| 1. |
- Li, Shuijie, et al.
(author)
-
Impaired oxygen-sensitive regulation of mitochondrial biogenesis within the von Hippel–Lindau syndrome
- 2022
-
In: Nature Metabolism. - : Nature Publishing Group. - 2522-5812. ; 4:6, s. 739-758
-
Journal article (peer-reviewed)abstract
- Mitochondria are the main consumers of oxygen within the cell. How mitochondria sense oxygen levels remains unknown. Here we show an oxygen-sensitive regulation of TFAM, an activator of mitochondrial transcription and replication, whose alteration is linked to tumours arising in the von Hippel–Lindau syndrome. TFAM is hydroxylated by EGLN3 and subsequently bound by the von Hippel–Lindau tumour-suppressor protein, which stabilizes TFAM by preventing mitochondrial proteolysis. Cells lacking wild-type VHL or in which EGLN3 is inactivated have reduced mitochondrial mass. Tumorigenic VHL variants leading to different clinical manifestations fail to bind hydroxylated TFAM. In contrast, cells harbouring the Chuvash polycythaemia VHLR200W mutation, involved in hypoxia-sensing disorders without tumour development, are capable of binding hydroxylated TFAM. Accordingly, VHL-related tumours, such as pheochromocytoma and renal cell carcinoma cells, display low mitochondrial content, suggesting that impaired mitochondrial biogenesis is linked to VHL tumorigenesis. Finally, inhibiting proteolysis by targeting LONP1 increases mitochondrial content in VHL-deficient cells and sensitizes therapy-resistant tumours to sorafenib treatment. Our results offer pharmacological avenues to sensitize therapy-resistant VHL tumours by focusing on the mitochondria.
|
|
| 2. |
- Wu, Jieyu
(author)
-
Targeting stromal components in the tumor microenvironment for cancer therapy
- 2022
-
Doctoral thesis (other academic/artistic)abstract
- In the tumor microenvironment (TME), different cell components crosstalk with each other through various growth factors, cytokines, chemokines, and enzymes. They offered crucial survival signals for tumor cell proliferation and metastasis. Data presented in this thesis demonstrate approaches to target the stroma of the TME, which provided a novel paradigm for cancer therapy. It involves the conception of overcoming the resistance of conventional therapy, cut-out cancer cell energy support, and interrupting invasive assistance of cancer cells. We specifically focused on these two aspects: first, to resolve antiangiogenic drugs (AAD) resistance in those cancers with a lipid-rich environment or high FGF expression. In addition, to manipulate the brown adipose tissue (BAT) into mega BAT can be an approach in cancer therapy (Paper I-III). Second, we revealed the roles of stromal cells, including the cancerassociated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), in pancreatic ductal adenocarcinoma (PDAC) (Paper IV); and the role of CAFs in the cancer hosts with disturbed circadian rhythm (CR) (Paper V). In Paper I, we revealed the mechanism of AAD drug resistance in tumors surrounded by adipose tissue or lipid-rich environment, for example, colorectal cancer (CRC), PDAC and hepatocellular carcinoma (HCC) in the steatotic liver. Anti-VEGF-based AAD failed to reduce tumor size but triggered vessel regression in tumor tissues, leading to severe hypoxia in the TME. Hypoxia resulted in tumor metabolic reprogramming from glucose-based metabolism to free fatty acids (FFAs)-based metabolism. FFAs provided energy support to tumor cells, leading to accelerate tumor cell proliferation. Inhibition of FFA transporter reversed AAD resistance in anti-tumor effect. Our data suggested a therapeutic approach to reverse the AAD resistance in tumors with a lipid-rich environment. Our previous study revealed the cold exposure and other β3-adrenorecptor stimuli induced the brown adipose tissue (BAT) activation by increasing the non-shivering thermogenesis (NST). The activated BAT decreased blood glucose and impeded glycolysis-based metabolism in cancer cells could suppress tumor growth. In Paper II, we addressed an approach to enlarge BAT into a mega-size BAT (megaBAT) in adult animals. In BAT, the differentiation of certain progenitor cells is controlled by the platelet-derived growth factor receptor α (PDGFRα). Using pharmacological approaches and genetic deletion, we downregulated the PDGFRα in BAT progenitor cells and promoted progenitor cells differentiation into functional brown adipocytes. We found a specific microRNA to target the PDGFRα signaling in vivo. The whole BAT tissue mass was markedly increased after PDGFRα inhibition owing to the increase of brown adipocyte numbers. We found that the obese mice with megaBAT under cold exposure showed improvement in blood glucose level, insulin tolerance, and blood lipid level. Histological analysis showed that the steatotic livers were markedly reversed in obese mice with megaBAT. The megaBAT could become a therapeutic approach to treat cancer and metabolic diseases. We previously reported that fibroblast growth factor 2 (FGF-2) as one of the angiogenic factors contributed to tumor vessel remodeling by recruiting NG2 positive pericytes onto tumor vessels through the PDGFRβ signaling. Therefore, monotherapy with anti-VEGF or anti-PDGFR had become resistant in tumors with high FGF-2 expression. So far, there are no potent anti-FGF drugs available. In Paper III, we found combination therapy with anti-VEGF and anti- PDGFRβ showed superior anti-tumor effects in high FGF-2 tumors. Anti-PDGFRβ treatment suppressed pericyte recruitment, and anti-VEGF precisely targeted tumor vessels. With this study, we provided a new paradigm for resolving AAD resistance by targeting FGF-2 off-target signaling, VEGF and PDGF in cancer therapy. In Paper IV, we identified the CAFs-TAMs crosstalk through the IL-33-ST2-CXCL3-CXCR2 axis in PDAC and triggered cancer cell metastasis. Mouse and human PDAC samples under unbiased genomic-wide profiling analysis and genetic and pharmacological gain/loss-offunction experiments demonstrated a high level of IL-33 expression. IL-33 bound to its receptor ST2 on the TAMs and induced TAMs infiltration. Transcriptomic analysis identified IL-33-ST2 induced high CXCL3 expression, which was produced by TMAs. CXCL3 bound to its receptors CXCR2 on CAFs induced CAFs-myoCAF transition and cell proliferation. CAFs transited to myoCAFs had a high expression of collagen III, which induced the formation of tumor cells and myofibroblast clusters. Tumor cells increased metastasis under this tumormyofibroblasts clusters. Pharmacological targeting of this pathway would provide a potential therapeutic strategy for treating PDAC. Paper V we presented the link between CR disruption and tumor metastasis. We explored CR disruption by using a genetic model of Bmal1 gene knockout (KO) mice. Various types of tumors in Bmal1 KO mice presented high growth speed with an elevated expression of myofibroblast markers. Unbiased genomic-wide profiling using the stromal vascular fraction (SVF) from the tumors of Bmal1 KO mice demonstrated a downregulated expression of the plasminogen activator inhibitor (PAI-1) gene. The BMAL1 protein directly regulated PAI-1 gene transcription. Lacking BMAL1 resulted in low PAI-1 expression, which continuously removed the inhibition of downstream proteins, including tissue plasmin activator (tPA) and urokinase (uPA). The tPA and uPA accumulation transformed plasminogen into plasmin, which converted the latent TGF-β into active form. The active TGF-β contributed to the CAFs transition into myofibroblasts, which induced tumor tissue mass expansion and increased metastasis. Inhibition of TGF-β in tumors with CR disruption or maintenance of CR homeostasis could be a therapeutic approach to tumor therapy. Collectively, the works in this thesis uncover important roles of stromal cellular components in the TME, which lay the ground for the development of novel pharmaceutical approaches in cancer therapy.
|
|
