bims-stacyt 2023-09-24 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2023‒09‒24
six papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Dietary fat and lipid metabolism in the tumor microenvironment.
GDF15 affects venous thrombosis by promoting EndMT through smad2/p-smad2 pathway.
Endoplasmic Reticulum Stress in Pancreatic β-Cells Induces Incretin Desensitization and β-Cell Dysfunction via ATF4-Mediated PDE4D Expression.
Suppression of tumor cell lactate-generating signaling pathways eradicates murine PTEN/p53-deficient aggressive-variant prostate cancer via macrophage phagocytosis.
Stem cell factor modulates HIF-1α levels and diminishes 5-FU sensitivity in 5-FU resistant pancreatic cells by altering the anabolic glucose metabolism.
PERK Inhibition by HC-5404 Sensitizes Renal Cell Carcinoma Tumor Models to Antiangiogenic Tyrosine Kinase Inhibitors.

Biochim Biophys Acta Rev Cancer. 2023 Sep 16. pii: S0304-419X(23)00133-6. [Epub ahead of print] 188984

Dietary fat and lipid metabolism in the tumor microenvironment.

Swagata Goswami, Qiming Zhang, Cigdem Elif Celik, Ethan M Reich, Ömer H Yilmaz.

  Metabolic reprogramming has been considered a core hallmark of cancer, in which excessive accumulation of lipids promote cancer initiation, progression and metastasis. Lipid metabolism is often considered as the digestion and absorption process of dietary fat, and the ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment. Among multiple cancer risk factors, obesity has a positive association with multiple cancer types, while diets like calorie restriction and fasting improve health and delay cancer. Impact of these diets on tumorigenesis or cancer prevention are generally studied on cancer cells, despite heterogeneity of the tumor microenvironment. Cancer cells regularly interact with these heterogeneous microenvironmental components, including immune and stromal cells, to promote cancer progression and metastasis, and there is an intricate metabolic crosstalk between these compartments. Here, we focus on discussing fat metabolism and response to dietary fat in the tumor microenvironment, focusing on both immune and stromal components and shedding light on therapeutic strategies surrounding lipid metabolic and signaling pathways.

Keywords:  Fatty acid; High fat diet; Immunosuppression; Lipid metabolism; Obesity; Therapeutic intervention; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2023.188984
Thromb J. 2023 Sep 18. 21(1): 98

GDF15 affects venous thrombosis by promoting EndMT through smad2/p-smad2 pathway.

Yeping Li, Huiqi Zhu, Wanghao Xin, Jiaoyan Wang, Chao Yan, Kejing Ying.

  BACKGROUND: Endothelial-to-mesenchymal transition (EndMT) is a pathophysiological change in the vascular endothelium commonly seen in the cardiovascular system. Elevated serum Growth differiention factor 15 (GDF15) has been reported in VTE patients, but the relationship and mechanism between GDF15, EndMT and VTE are still unclear.METHODS: We performed a retrospective clinical study, and human serum GDF15 expression levels were detected. The mouse DVT model was established through subtotal ligation of the mouse inferior vena cava, and then we detected intimal changes and thrombi in the stenotic inferior vena cava by haematoxylin-eosin (HE) staining, Masson staining, and Sirius Red staining. The expression levels of GDF15 and SM22 were detected by immunohistochemistry and RT‒qPCR. Serum samples of mice were collected, and the expression level of GDF15 in serum was detected. Human umbilical vein endothelial cells (HUVECs) were stimulated with a cytokine mixture (TGF-β1 + TNF-α + IL-1β). The role and mechanism of GDF15 in EndMT and VTE were detected in HUVECs and in a DVT mice model.
RESULTS: We found that serum GDF15 levels in both VTE patients and mouse DVT models were higher than those in the control group. EndMT was increased in the stenotic vascular tissue of mice. Further experiments showed that GDF15 could promote the EndMT of HUVECs and reduce their anticoagulation and antifibrinolytic ability through the smad2/p-smad2/snail pathway. Inhibition of mature GDF15 release can significantly reduce venous thrombotic fibre deposition in mice.
CONCLUSIONS: GDF15 positively promotes EndMT through activation of the Smad2/psmad2/snail pathway, and inhibition of GDF15 expression can alleviate the EndMT process, further improving the coagulation and fibrinolytic function of endothelial cells and thus reducing the local fibre deposition of venous thrombi.

Keywords:  Endothelial-to-mesenchymal transition (EndMT); Growth Differentiation Factor 15 (GDF15); Venous thromboembolism

DOI:  https://doi.org/10.1186/s12959-023-00547-7
Am J Physiol Endocrinol Metab. 2023 Sep 20.

