77 research outputs found
Comprehensive analysis of normal adjacent to tumor transcriptomes.
Histologically normal tissue adjacent to the tumor (NAT) is commonly used as a control in cancer studies. However, little is known about the transcriptomic profile of NAT, how it is influenced by the tumor, and how the profile compares with non-tumor-bearing tissues. Here, we integrate data from the Genotype-Tissue Expression project and The Cancer Genome Atlas to comprehensively analyze the transcriptomes of healthy, NAT, and tumor tissues in 6506 samples across eight tissues and corresponding tumor types. Our analysis shows that NAT presents a unique intermediate state between healthy and tumor. Differential gene expression and protein-protein interaction analyses reveal altered pathways shared among NATs across tissue types. We characterize a set of 18 genes that are specifically activated in NATs. By applying pathway and tissue composition analyses, we suggest a pan-cancer mechanism of pro-inflammatory signals from the tumor stimulates an inflammatory response in the adjacent endothelium
Recommended from our members
HDAC inhibition potentiates immunotherapy in triple negative breast cancer.
Triple-negative breast cancer (TNBC) represents a more aggressive and difficult subtype of breast cancer where responses to chemotherapy occur, but toxicity is significant and resistance often follows. Immunotherapy has shown promising results in various types of cancer, including breast cancer. Here, we investigated a new combination strategy where histone deacetylase inhibitors (HDACi) are applied with immune checkpoint inhibitors to improve immunotherapy responses in TNBC. Testing different epigenetic modifiers, we focused on the mechanisms underlying HDACi as priming modulators of immunotherapy. Tumor cells were co-cultured with human peripheral blood mononuclear cells (PBMCs) and flow cytometric immunophenotyping was performed to define the role of epigenetic priming in promoting tumor antigen presentation and immune cell activation. We found that HDACi up-regulate PD-L1 mRNA and protein expression in a time-dependent manner in TNBC cells, but not in hormone responsive cells. Focusing on TNBC, HDACi up-regulated PD-L1 and HLA-DR on tumor cells when co-cultured with PBMCs and down-regulated CD4+ Foxp3+ Treg in vitro. HDACi significantly enhanced the in vivo response to PD-1/CTLA-4 blockade in the triple-negative 4T1 breast cancer mouse model, the only currently available experimental system with functional resemblance to human TNBC. This resulted in a significant decrease in tumor growth and increased survival, associated with increased T cell tumor infiltration and a reduction in CD4+ Foxp3+ T cells in the tumor microenvironment. Overall, our results suggest a novel role for HDAC inhibition in combination with immune checkpoint inhibitors and identify a promising therapeutic strategy, supporting its further clinical evaluation for TNBC treatment
Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer.
Expression of the oncogenic transcription factor MYC is disproportionately elevated in triple-negative breast cancer (TNBC), as compared to estrogen receptor-, progesterone receptor- or human epidermal growth factor 2 receptor-positive (RP) breast cancer. We and others have shown that MYC alters metabolism during tumorigenesis. However, the role of MYC in TNBC metabolism remains mostly unexplored. We hypothesized that MYC-dependent metabolic dysregulation is essential for the growth of MYC-overexpressing TNBC cells and may identify new therapeutic targets for this clinically challenging subset of breast cancer. Using a targeted metabolomics approach, we identified fatty acid oxidation (FAO) intermediates as being dramatically upregulated in a MYC-driven model of TNBC. We also identified a lipid metabolism gene signature in patients with TNBC that were identified from The Cancer Genome Atlas database and from multiple other clinical data sets, implicating FAO as a dysregulated pathway that is critical for TNBC cell metabolism. We found that pharmacologic inhibition of FAO catastrophically decreased energy metabolism in MYC-overexpressing TNBC cells and blocked tumor growth in a MYC-driven transgenic TNBC model and in a MYC-overexpressing TNBC patient-derived xenograft. These findings demonstrate that MYC-overexpressing TNBC shows an increased bioenergetic reliance on FAO and identify the inhibition of FAO as a potential therapeutic strategy for this subset of breast cancer
Recommended from our members
Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer.
