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
19-Mayo-2025 al 19-Mayo-2025
12:00 PM
Dra. Melisa Bernard Valle
12:00 PM
Dra. Melisa Bernard Valle
Descubriendo y diseñando proteínas para neutralizar venenos de serpientes en África subsahariana
El único tratamiento específico actualmente disponible para el envenenamiento por mordedura de serpientes es el uso de antivenenos policlonales elaborados a partir del plasma de animales hiperinmunizados. Aunque estos antivenenos actualmente han salvado innumerables vidas, presentan diversas desventajas, incluyendo una eficacia terapéutica limitada frente a varias especies de serpientes, variabilidad entre lotes, estabilidad restringida y en algunos casos, propensión a causar reacciones adversas. Además, la generación de antivenenos policlonales polivalentes que neutralicen eficazmente múltiples venenos de serpiente se ve obstaculizada por la baja proporción y limitada inmunogenicidad de algunas toxinas médicamente relevantes presentes en los venenos.
Con el objetivo de mejorar la terapia contra mordeduras de serpiente, en el grupo de tecnologías de anticuerpos de la Technical University of Denmark, proponemos el diseño de antivenenos recombinantes basados en mezclas oligoclonales definidas de anticuerpos de un solo dominio (VHHs), comúnmente llamados nanocuerpos. Cada uno de estos VHHs posee propiedades de neutralización amplia contra una subfamilia seleccionada de toxinas. En este seminario, describo el descubrimiento de dichos VHHs mediante la tecnología de despliegue en fagos y el diseño de una mezcla oligoclonal capaz de neutralizar los venenos completos de las 17 especies de serpientes de la familia Elapidae de mayor importancia medica en África subsahariana. Finalmente, describiré la generación de otras moléculas neutralizantes (minibinders) utilizando inteligencia artificial, como una prueba de concepto para el desarrollo de futuras tecnologías.
Consideramos que las mezclas oligoclonales de anticuerpos y minibinders, podrían emplearse como terapia para tratar diversos envenenamientos, con la perspectiva de ofrecer tratamientos más seguros y eficaces, a menor costo y con menor variabilidad entre lotes en comparación con los antivenenos derivados de plasma actualmente disponibles.