Endoplasmic Reticulum Stress in Pancreatic β-Cells Induces Incretin Desensitization and β-Cell Dysfunction via ATF4-Mediated PDE4D Expression.

Ji-Hye Lee, Hanguk Ryu, Hyejin Lee, Hye Ram Yu, Yurong Gao, Kyeong-Min Lee, Young-Joon Kim, Jaemin Lee.

  Pancreatic β-cell dysfunction and eventual loss are key steps in the progression of type 2 diabetes (T2D). Endoplasmic reticulum (ER) stress responses, especially those mediated by the PERK-ATF4 pathway, have been implicated in promoting these β-cell pathologies. However, the exact molecular events surrounding the role of the PERK-ATF4 pathway in β-cell dysfunction remain unknown. Here, we report our discovery that ATF4 promotes the expression of PDE4D, which disrupts β-cell function via a downregulation of cAMP signaling. We found that β-cell-specific transgenic expression of ATF4 led to early β-cell dysfunction and loss, a phenotype that resembles accelerated T2D. Expression of ATF4, rather than CHOP, promoted PDE4D expression, reduced cAMP signaling, and attenuated responses to incretins and elevated glucose. Furthermore, we found that β-cells of leptin receptor-deficient diabetic (db/db) mice had elevated nuclear localization of ATF4 and PDE4D expression, accompanied by impaired β-cell function. Accordingly, pharmacological inhibition of the ATF4 pathway attenuated PDE4D expression in the islets and promoted incretin-simulated glucose tolerance and insulin secretion in db/db mice. Finally, we found that inhibiting PDE4 activity with selective pharmacological inhibitors improved β-cell function in both db/db mice and β-cell-specific ATF4 transgenic mice. In summary, our results indicate that ER stress causes β-cell failure via ATF4-mediated PDE4D production, suggesting the ATF4-PDE4D pathway could be a therapeutic target for protecting β-cell function during the progression of T2D.

Keywords:  ATF4; ER stress; PDE4D; beta cell dysfunction; incretin resistance

DOI:  https://doi.org/10.1152/ajpendo.00156.2023
Clin Cancer Res. 2023 Sep 18.

Suppression of tumor cell lactate-generating signaling pathways eradicates murine PTEN/p53-deficient aggressive-variant prostate cancer via macrophage phagocytosis.

Kiranj Chaudagar, Hanna M Hieromnimon, Anne Kelley, Brian Labadie, Jordan Shafran, Srikrishnan Rameshbabu, Catherine Drovetsky, Kaela Bynoe, Ani Solanki, Erica Markiewicz, Xiaobing Fan, Massimo Loda, Akash Patnaik.

PURPOSE: PTEN loss-of-function/PI3K pathway hyperactivation is associated with poor therapeutic outcomes and immune checkpoint inhibitor resistance across multiple malignancies. Our prior studies in Pb-Cre;PTENfl/flTrp53fl/fl genetically engineered mice (GEM) with aggressive-variant prostate cancer (AVPC) demonstrated tumor growth control in 60% mice following androgen deprivation therapy (ADT)/PI3K inhibitor (PI3Ki)/PD-1 antibody combination, via abrogating lactate cross-talk between cancer cells and tumor-associated macrophages (TAM), and suppression of histone lactylation (H3K18lac)/phagocytic activation within TAM. Here, we targeted immunometabolic mechanism(s) of PI3Ki resistance, with the goal of durable tumor control in AVPC.EXPERIMENTAL DESIGN: Pb-Cre;PTENfl/flTrp53fl/fl GEM were treated with PI3Ki (copanlisib), MEK inhibitor (trametinib) or Porcupine inhibitor (LGK`974) singly or their combinations. MRI was used to monitor tumor kinetics and immune/proteomic profiling/ex vivo co-culture mechanistic studies were performed on GEM tumors or corresponding tumor-derived cell lines.
RESULTS: Given our proteomic profiling showing persistent MEK signaling within tumors of PI3Ki-resistant GEM, we tested whether addition of trametinib to copanlisib enhances tumor control in GEM, and observed 80% overall response rate via additive suppression of lactate within TME and H3K18lac within TAM, relative to copanlisib (37.5%) monotherapy. The 20% resistant mice demonstrated feedback Wnt/b-catenin activation, resulting in restoration of lactate secretion by tumor cells and H3K18lac within TAM. Co-targeting Wnt/b-catenin signaling with LGK'974 in combination with PI3Ki/MEKi, demonstrated durable tumor control in 100% mice via H3K18lac suppression and complete TAM activation.
CONCLUSIONS: Abrogation of lactate-mediated cross-talk between cancer cells and TAM results in durable ADT-independent tumor control in PTEN/p53-deficient AVPC, and warrants further investigation in clinical trials.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-1441
J Biochem Mol Toxicol. 2023 Sep 17. e23487

Stem cell factor modulates HIF-1α levels and diminishes 5-FU sensitivity in 5-FU resistant pancreatic cells by altering the anabolic glucose metabolism.