Background:Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer. Methods:The STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Rao's quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics. Results:A statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P < .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio [HR] = 1.98, 95% confidence interval [CI] = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI = 1.18 to 4.99). Conclusions:Patients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors
Cardiovascular morbidity and mortality in adult patients with repaired aortic coarctation
BACKGROUND: The long‐term burden of cardiovascular disease after repair of coarctation of the aorta (CoA) has not been elucidated. We aimed to determine the incidence of and risk factors for cardiovascular events in adult patients with repaired CoA. Additionally, mortality rates were compared between adults with repaired CoA and the general population. METHODS AND RESULTS: Using the Dutch Congenital Corvitia (CONCOR) registry, patients aged ≥16 years with previous surgical or transcatheter CoA repair from 5 tertiary referral centers were included. Cardiovascular events were recorded, comprising coronary artery disease, stroke/transient ischemic attack, aortic complications, arrhythmias, heart failure hospitalizations, endocarditis, and cardiovascular death. In total, 920 patients (median age, 24 years [range 16–74 years]) were included. After a mean follow‐up of 9.3±5.1 years, 191 patients (21%) experienced at least 1 cardiovascular event. A total of 270 cardiovascular events occurred, of which aortic complications and arrhythmias were most frequent. Older age at initial CoA repair (hazard ratio [HR], 1.017; 95% CI, 1.000–1.033 [P=0.048]) and elevated left ventricular mass index (HR, 1.009; 95% CI, 1.005–1.013 [P<0.001]) were independently associated with an increased risk of cardiovascular events. The mortality rate was 3.3 times higher than expected based on an age‐ and sex‐matched cohort from the Dutch general population (standardized mortality ratio, 3.3; 95% CI, 2.3–4.4 [P<0.001]). CONCLUSIONS: This large, prospective cohort of adults with repaired CoA showed a high burden of cardiovascular events, particularly aortic complications and arrhythmias, during long‐term follow‐up. Older age at initial CoA repair and elevated left ventricular mass index were independent risk factors for the occurrence of cardiovascular events. Mortality was 3.3‐fold higher compared with the general population. These results advocate stringent follow‐up after CoA repair and emphasize the need for improved preventive strategies
Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.
Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance
Hypertensive response to exercise in adult patients with repaired aortic coarctation
OBJECTIVE: The clinical and prognostic implications of a hypertensive response to exercise after repair of coarctation of the aorta (CoA) remain controversial. We aimed to determine the prevalence of a hypertensive response to exercise, identify factors associated with peak exercise systolic blood pressure (SBP) and explore the association of peak exercise SBP with resting blood pressure and cardiovascular events during follow-up. METHODS: From the Dutch national CONgenital CORvitia (CONCOR) registry, adults with repaired CoA who underwent exercise stress testing were included. A hypertensive response to exercise was defined as a peak exercise SBP ≥210 mm Hg in men and ≥190 mm Hg in women. Cardiovascular events consisted of coronary artery disease, stroke, aortic complications and cardiovascular death. RESULTS: Of the original cohort of 920 adults with repaired CoA, 675 patients (median age 24 years (range 16-72 years)) underwent exercise stress testing. Of these, 299 patients (44%) had a hypertensive response to exercise. Mean follow-up duration was 10.1 years. Male sex, absence of a bicuspid aortic valve and elevated resting SBP were independently associated with increased peak exercise SBP. Peak exercise SBP was positively predictive of office SBP (β=0.11, p<0.001) and 24-hour SBP (β=0.05, p=0.03) at follow-up, despite correction for baseline SBP. During follow-up, 100 patients (15%) developed at least 1 cardiovascular event. Peak exercise SBP was not significantly associated with the occurrence of cardiovascular events (HR 0.994 (95% CI 0.987 to 1.001), p=0.11). CONCLUSIONS: A hypertensive response to exercise was present in nearly half of the patients in this large, prospective cohort of adults with repaired CoA. Risk factors for increased peak exercise SBP were male sex, absence of a bicuspid aortic valve and elevated resting SBP. Increased peak exercise SBP independently predicted hypertension at follow-up. These results support close follow-up of patients with a hypertensive response to exercise to ensure timely diagnosis and treatment of future hypertension
The molecular basis of breast cancer pathological phenotypes
