SHATTER-AML
Financiado
Decoding consequences of complex chromosomal aberrations by multi-modal single-c...
Decoding consequences of complex chromosomal aberrations by multi-modal single-cell deconstruction to overcome treatment-resistance cancer
How does a cell with unstable, complex genomic rearrangements stay alive, and even give rise to aggressive, highly resistant malignancies? This question remains an ultimate research challenge for cancers with highly aberrant genom...
How does a cell with unstable, complex genomic rearrangements stay alive, and even give rise to aggressive, highly resistant malignancies? This question remains an ultimate research challenge for cancers with highly aberrant genomes, such as acute myeloid leukemia with complex karyotype (CK-AML). Its etiology, time-resolved clonal dynamics, molecular heterogeneity, and treatment resistance mechanisms are still largely elusive. In particular, the genetic and non-genetic dynamics that drive cancer progression under treatment are elusive to current technologies and escape single-cell resolution. SHATTER-AML will tackle the genomic enigma of CK-AML by analyzing longitudinally obtained triplicate (diagnosis, treated, relapse) samples to examine intra-patient genetic and non-genetic heterogeneity using scNOVA-CITE, a newly developed multi-modal single-cell omics approach. This approach combines (i) structural variation discovery with nucleosome occupancy and cis-regulatory element accessibility profiling (scNOVA) with (ii) cellular indexing of transcriptomes and epitome sequencing (CITE-seq). We will uncover multi-level disease dynamics at single-cell and subclonal levels along the disease course, providing a blueprint for studies of other structurally instable cancers. Identified molecular insights into the networks mediating therapy resistance, leukemic stem cell activity and immune escape will be further explored functionally in patient-derived in vivo models. Pharmacological interference and CRISPRi are used to engineer deregulated signaling pathways for precision oncology, and CRISPRa screens are applied to sensitize CK-AML stem cells to natural killer cell-mediated elimination. • SHATTER-AML will fundamentally transform our understanding of the impact of clonal evolutionary dynamics of malignancies triggered by aberrant genomes and aims to develop novel preclinical strategies to combat CK-AML resistance via immunological and precision oncology approaches.
ver más
Duración del proyecto: 59 meses
Fecha Inicio: 2022-07-01
Fecha Fin: 2027-06-30
Fecha Fin: 2027-06-30
Línea de financiación: concedida
El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2022-07-01
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2021-ADG:
ERC ADVANCED GRANTS
Cerrada
hace 3 años
Presupuesto
El presupuesto total del proyecto asciende a
2M€
Líder del proyecto
DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5