Neuroendocrine tumors of the thymus (TNET) are exceedingly rare neoplasms. Their histomorphology is identical to neuroendocrine tumors elsewhere in the body (in particular the lungs) and bears no ...similarity with thymomas and thymic carcinomas. Recent molecular findings have profoundly changed our perception of these tumors and may impact future histological classification systems.
Over half of colorectal cancers (CRCs) harbor TP53 missense mutations (mutp53). We show that the most common mutp53 allele R248Q (p53Q) exerts gain of function (GOF) and creates tumor dependence in ...mouse CRC models. mutp53 protein binds Stat3 and enhances activating Stat3 phosphorylation by displacing the phosphatase SHP2. Ablation of the p53Q allele suppressed Jak2/Stat3 signaling, growth, and invasiveness of established, mutp53-driven tumors. Treating tumor-bearing mice with an HSP90 inhibitor suppressed mutp53 levels and tumor growth. Importantly, human CRCs with stabilized mutp53 exhibit enhanced Jak2/Stat3 signaling and are associated with poorer patient survival. Cancers with TP53R248Q/W are associated with a higher patient death risk than are those having nonR248 mutp53. These findings identify GOF mutp53 as a therapeutic target in CRC.
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•mutp53 R248Q, the most common p53 mutant in human CRC, promotes CRC in mice•mutp53 R248Q binds to and deregulates Stat3, correlating with poor patient survival•Genetic ablation of mutp53 R248Q reduces growth and invasion of established CRCs•Hsp90 inhibition reduces the mutp53 R248Q level and inhibits CRC progression
Schulz-Heddergott et al. show that the most common p53 mutant R248Q (mutp53) enhances Stat3 activation by binding to Stat3 and displacing SHP2 in colorectal cancer cells. Reduction of mutp53 genetically or by using the HSP90 inhibitor 17AAG reduces Stat3 signaling and the growth of mutp53-driven tumors.
Heterogeneity of lung tumor endothelial cell (TEC) phenotypes across patients, species (human/mouse), and models (in vivo/in vitro) remains poorly inventoried at the single-cell level. We single-cell ...RNA (scRNA)-sequenced 56,771 endothelial cells from human/mouse (peri)-tumoral lung and cultured human lung TECs, and detected 17 known and 16 previously unrecognized phenotypes, including TECs putatively regulating immune surveillance. We resolved the canonical tip TECs into a known migratory tip and a putative basement-membrane remodeling breach phenotype. Tip TEC signatures correlated with patient survival, and tip/breach TECs were most sensitive to vascular endothelial growth factor blockade. Only tip TECs were congruent across species/models and shared conserved markers. Integrated analysis of the scRNA-sequenced data with orthogonal multi-omics and meta-analysis data across different human tumors, validated by functional analysis, identified collagen modification as a candidate angiogenic pathway.
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•We single-cell RNA-sequenced 56,771 endothelial cells (ECs) from human, mouse, and cultured lung tumor models•Tip ECs were resolved into migratory and basement-membrane remodeling phenotypes•Capillary and venous ECs expressed immunoregulatory gene signatures•Integrated analysis identified collagen modification as an angiogenic pathway
Goveia et al. use single-cell RNA sequencing to provide an inventory of tumor endothelial cell (TEC) phenotypes from human and mouse non-small cell lung cancer and validate them functionally. Specific TEC phenotypes are associated with prognosis and response to anti-angiogenic therapy.
Standard cancer therapy targets tumor cells without considering possible damage on the tumor microenvironment that could impair therapy response. In rectal cancer patients we find that inflammatory ...cancer-associated fibroblasts (iCAFs) are associated with poor chemoradiotherapy response. Employing a murine rectal cancer model or patient-derived tumor organoids and primary stroma cells, we show that, upon irradiation, interleukin-1α (IL-1α) not only polarizes cancer-associated fibroblasts toward the inflammatory phenotype but also triggers oxidative DNA damage, thereby predisposing iCAFs to p53-mediated therapy-induced senescence, which in turn results in chemoradiotherapy resistance and disease progression. Consistently, IL-1 inhibition, prevention of iCAFs senescence, or senolytic therapy sensitizes mice to irradiation, while lower IL-1 receptor antagonist serum levels in rectal patients correlate with poor prognosis. Collectively, we unravel a critical role for iCAFs in rectal cancer therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of cancer-associated fibroblasts senescence.
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•Inflammatory CAFs are associated with poor prognosis in rectal cancer•Oxidative DNA damage in iCAFs is a pre-requisite for irradiation-induced senescence•IL-1 inhibition prevents iCAF senescence upon irradiation, improving therapy response•IL-1 signaling is enhanced by low serum IL-1RA in patients with poor prognosis
Nicolas et al. highlight the important role of inflammatory cancer-associated fibroblasts (iCAFs) for therapy response of rectal cancer patients. They demonstrate that IL-1-dependent signaling elevates oxidative DNA damage in iCAFs, which upon irradiation undergo senescence. This causes tissue remodeling and therapy resistance that can be overcome by inhibiting IL-1.
Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity, but its expression is increased in some cancers via stabilization with HSP90-associated chaperones. Here, we ...show that MIF stabilization is tumor-specific in an acute colitis-associated colorectal cancer (CRC) mouse model, leading to tumor-specific functions and selective therapeutic vulnerabilities. Therefore, we demonstrate that a Mif deletion reduced CRC tumor growth. Further, we define a dual role for MIF in CRC tumor progression. Mif deletion protects mice from inflammation-associated tumor initiation, confirming the action of MIF on host inflammatory pathways; however, macrophage recruitment, neoangiogenesis, and proliferative responses are reduced in Mif-deficient tumors once the tumors are established. Thus, during neoplastic transformation, the function of MIF switches from a proinflammatory cytokine to an angiogenesis promoting factor within our experimental model. Mechanistically, Mif-containing tumor cells regulate angiogenic gene expression via a MIF/CD74/MAPK axis in vitro. Clinical correlation studies of CRC patients show the shortest overall survival for patients with high MIF levels in combination with CD74 expression. Pharmacological inhibition of HSP90 to reduce MIF levels decreased tumor growth in vivo, and selectively reduced the growth of organoids derived from murine and human tumors without affecting organoids derived from healthy epithelial cells. Therefore, novel, clinically relevant Hsp90 inhibitors provide therapeutic selectivity by interfering with tumorigenic MIF in tumor epithelial cells but not in normal cells. Furthermore, Mif-depleted colonic tumor organoids showed growth defects compared to wild-type organoids and were less susceptible toward HSP90 inhibitor treatment. Our data support that tumor-specific stabilization of MIF promotes CRC progression and allows MIF to become a potential and selective therapeutic target in CRC.
Pancreatic ductal adenocarcinomas (PDAC) harbor recurrent functional mutations of the master DNA damage response kinase ATM, which has been shown to accelerate tumorigenesis and ...epithelial-mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional
deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements, and deregulated DNA integrity checkpoints, reminiscent of human PDAC. We hypothesized that altered genome integrity might allow synthetic lethality-based options for targeted therapeutic intervention. Supporting this possibility, we found that the PARP inhibitor olaparib or ATR inhibitors reduced the viability of PDAC cells
and
associated with a genotype-selective increase in apoptosis. Overall, our results offered a preclinical mechanistic rationale for the use of PARP and ATR inhibitors to improve treatment of ATM-mutant PDAC.
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Although glucocorticoids (GCs) are a mainstay in the clinical management of asthma, the target cells that mediate their therapeutic effects are unknown. Contrary to our expectation, we found that GC ...receptor (GR) expression in immune cells was dispensable for successful therapy of allergic airway inflammation (AAI) with dexamethasone. Instead, GC treatment was compromised in mice expressing a defective GR in the nonhematopoietic compartment or selectively lacking the GR in airway epithelial cells. Further, we found that an intact GR dimerization interface was a prerequisite for the suppression of AAI and airway hyperresponsiveness by GCs. Our observation that the ability of dexamethasone to modulate gene expression in airway epithelial cells coincided with its potency to resolve AAI supports a crucial role for transcriptional regulation by the GR in this cell type. Taken together, we identified an unknown mode of GC action in the treatment of allergic asthma that might help to develop more specific therapies in the future.
Sarcopenia describes the loss of skeletal muscle mass. While this condition is associated with a high mortality in cancer patients, its influence on survival is still underestimated.
A systematic ...review for articles was performed using the PubMed database, Cochrane Library, Biomed Central, Science Direct and by manual search. We used data of overall survival in sarcopenic patients for assessing the death risk. We extracted hazard ratio estimates from univariate and multivariate Cox proportional hazards models for meta-analysis.
A total of 15 studies were eligible for meta-analysis including a total of 2,521 lung cancer patients. Univariate meta-analysis revealed a two-fold increased death risk in sarcopenic patients; multivariate meta-analysis yielded a significant, three-fold elevated risk of death. This higher mortality is independent of tumour stage.
Muscle loss is an independent risk factor for increased death risk in lung cancer patients independent of cancer stage. This argues for implementing screening for sarcopenia into cancer care.
Aortic valve stenosis (AVS) is one of the most common valve diseases in the world. However, detailed biological understanding of the myocardial changes in AVS hearts on the proteome level is still ...lacking. Proteomic studies using high-resolution mass spectrometry of formalin-fixed and paraffin-embedded (FFPE) human myocardial tissue of AVS-patients are very rare due to methodical issues. To overcome these issues this study used high resolution mass spectrometry in combination with a stem cell-derived cardiac specific protein quantification-standard to profile the proteomes of 17 atrial and 29 left ventricular myocardial FFPE human myocardial tissue samples from AVS-patients. In our proteomic analysis we quantified a median of 1980 (range 1495-2281) proteins in every single sample and identified significant upregulation of 239 proteins in atrial and 54 proteins in ventricular myocardium. We compared the proteins with published data. Well studied proteins reflect disease-related changes in AVS, such as cardiac hypertrophy, development of fibrosis, impairment of mitochondria and downregulated blood supply. In summary, we provide both a workflow for quantitative proteomics of human FFPE heart tissue and a comprehensive proteomic resource for AVS induced changes in the human myocardium.
Translational data is of paramount importance for medical research and clinical innovation. It has the potential to benefit individuals and organizations, however, the protection of personal data ...must be guaranteed. Collecting diverse omics data and electronic health records (EHR), re-using the minimized data, as well as providing a reliable data transfer between different institutions are mandatory steps for the development of the promising field of big data and artificial intelligence in medical research. This is made possible within the proposed data platform in this research project. The established data platform enables the collaboration between public and commercial organizations by data transfer from various clinical systems into a cloud for supporting multi-site research while ensuring compliant data governance.
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