The histopathological evaluation of morphological features in breast tumours provides prognostic information to guide therapy. Adjunct molecular analyses provide further diagnostic, prognostic and predictive information. However, there is limited knowledge of the molecular basis of morphological phenotypes in invasive breast cancer. This study integrated genomic, transcriptomic and protein data to provide a comprehensive molecular profiling of morphological features in breast cancer. Fifteen pathologists assessed 850 invasive breast cancer cases from The Cancer Genome Atlas (TCGA). Morphological features were significantly associated with genomic alteration, DNA methylation subtype, PAM50 and microRNA subtypes, proliferation scores, gene expression and/or RPPA subtype. Marked nuclear pleomorphism, necrosis, inflammation and high mitotic count were associated with Basal-like subtype and have similar molecular basis. Omics-based signatures were constructed to predict morphological features. The association of morphology transcriptome signatures with overall survival in oestrogen receptor (ER)-positive and ER-negative breast cancer was first assessed using the METABRIC dataset; signatures that remained prognostic in the METABRIC multivariate analysis were further evaluated in five additional datasets. The transcriptomic signature of epithelial tubule formation was prognostic in ER-positive breast cancer. No signature was prognostic in ER-negative. This study provided new insights into the molecular basis of breast cancer morphological phenotypes. The integration of morphological with molecular data has potential to refine breast cancer classification, predict response to therapy, enhance our understanding of breast cancer biology and improve clinical management. This work is publicly accessible at www.dx.ai/tcga_breast
Conception, development and experimental testing of an externally adjustable vasular clamp
Titelblatt und Inhaltsverzeichnis
Einleitung
Methoden
Entwicklung
Ergebnisse
Diskussion
Zusammenfassung
Konstruktionszeichnungen, Patent
Literaturverzeichnis
Präsentationen, Publikat., Abbild.verz., Eidesstattl. Erklär., Ethikvotum,
Danksag., Lebenslauf, PublikationslisteBei erwachsenen Patienten nach einer Vorhofumkehroperation als Palliation
einer d-Transposition der großen Arterien ist die Prognose angesichts der
zunehmenden Insuffizienz des rechten Ventrikels als Systemventrikel ab der
zweiten Lebensdekade erheblich eingeschränkt. Um diese Patienten längerfristig
einer verbesserten Prognose zuzuführen ist es notwendig, den bis dahin
hypotrophierten, nicht an Systemdruck adaptierten linken Ventrikel auf ein
entsprechendes Druckniveau zu trainieren. Mehrere Methoden -basierend auf
regulierbaren oder nicht-regulierbaren Instrumenten zur Drosselung des
pulmonalen Blutflusses- wurden bisher überwiegend bei Säuglingen angewendet,
von denen jedoch bisher keine routinemäßig beim erwachsenen Patienten klinisch
einsetzbar ist. Das Projekt Adjustierbarer Gefäßkonstriktor befasste sich
mit der Konzeption, Entwicklung und tierexperimentellen Erprobung einer von
extrakorporal regulierbaren, spaltförmigen Gefäßklemme, dem Konstriktor .
Seine Funktion bestand nach der Platzierung um den Pulmonalarterienstamm in
der chronisch progressiven Verringerung der durchströmten Querschnittsfläche.
Durch schrittweise Nachlasterhöhung sollte eine Myokardhypertrophie des
rechten Ventrikels ohne myokardiale Schädigung induziert werden. Nach der
Konzeption des Funktionsprinzips und der Validierung in Strömungsmodellen
durchliefen mehrere Prototypen des Konstriktors tierexperimentelle Akut- und
Langzeitversuche. Die an 25 Jungschweinen gewonnenen Erkenntnisse führten zu
einer patentierten Funktionseinheit, mit der progressiv eine Hypertrophie des
rechten Ventrikels erreicht werden kann. Die Auswertung der Biopsien, der
echokardiographischen Parameter als auch der invasiv gemessenen Druckwerte
ergaben, dass mit dem von extern adjustierbaren Spaltkonstriktor innerhalb von
3 Wochen durch chronisch progressive Nachlasterhöhung auf 80% des Systemdrucks
eine Myokardhypertrophie unter Erhalt einer intakten Ventrikelfunktion im
Tierversuch bei Jungschweinen möglich ist.In adult patients with d-transposition of the great arteries (dTGA) and
palliativ atrial switch operation prognosis after the second decade is limited
due to the progressive insufficiency of the systemic right ventricle. In order
to improve those patients long-term prognosis it is necessary to trainee the
low pressure adapted hypotroph left ventricle to systemic load. Several
procedures were performed and adjustable or non-adjustable instruments have
been used to decrease pulmonary blood flow. Most of them were applied to
newborns, but no instrument is designed and available for the use in adults.
The study "Adjustable Vessel Constrictor" was performed for the conception,
development and experimental animal trial of an externally adjustable vessel
clamp, called "Constrictor". It was surgically placed around the pulmonary
artery trunc and allowed chronically progressive reduction of the perfused
diametral area. Right ventricular myocardhypertrophy was achieved by stepwise
increase of the ventricular afterload. After conception and design the
constrictor function was validated using a flowmodell. In different stages of
its development the constrictor was implanted in piglets in acute trials (over
one day) and finally long-term trials (up to 3 weeks). The analysis of 25
experimental animal trials and the consequent modifications of the constrictor
led to the patented final version, which allows the chronically progressive
induction of right ventricular hypertrophy. The analysis of the animal trials
data (histology of myocard, echocardiographic parameters and characteristic
changes in pressure load) revealed, that the externally adjustable constrictor
allows the increase in ventricular afterload up to 80% of the systemic
pressure and thereby leads to myocardhypertrophy with preservation of intact
ventricular function within 3 weeks of chronically progressive constriction
- …