Decoding consequences of complex chromosomal aberrations by multi-modal single-cell deconstruction to overcome treatment-resistance cancer

Introduction

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).

Research Challenges

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.

Project Overview

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.

Methodology

This approach combines:

1. Structural variation discovery with nucleosome occupancy and cis-regulatory element accessibility profiling (scNOVA)
2. Cellular indexing of transcriptomes and epitome sequencing (CITE-seq)

Expected Outcomes

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.

Techniques Used

• Pharmacological interference and CRISPRi are used to engineer deregulated signaling pathways for precision oncology.
• CRISPRa screens are applied to sensitize CK-AML stem cells to natural killer cell-mediated elimination.

Conclusion

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.