and Tumor Microenvironment: The Emerging Roles of the Metabolic Master Regulators in Tumor Stromal–Epithelial Crosstalk and Carcinogenesis

Signaling pathways in cancer‐associated fibroblasts: recent advances and future perspectives

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