RESUMO
Identifying master epigenetic factors controlling proliferation and survival of cancer cells allows to discover new molecular targets exploitable to overcome resistance to current pharmacological regimens. In breast cancer (BC), resistance to endocrine therapy (ET) arises from aberrant Estrogen Receptor alpha (ERα) signaling caused by genetic and epigenetic events still mainly unknown. Targeting key upstream components of the ERα pathway provides a way to interfere with estrogen signaling in cancer cells independently from any other downstream event. By combining computational analysis of genome-wide 'drop-out' screenings with siRNA-mediated gene knock-down (kd), we identified a set of essential genes in luminal-like, ERα + BC that includes BRPF1, encoding a bromodomain-containing protein belonging to a family of epigenetic readers that act as chromatin remodelers to control gene transcription. To gather mechanistic insights into the role of BRPF1 in BC and ERα signaling, we applied chromatin and transcriptome profiling, gene ablation and targeted pharmacological inhibition coupled to cellular and functional assays. Results indicate that BRPF1 associates with ERα onto BC cell chromatin and its blockade inhibits cell cycle progression, reduces cell proliferation and mediates transcriptome changes through the modulation of chromatin accessibility. This effect is elicited by a widespread inhibition of estrogen signaling, consequent to ERα gene silencing, in antiestrogen (AE) -sensitive and -resistant BC cells and pre-clinical patient-derived models (PDOs). Characterization of the functional interplay of BRPF1 with ERα reveals a new regulator of estrogen-responsive BC cell survival and suggests that this epigenetic factor is a potential new target for treatment of these tumors.
Assuntos
Neoplasias da Mama , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Receptor alfa de Estrogênio , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linhagem Celular Tumoral , Genes Essenciais , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Células MCF-7 , Cromatina/metabolismo , Cromatina/genética , Epigênese Genética , Transdução de Sinais/efeitos dos fármacos , Perfilação da Expressão GênicaRESUMO
This study investigates the remarkable attributes of sulfur-doped carbon nanodots (CDs) synthesized in high yield and a narrow size distribution (4.8 nm). These CDs exhibit notable features, including potential bioelimination through renal clearance and efficient photothermal conversion in the near-infrared region with multicolor photoluminescence across the visible spectrum. Our research demonstrates high biocompatibility and effective near-infrared (NIR)-triggered photothermal toxicity when targeting mammospheres and patient-derived tumor organoids. Moreover, the study delves into the intricate cellular responses induced by CD-mediated hyperthermia. This involves efficient tumor mass death, activation of the p38-mitogen-activated protein kinase (MAPK) pathway, and upregulation of genes associated with apoptosis, hypoxia, and autophagy. The interaction of CDs with mammospheres reveals their ability to penetrate the complex microenvironment, impeded at 4 °C, indicating an energy-dependent endocytosis mechanism. This observation underscores the CDs' potential for targeted drug delivery, particularly in anticancer therapeutics. This investigation contributes to understanding the multifunctional properties of sulfur-doped CDs and highlights their promising applications in cancer therapeutics. Utilizing 3-D tumor-in-a-dish patients' organoids enhances translational potential, providing a clinically relevant platform for assessing therapeutic efficacy in a context mirroring the physiological conditions of cancerous tissues.
Assuntos
Neoplasias da Mama , Carbono , Nanomedicina Teranóstica , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Carbono/química , Carbono/uso terapêutico , Feminino , Fototerapia/métodos , Pontos Quânticos/uso terapêutico , Pontos Quânticos/química , Nanopartículas/química , Nanopartículas/uso terapêutico , Linhagem Celular Tumoral , Hipertermia Induzida/métodos , AnimaisRESUMO
BACKGROUND: Acute kidney injury (AKI) is common in patients with acute coronary syndromes (ACS) treated by percutaneous coronary intervention. OBJECTIVES: Contrast media (CM) volume minimization has been advocated for prevention of AKI. The DyeVert CM diversion system (Osprey Medical, Inc) is designed to reduce CM volume during coronary procedures. METHODS: In this randomized, single-blind, investigator-driven clinical trial conducted in 4 Italian centers from February 4, 2020 to September 13, 2022, 550 participants with ACS were randomly assigned in a 1:1 ratio to the following: 1) the contrast volume reduction (CVR) group (n = 276), in which CM injection was handled by the CM diversion system; and 2) the control group (n = 274), in which a conventional manual or automatic injection syringe was used. The primary endpoint was the rate of AKI, defined as a serum creatinine (sCr) increase ≥0.3 mg/dL within 48 hours after CM exposure. RESULTS: There were 412 of 550 (74.5%) participants with ST-segment elevation myocardial infarction (211 of 276 [76.4%] in the CVR group and 201 of 274 [73.3%] in the control group). The CM volume was lower in the CVR group (95 ± 30 mL vs 160 ± 23 mL; P < 0.001). Seven participants (1 in the CVR group and 6 in the control group) did not have postprocedural sCr values. AKI occurred in 44 of 275 (16%) participants in the CVR group and in 65 of 268 (24.3%) participants in the control group (relative risk: 0.66; 95% CI: 0.47-0.93; P = 0.018). CONCLUSIONS: CM volume reduction obtained using the CM diversion system is effective for prevention of AKI in patients with ACS undergoing invasive procedures. (REnal Insufficiency Following Contrast MEDIA Administration TriaL IV [REMEDIALIV]: NCT04714736).
