12Mar - 2024
FRONTIERS IN GENOMICS.
05:00 PM - 06:00 PM|Peter Van Loo.|Department of Genomic Medicine. The University of Texas MD Anderson Cancer Center.
Seminario
Molecular archeology of cancer.
Resumen
Tumor development is driven by changes to the genome leading to fitness advantages underlying successive clonal expansions. As somatic changes occur across most or all cell cycles, the cancer genome carries an archeological record of its past. Over the past years, we have developed several approaches to mine that archeological record from the cancer genome, which we collectively call ‘molecular archeology of cancer’. Using these approaches, we are able to infer the subclonal architecture of tumors, and gain key insights into the order and timing of the genomic changes that occurred over their evolutionary history. We have applied these approaches in a large-scale pan-cancer setting, showing that intra-tumor heterogeneity is pervasive across cancers and that the timelines of tumor evolution span multiple years to decades. Key driver events in tumor evolution typically occur early, and copy number gains often accumulate as punctuated bursts, commonly after genome doubling. Late genome doubling is frequent in cancer evolution and is typically followed by an increase in the rate of copy number gains. Genome duplications affect the selection landscape of copy number losses, while only minimally impacting copy number gains. Extending our timing framework to time mutational signatures, we find that, as expected, environmentally associated mutations are associated with early tumor development. We also find evidence of episodic APOBEC mutagenesis across many tumors and clear timing patterns in many mutational processes that have unknown origins. Our approaches increase the evolutionary information that can be obtained from tumor genome sequences and, therefore, improve our understanding of the developmental history of cancer.
Peter Van Loo. Professor and CPRIT Scholar in Cancer Research. Department of Genetics. Department of Genomic Medicine. The University of Texas MD Anderson Cancer Center
Tumor development is driven by changes to the genome leading to fitness advantages underlying successive clonal expansions. As somatic changes occur across most or all cell cycles, the cancer genome carries an archeological record of its past. Over the past years, we have developed several approaches to mine that archeological record from the cancer genome, which we collectively call ‘molecular archeology of cancer’. Using these approaches, we are able to infer the subclonal architecture of tumors, and gain key insights into the order and timing of the genomic changes that occurred over their evolutionary history. We have applied these approaches in a large-scale pan-cancer setting, showing that intra-tumor heterogeneity is pervasive across cancers and that the timelines of tumor evolution span multiple years to decades. Key driver events in tumor evolution typically occur early, and copy number gains often accumulate as punctuated bursts, commonly after genome doubling. Late genome doubling is frequent in cancer evolution and is typically followed by an increase in the rate of copy number gains. Genome duplications affect the selection landscape of copy number losses, while only minimally impacting copy number gains. Extending our timing framework to time mutational signatures, we find that, as expected, environmentally associated mutations are associated with early tumor development. We also find evidence of episodic APOBEC mutagenesis across many tumors and clear timing patterns in many mutational processes that have unknown origins. Our approaches increase the evolutionary information that can be obtained from tumor genome sequences and, therefore, improve our understanding of the developmental history of cancer.
Peter Van Loo. Professor and CPRIT Scholar in Cancer Research. Department of Genetics. Department of Genomic Medicine. The University of Texas MD Anderson Cancer Center
Auditorio Dr. Guillermo Soberón, del CCG.
Actualizado 2024-03-07 19:57:44
20-Mayo-2024 al 20-Mayo-2024
12:00 PM
Dr. Rogelio Arellano
12:00 PM
Dr. Rogelio Arellano
Las funciones cerebrales dependen del fenómeno de mielinización, éste permite la conectividad y la sobrevivencia neuronales, funciones que han promovido la generación de circuitos neuronales complejos en el sistema nervioso de los vertebrados, que es la base de las funciones cognitivas en el cerebro humano. La mielinización depende del dialogo continuo entre el linaje oligodendroglial y las neuronas, esta interacción se lleva a cabo en diferentes niveles de comunicación, cuando el dialogo se interrumpe o se ve alterado el sistema puede sufrir eventos desmielinizantes que disminuyen las capacidades cerebrales. Mas allá de ser un proceso que tiene etapas de gran importancia a lo largo del curso de la vida, la mielinización es un evento plástico que es continuo, implicado en todas las funciones del cerebro sano y partícipe en la etiología de diversas enfermedades. Conocer los mecanismos de comunicación intercelular oligodendrocitos-neurona es fundamental para lograr el control del fenómeno que permitirá sin duda su promoción en procesos patológicos, pero también daría luz sobre su papel en fenómenos fisiológicos de gran importancia tales como el aprendizaje o el decaimiento de las funciones cerebrales en la senectud. Nuestro grupo ha identificado algunos de los mecanismos de comunicación que se activan durante el reconocimiento oligodendrocito-neurona, durante la plática hablaré de la participación del sistema de señalización mediada por el GABA, en donde hemos mostrado que participan moléculas receptoras específicas del linaje oligodendroglial; característica que brinda la oportunidad de desarrollar estrategias de control dirigidas a promover el dialogo oligodendrocito-neurona. La caracterización de las moléculas receptoras a GABA en los oligodendrocitos, ha permitido identificar un grupo de fármacos que potencian su respuesta sin afectar a la mayoría de los receptores neuronales, su administración en modelos in vitro o in vivo promueven la función mielinizante de los oligodendrocitos maduros, este hallazgo, proponemos, tiene un potencial de control terapéutico importante ante las devastadoras enfermedades desmielinizantes.