5 research outputs found
A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma
The heterogeneity of cellular states in cancer has been linked to drug resistance, cancer progression and the presence of cancer cells with properties of normal tissue stem cells. Secreted Wnt signals maintain stem cells in various epithelial tissues, including in lung development and regeneration. Here we show that mouse and human lung adenocarcinomas display hierarchical features with two distinct subpopulations, one with high Wnt signalling activity and another forming a niche that provides the Wnt ligand. The Wnt responder cells showed increased tumour propagation ability, suggesting that these cells have features of normal tissue stem cells. Genetic perturbation of Wnt production or signalling suppressed tumour progression. Small-molecule inhibitors targeting essential posttranslational modification of Wnt reduced tumour growth and markedly decreased the proliferative potential of lung cancer cells, leading to improved survival of tumour-bearing mice. These results indicate that strategies for disrupting pathways that maintain stem-like and niche cell phenotypes can translate into effective anti-cancer therapies
Recommended from our members
The Mitochondrial Iron-Sulfur Cluster Protein BOLA3 in Beta Cell Metabolism and Function
Beta cell dysfunction is a major contributor to the pathogenesis of type 2 diabetes. This dysfunction, which results in the inability of the beta cell to produce and secrete insulin upon elevations in blood glucose, has been linked to various metabolic and mitochondrial insults. It has been previously been shown that perturbations of the iron metabolism and mitochondrial iron-sulfur (Fe-S) cluster biogenesis and transport may lead to beta cell dysfunction; we therefore sought to explore the role of the mitochondrial Fe-S cluster protein BOLA3 in beta cell metabolism and function. In this study we determine that beta cell-specific loss of Bola3 in both murine and human beta cells results in a gradual perturbation of glucose homeostasis and beta cell degradation. Our data further indicate that both treatment with exogenous recombinant BOLA3 protein and supraphysiological expression of endogenous Bola3 improves glucose-stimulated insulin secretion in beta cells, thereby establishing a potential therapeutic role for Bola3 and other regulators of mitochondrial metabolism in type 2 diabetes
Recommended from our members
The Mitochondrial Iron-Sulfur Cluster Protein BOLA3 in Beta Cell Metabolism and Function
Beta cell dysfunction is a major contributor to the pathogenesis of type 2 diabetes. This dysfunction, which results in the inability of the beta cell to produce and secrete insulin upon elevations in blood glucose, has been linked to various metabolic and mitochondrial insults. It has been previously been shown that perturbations of the iron metabolism and mitochondrial iron-sulfur (Fe-S) cluster biogenesis and transport may lead to beta cell dysfunction; we therefore sought to explore the role of the mitochondrial Fe-S cluster protein BOLA3 in beta cell metabolism and function. In this study we determine that beta cell-specific loss of Bola3 in both murine and human beta cells results in a gradual perturbation of glucose homeostasis and beta cell degradation. Our data further indicate that both treatment with exogenous recombinant BOLA3 protein and supraphysiological expression of endogenous Bola3 improves glucose-stimulated insulin secretion in beta cells, thereby establishing a potential therapeutic role for Bola3 and other regulators of mitochondrial metabolism in type 2 diabetes
Regulatory T Cells in Tumor-Associated Tertiary Lymphoid Structures Suppress Anti-tumor T Cell Responses
Infiltration of regulatory T (Treg) cells into many tumor types correlates with poor patient prognoses. However, mechanisms of intratumoral Treg cell function remain to be elucidated. We investigated Treg cell function in a genetically-engineered mouse lung adenocarcinoma model and
found Treg cells suppress anti-tumor responses in tumor-associated tertiary lymphoid structures (TA-TLS). TA-TLS have been described in human lung cancers, but their function remains to be determined. TLS in this model were spatially associated with >90% of tumors and facilitated
interactions between T cells and tumor-antigen presenting dendritic cells (DCs). Costimulatory ligand expression by DCs and T cell proliferation rates increased in TA-TLS upon Treg cell depletion, leading to tumor destruction. Thus, we propose Treg cells in TA-TLS can inhibit endogenous immune responses against tumors, and targeting these cells may provide therapeutic benefit for cancer patients.National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051)Howard Hughes Medical InstituteNational Institutes of Health (U.S.) (Grants 1 U54 CA126515-01, R01-CA185020-01 and T32 GM007753)Damon Runyon Cancer Research FoundationJohn D. Proctor Foundation (Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship Award)Lung Cancer Research FoundationHoward Hughes Medical Institute (Investigator)Daniel K. Ludwig Schola