RESUMO
Gastric cancer is among the most prevalent and deadliest of cancers globally. To derive mechanistic insight into the pathways governing this disease, we generated a Claudin18-IRES-CreERT2 allele to selectively drive conditional dysregulation of the Wnt, Receptor Tyrosine Kinase and Trp53 pathways within the gastric epithelium. This resulted in highly reproducible metastatic, chromosomal-instable-type gastric cancer. In parallel, we developed orthotopic cancer organoid transplantation models to evaluate tumour-resident Lgr5+ populations as functional cancer stem cells via in vivo ablation. We show that Cldn18 tumours accurately recapitulate advanced human gastric cancer in terms of disease morphology, aberrant gene expression, molecular markers and sites of distant metastases. Importantly, we establish that tumour-resident Lgr5+ stem-like cells are critical to the initiation and maintenance of tumour burden and are obligatory for the establishment of metastases. These models will be invaluable for deriving clinically relevant mechanistic insights into cancer progression and as preclinical models for evaluating therapeutic targets.
Assuntos
Claudinas/genética , Células-Tronco Neoplásicas/patologia , Receptores Acoplados a Proteínas G/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Mucosa Gástrica/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Organoides/transplante , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Wnt/metabolismoRESUMO
Last-order interneurones, which were identified by antidromic invasion from the elbow extensor motor nuclei (triceps brachii), were examined for rhythmic activity during fictive locomotion. Last-order neurones with activity modulated were divided into 3 groups: one exhibited flexor-like activity, another extensor-like, and the third activity which had properties of both. Flexor-like neurones, presumably inhibitory, were located in the rostral segments (C6-C7), whereas extensor-like ones, presumably excitatory, were located in the caudal (C7-T1). Neurones of the third group were found in the most caudal segments (C8-T1). The results seem to suggest the existence of functional localization in the stepping generator.
Assuntos
Membro Anterior/inervação , Interneurônios/fisiologia , Locomoção/fisiologia , Neurônios Motores/fisiologia , Animais , Gatos , Estado de Descerebração , Estimulação Elétrica , Membro Anterior/fisiologia , Medula Espinal/citologia , Medula Espinal/crescimento & desenvolvimentoRESUMO
Activity of C5-C7 last-order interneurones, which were identified by antidromic invasion from the elbow flexor motor nuclei, was examined during fictive locomotion. Three groups of neurones were found: one showing no rhythmic modulation of activity (non-modulated neurones), another rhythmically active mainly in phase with the target motoneurones (modulated neurones of group 1), the other out of phase with them (modulated neurones of group 2). Activity pattern suggested group 1 and group 2 neurones distributing excitation and inhibition to flexor motoneurones, respectively. Location of neurones seemed to be differentiated as well, group 1 located dorsally, group 2 ventrally in the gray matter.