Conversion of cancer-associated fibroblasts from pro- to antitumor improves the sensitivity of pancreatic cancer to chemotherapeutics

Previous therapeutic attempts to deplete cancer-associated fibroblasts (CAFs) or inhibit their proliferation in pancreatic ductal adenocarcinoma (PDAC) were not successful in mice or patients. Thus, CAFs may be tumor suppressive or heterogeneous, with distinct cancer-restraining and -promoting CAFs (rCAFs and pCAFs, respectively). Here, we show that induced expression of the glycosylphosphatidylinositol-anchored protein Meflin, a rCAF-specific marker, in CAFs by genetic and pharmacological approaches improved the chemosensitivity of mouse PDAC. A chemical library screen identified Am80, a synthetic, non-natural retinoid, as a reagent that effectively induced Meflin expression in CAFs. Am80 administration improved the sensitivity of PDAC to chemotherapeutics, accompanied by increases in tumor vessel area and intratumoral drug delivery. Mechanistically, Meflin was involved in the suppression of tissue stiffening by interacting with lysyl oxidase to inhibit its collagen crosslinking activity. These data suggested that modulation of CAF heterogeneity may represent a strategy for PDAC treatment.

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Lysyl Oxidase Enhances Warburg Effect to Mediate Reciprocal Interactions between Tumor Cells and Cancer Associated Fibroblasts in Liver Metastasis of Gastric Cancer

SSRN Electronic Journal ◽

10.2139/ssrn.3427293 ◽

2019 ◽

Author(s):

Qing Li ◽

Chunchao Zhu ◽

Bo Ni ◽

Zizhen Zhang ◽

Shuheng Jiang ◽

...

Keyword(s):

Gastric Cancer ◽

Liver Metastasis ◽

Tumor Cells ◽

Warburg Effect ◽

Lysyl Oxidase ◽

Cancer Associated Fibroblasts ◽

Reciprocal Interactions

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Interactions between Cancer-Associated Fibroblasts and T Cells in the Pancreatic Tumor Microenvironment and the Role of Chemokines

Cancers ◽

10.3390/cancers13122995 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2995

Author(s):

Laia Gorchs ◽

Helen Kaipe

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Current Knowledge ◽

Ductal Adenocarcinoma ◽

Pancreatic Tumors ◽

Cell Trafficking ◽

Cancer Associated Fibroblasts ◽

Cell Axis ◽

Combinational Treatment

Less than 10% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) survive 5 years or more, making it one of the most fatal cancers. Accumulation of T cells in pancreatic tumors is associated with better prognosis, but immunotherapies to enhance the anti-tumor activity of infiltrating T cells are failing in this devastating disease. Pancreatic tumors are characterized by a desmoplastic stroma, which mainly consists of activated cancer-associated fibroblasts (CAFs). Pancreatic CAFs have emerged as important regulators of the tumor microenvironment by contributing to immune evasion through the release of chemokines, cytokines, and growth factors, which alters T-cell migration, differentiation and cytotoxic activity. However, recent discoveries have also revealed that subsets of CAFs with diverse functions can either restrain or promote tumor progression. Here, we discuss our current knowledge about the interactions between CAFs and T cells in PDAC and summarize different therapy strategies targeting the CAF–T cell axis with focus on CAF-derived soluble immunosuppressive factors and chemokines. Identifying the functions of different CAF subsets and understanding their roles in T-cell trafficking within the tumor may be fundamental for the development of an effective combinational treatment for PDAC.

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Newly Identified Antibacterial Compounds Are Topoisomerase Poisons in African Trypanosomes

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01025-09 ◽

2009 ◽

Vol 54 (2) ◽

pp. 620-626 ◽

Cited By ~ 8

Author(s):

Sonya C. Tang ◽

Theresa A. Shapiro

Keyword(s):

Topoisomerase Ii ◽

Protozoan Parasite ◽

New Drugs ◽

Chemical Library ◽

African Trypanosomes ◽

Topoisomerase Poisons ◽

Type Ia ◽

Library Screen ◽

Circular Dnas ◽

Current Therapies

ABSTRACT Human African trypanosomiasis, caused by the Trypanosoma brucei protozoan parasite, is fatal when left untreated. Current therapies are antiquated, and there is a need for new pharmacologic agents against T. brucei targets that have no human ortholog. Trypanosomes have a single mitochondrion with a unique mitochondrial DNA, known as kinetoplast DNA (kDNA), a topologically complex network that contains thousands of interlocking circular DNAs, termed minicircles (∼1 kb) and maxicircles (∼23 kb). Replication of kDNA depends on topoisomerases, enzymes that catalyze reactions that change DNA topology. T. brucei has an unusual type IA topoisomerase that is dedicated to kDNA metabolism. This enzyme has no ortholog in humans, and RNA interference (RNAi) studies have shown that it is essential for parasite survival, making it an ideal drug target. In a large chemical library screen, two compounds were recently identified as poisons of bacterial topoisomerase IA. We found that these compounds are trypanocidal in the low micromolar range and that they promote the formation of linearized minicircles covalently bound to protein on the 5′ end, consistent with the poisoning of mitochondrial topoisomerase IA. Surprisingly, however, band depletion studies showed that it is topoisomerase IImt, and not topoisomerase IAmt, that is trapped. Both compounds are planar aromatic polycyclic structures that intercalate into and unwind DNA. These findings reinforce the utility of topoisomerase IImt as a target for development of new drugs for African sleeping sickness.