Assuntos
Síndrome Coronariana Aguda , Injúria Renal Aguda , Intervenção Coronária Percutânea , Humanos , Síndrome Coronariana Aguda/diagnóstico por imagem , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/epidemiologia , Meios de Contraste/efeitos adversos , Creatinina , Rim , Intervenção Coronária Percutânea/efeitos adversos , Fatores de Risco , Método Simples-CegoRESUMO
Multiple oncogenic alterations contribute to breast cancer development. Metabolic reprogramming, deeply contributing to tumor microenvironment (TME) education, is now widely recognized as a hallmark of cancer. The reverse Warburg effect induces cancer-associated fibroblasts (CAFs) to produce and secrete L-lactate, enhancing malignant characteristics such as neoangiogenesis, metastatic dissemination, and treatment resistance. Monocarboxylate transporter (MCT) 4 is involved in lactate efflux from CAFs into stromal and epithelial cells. Here, we first assess the expression of miR-425-5p and its target MCT4 in breast cancer CAFs and normal fibroblasts. We analyzed the metabolic changes induced by miR-425-5p in CAFs and its role in the education of breast cancer epithelial cells. We show that miR-425-5p-induced MCT4 knockdown decreased lactate extrusion from CAFs and its availability in the TME. miR-425-5p overexpression induced profound metabolic transformation in CAFs, ultimately influencing breast cancer metabolism. Furthermore, miR-425-5p impaired the capacity of CAFs to sustain vessel formation and breast cancer cell migration, viability, and proliferation. These findings emphasize the key role of miR-425-5p in breast cancer metabolism and aggressiveness, and its possible importance for breast cancer therapy and monitoring.
RESUMO
The primary treatment for glioblastoma (GBM) is removing the tumor mass as defined by MRI. However, MRI has limited diagnostic and predictive value. Tumor-associated macrophages (TAM) are abundant in GBM tumor microenvironment (TME) and are found in peripheral blood (PB). FKBP51 expression, with its canonical and spliced isoforms, is constitutive in immune cells and aberrant in GBM. Spliced FKBP51s supports M2 polarization. To find an immunologic signature that combined with MRI could advance in diagnosis, we immunophenotyped the macrophages of TME and PB from 37 patients with GBM using FKBP51s and classical M1-M2 markers. We also determined the tumor levels of FKBP51s, PD-L1, and HLA-DR. Tumors expressing FKBP51s showed an increase in various M2 phenotypes and regulatory T cells in PB, indicating immunosuppression. Tumors expressing FKBP51s also activated STAT3 and were associated with reduced survival. Correlative studies with MRI and tumor/macrophages cocultures allowed to interpret TAMs. Tumor volume correlated with M1 infiltration of TME. Cocultures with spheroids produced M1 polarization, suggesting that M1 macrophages may infiltrate alongside cancer stem cells. Cocultures of adherent cells developed the M2 phenotype CD163/FKBP51s expressing pSTAT6, a transcription factor enabling migration and invasion. In patients with recurrences, increased counts of CD163/FKBP51s monocyte/macrophages in PB correlated with callosal infiltration and were accompanied by a concomitant decrease in TME-infiltrating M1 macrophages. PB PD-L1/FKBP51s connoted necrotic tumors. In conclusion, FKBP51s identifies a GBM subtype that significantly impairs the immune system. Moreover, FKBP51s marks PB macrophages associated with MRI features of glioma malignancy that can aid in patient monitoring. SIGNIFICANCE: Our research suggests that by combining imaging with analysis of monocyte/macrophage subsets in patients with GBM, we can enhance our understanding of the disease and assist in its treatment. We discovered a similarity in the macrophage composition between the TME and PB, and through association with imaging, we could interpret macrophages. In addition, we identified a predictive biomarker that drew more attention to immune suppression of patients with GBM.