Fu Xiang, Fuwen Luo.

  Resistance to chemotherapy in cancer leads to poor therapeutic outcomes and also leads to challenges in treatment. The present work evaluated the mechanism involved in the resistance of 5-flurouracil (5-FU) in pancreatic cancer. At least 14 different pancreatic cancer (PC) cell lines were used for the study. For in vivo study female nude mice were selected. Patient-derived tumor xenograft samples were obtained from patients. The study involved, study for glucose uptake, fluorescence-activated cell sorting for glucose transporter, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide for cell survival, Picto-micrography for clonogenic assay, glutamine uptake assay, extracellular acidification and oxygen consumption rate, carbon dioxide release assay and lactate assay were also done. In addition to this, quantitative real-time polymerase chain reaction analysis for expression of genes, chromatin immunoprecipitation assay, western blot for protein expression, and immunohistochemical analysis in tumor sections, the tumors were studied by imaging for hypoxia and localization of TKT and CTPS-2. Also, patient-derived xenograft tumors were engrafted in nude mice, followed by a glucose uptake assay. We reported that elevated glycolytic flux causes dependence on glucose in cancer cells and, at the same time, increases pyrimidine biosynthesis. It was also found that stem cell factor-mediated stabilization of hypoxia-inducible factor-1a (HIF-1α) modulates the resistance in PC. Targeting HIF-1α in combination with 5-FU, strongly reduced the tumor burden. The study concludes that stem cell factor modulates HIF-1α and decreases the sensitivity in 5-FU resistant pancreatic cancer cells by targeting glucose metabolism. Deceased expression levels of CTPS-2 and TKT, which are regulators of pyrimidine biosynthesis could better the chance of survival in patients of pancreatic cancer receiving treatment of 5-FU.

Keywords:  CTPS1; HIF-1α; TKT; pancreatic cancer

DOI:  https://doi.org/10.1002/jbt.23487
Clin Cancer Res. 2023 Sep 21.

PERK Inhibition by HC-5404 Sensitizes Renal Cell Carcinoma Tumor Models to Antiangiogenic Tyrosine Kinase Inhibitors.

Michael E Stokes, Veronica Calvo, Sho Fujisawa, Crissy Dudgeon, Sharon Huang, Nupur Ballal, Leyi Shen, Jennifer Gasparek, Matthew Betzenhauser, Simon J Taylor, Kirk A Staschke, Alan C Rigby, Mark J Mulvihill, Nandita Bose, Eric S Lightcap, David Surguladze.

PURPOSE: Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a stress-mitigation strategy. Here, we tested the hypothesis that inhibiting PERK with HC-5404 enhances the antitumor efficacy of standard-of-care vascular endothelial growth factor tyrosine kinase inhibitors (VEGFR-TKIs).EXPERIMENTAL DESIGN: HC-5404 was characterized as a potent and selective PERK inhibitor, with favorable in vivo properties. Multiple renal cell carcinoma (RCC) tumor models were then co-treated with both HC-5404 and VEGFR-TKIs in vivo, measuring tumor volume across time and evaluating tumor response by protein analysis and IHC.
RESULTS: VEGFR-TKIs including axitinib, cabozantinib, lenvatinib, and sunitinib induce PERK activation in 786-O RCC xenografts. Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKIs across multiple RCC models, resulting in tumor stasis or regression. Analysis of tumor sections revealed that HC-5404 enhanced the antiangiogenic effects of axitinib and lenvatinib by inhibiting both new vasculature and mature tumor blood vessels. Xenografts that progress on axitinib monotherapy remain sensitive to the combination treatment, resulting in ~20% tumor regression in the combination group. When tested across a panel of 18 RCC patient-derived xenograft (PDX) models, the combination induced greater antitumor effects relative to monotherapies. In this single animal study, 9/18 models responded with ≥50% tumor regression from baseline in the combination group.
CONCLUSIONS: By disrupting an adaptive stress response evoked by VEGFR-TKIs, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard of care therapies in RCC.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-1182