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ToxCast chemical library screen identifies diethanolamine as an activator of Wnt signaling

10.1101/2021.02.15.430319 ◽

2021 ◽

Author(s):

Justin M. Wolter ◽

Jessica A. Jimenez ◽

Jason L. Stein ◽

Mark J. Zylka

Keyword(s):

Wnt Signaling ◽

Human Exposure ◽

Neural Progenitor Cell ◽

Autism Spectrum ◽

Chemical Library ◽

Gain Of Function ◽

Agricultural Pesticides ◽

Library Screen ◽

Hormone Analogs ◽

Mutant Construct

AbstractNumerous autism spectrum disorder (ASD) risk genes are associated with Wnt signaling, suggesting that brain development may be especially sensitive to genetic perturbation of this pathway. Additionally, valproic acid, which modulates Wnt signaling, increases risk for ASD when taken during pregnancy. We previously found that an autism-linked gain-of-function UBE3AT485A mutant construct hyperactivated canonical Wnt signaling, providing a genetic means to elevate Wnt signaling above baseline levels. To identify environmental use chemicals that enhance or suppress Wnt signaling, we screened the ToxCast Phase I and II libraries in cells expressing this autism linked UBE3AT485 gain-of-function mutant construct. Using structural comparisons, we identify classes of chemicals that stimulated Wnt signaling, including ethanolamines, as well as chemicals that inhibited Wnt signaling, such as agricultural pesticides, and synthetic hormone analogs. To prioritize chemicals for follow-up, we leveraged predicted human exposure data, and identified diethanolamine (DEA) as a chemical that both stimulates Wnt signaling in UBE3AT485A–transfected cells and has a high potential for prenatal exposure in humans. DEA also enhanced proliferation in two primary human neural progenitor cell lines. Overall, this study identifies chemicals with the potential for human exposure that influence Wnt signaling in human cells.

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Collagen Biosynthesis, Processing, and Maturation in Lung Ageing

Frontiers in Medicine ◽

10.3389/fmed.2021.593874 ◽

2021 ◽

Vol 8 ◽

Author(s):

Ceylan Onursal ◽

Elisabeth Dick ◽

Ilias Angelidis ◽

Herbert B. Schiller ◽

Claudia A. Staab-Weijnitz

Keyword(s):

Lung Disease ◽

Cell Function ◽

Lysyl Oxidase ◽

Advanced Glycation Endproducts ◽

Mouse Lung ◽

Chronic Obstructive ◽

Collagen Biosynthesis ◽

Collagen Crosslinks ◽

Collagen Crosslinking ◽

Chronic Lung Diseases

In addition to providing a macromolecular scaffold, the extracellular matrix (ECM) is a critical regulator of cell function by virtue of specific physical, biochemical, and mechanical properties. Collagen is the main ECM component and hence plays an essential role in the pathogenesis and progression of chronic lung disease. It is well-established that many chronic lung diseases, e.g., chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) primarily manifest in the elderly, suggesting increased susceptibility of the aged lung or accumulated alterations in lung structure over time that favour disease. Here, we review the main steps of collagen biosynthesis, processing, and turnover and summarise what is currently known about alterations upon lung ageing, including changes in collagen composition, modification, and crosslinking. Recent proteomic data on mouse lung ageing indicates that, while the ER-resident machinery of collagen biosynthesis, modification and triple helix formation appears largely unchanged, there are specific changes in levels of type IV and type VI as well as the two fibril-associated collagens with interrupted triple helices (FACIT), namely type XIV and type XVI collagens. In addition, levels of the extracellular collagen crosslinking enzyme lysyl oxidase are decreased, indicating less enzymatically mediated collagen crosslinking upon ageing. The latter contrasts with the ageing-associated increase in collagen crosslinking by advanced glycation endproducts (AGEs), a result of spontaneous reactions of protein amino groups with reactive carbonyls, e.g., from monosaccharides or reactive dicarbonyls like methylglyoxal. Given the slow turnover of extracellular collagen such modifications accumulate even more in ageing tissues. In summary, the collective evidence points mainly toward age-induced alterations in collagen composition and drastic changes in the molecular nature of collagen crosslinks. Future work addressing the consequences of these changes may provide important clues for prevention of lung disease and for lung bioengineering and ultimately pave the way to novel targeted approaches in lung regenerative medicine.

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