RESUMEN
Identifying the adaptive mechanisms of metastatic cancer cells remains an elusive question in the treatment of metastatic disease, particularly in pancreatic cancer (pancreatic adenocarcinoma, PDA). A loss-of-function shRNA targeted screen in metastatic-derived cells identified Gstt1, a member of the glutathione S-transferase superfamily, as uniquely required for dissemination and metastasis, but dispensable for primary tumour growth. Gstt1 is expressed in latent disseminated tumour cells (DTCs), is retained within a subpopulation of slow-cycling cells within existing metastases, and its inhibition leads to complete regression of macrometastatic tumours. This distinct Gstt1high population is highly metastatic and retains slow-cycling phenotypes, epithelial-mesenchymal transition features and DTC characteristics compared to the Gstt1low population. Mechanistic studies indicate that in this subset of cancer cells, Gstt1 maintains metastases by binding and glutathione-modifying intracellular fibronectin, in turn promoting its secretion and deposition into the metastatic microenvironment. We identified Gstt1 as a mediator of metastasis, highlighting the importance of heterogeneity and its influence on the metastatic tumour microenvironment.
Asunto(s)
Glutatión Transferasa , Neoplasias Pancreáticas , Microambiente Tumoral , Glutatión Transferasa/metabolismo , Glutatión Transferasa/genética , Humanos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/enzimología , Neoplasias Pancreáticas/metabolismo , Animales , Línea Celular Tumoral , Transición Epitelial-Mesenquimal , Fibronectinas/metabolismo , Metástasis de la Neoplasia , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/metabolismo , Adenocarcinoma/enzimología , Supervivencia Celular , Regulación Neoplásica de la Expresión Génica , Ratones , Femenino , Ratones Endogámicos C57BLRESUMEN
Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated metabolic gene across human cancers. Mutant IDH1 (mIDH1) generates the oncometabolite (R)-2-hydroxyglutarate, disrupting enzymes involved in epigenetics and other processes. A hallmark of IDH1-mutant solid tumors is T cell exclusion, whereas mIDH1 inhibition in preclinical models restores antitumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. IDH1-mutant solid tumors show selective hypermethylation and silencing of the cytoplasmic double-stranded DNA (dsDNA) sensor CGAS, compromising innate immune signaling. mIDH1 inhibition restores DNA demethylation, derepressing CGAS and transposable element (TE) subclasses. dsDNA produced by TE-reverse transcriptase (TE-RT) activates cGAS, triggering viral mimicry and stimulating antitumor immunity. In summary, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous RT activity to the mechanism of action of a US Food and Drug Administration-approved oncology drug.
Asunto(s)
Evasión Inmune , Inmunidad Innata , Isocitrato Deshidrogenasa , Neoplasias , Animales , Humanos , Ratones , Línea Celular Tumoral , ADN/metabolismo , Desmetilación del ADN , Metilación de ADN , Elementos Transponibles de ADN , Epigénesis Genética , Glutaratos/metabolismo , Inmunidad Innata/genética , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Mutación , Neoplasias/inmunología , Neoplasias/genética , Nucleotidiltransferasas/genética , Escape del Tumor , Evasión Inmune/genéticaRESUMEN
SUMMARY: There is a lack of visualization on gross anatomy planes for the non-orthogonal sections, such as subcostal and intercostal oblique scanning planes of ultrasound imaging. The aim of the present study was to visualize the anatomical image of corresponding plane for the oblique ultrasound scanning using a virtual dissection system. the oblique gross anatomy plane was constructed by appropriate segmentation using a virtual dissection table. A suitable cutting of the body plane was accomplished by turning on and off the organ systems, particularly the skeletal system, category, and structure. The right hepatic vein (RHV), middle hepatic vein (MHV), and left hepatic vein (LHV) for the right subcostal oblique plane appeared in the single slice plane. The location of the liver, gallbladder, and kidneys differently appeared in the oblique anatomical plane and body position. The results of this study suggest that using a virtual anatomy system contributes to improving the sonographer's ability to understand anatomy.
RESUMEN: Existe una falta de visualización en los planos de anatomía macroscópica para las secciones no ortogonales, tal como los planos de exploración oblicuos subcostales e intercostales en las imágenes de ultrasonido. El objetivo del presente estudio fue visualizar la imagen anatómica del plano correspondiente para la ecografía oblicua mediante un sistema de disección virtual. El plano de anatomía macroscópica oblicua se construyó mediante una adecuada segmentación utilizando una mesa de disección virtual. Se logró un corte correcto del plano corporal al encender y apagar los sistemas de órganos, particularmente el sistema esquelético, la categoría y la estructura. La vena hepática derecha, la vena hepática media y la vena hepática izquierda para el plano oblicuo subcostal derecho aparecieron en el plano de corte único. La ubicación del hígado, la vesícula biliar y los riñones aparecieron de manera diferente en el plano anatómico oblicuo y en la posición del cuerpo. Los resultados de este estudio sugieren que el uso de un sistema de anatomía virtual ayuda a mejorar la capacidad del ecografista para comprender la anatomía humana.