Personal Regulome Navigation of Cancer
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COMMENT Personal regulome navigation of cancer Howard Y. Chang A systematic approach to understanding the noncoding genome in cancer promises to improve cancer diagnosis and therapy. Tracking the landscape of gene control in individual patients and single cells yields many insights for inherited and somatic mutations in cancer, extrachromosomal oncogene amplifications and cancer immunotherapy. New technologies and bold therapeutic approaches are paving the way to truly envisage personalized cancer medicine in the future. The era of the personal genome has arrived, but the microenvironment, lineage relationship and functional dream of precision medicine enabled by a personal- dependencies from a snapshot of gene regulation (Fig. 1). ized understanding of disease etiology and dynamic response to treatment is only now starting to be real- Insights into cancer mechanisms and therapies ized. Cancer is a disease of genes, and much of cancer Several examples highlight the promise of a personal genetics has focused on coding mutations that alter regulome viewpoint of cancer. Building a map of open protein sequence. By contrast, unbiased genome- wide chromatin in primary human cancers, Corces et al.4 association studies, including for cancer predisposi- showed that nearly half of active DNA regulatory ele- tion, showed that the vast majority of inherited vari- ments in cancer are not observed in normal tissues. ants associated with human disease are located tens of These cancer- specific DNA elements highlight inher- thousands of bases away from genes, in the noncoding ited noncoding variants associated with cancer pre- genome that comprise 98% of human DNA. A deep di sposition, as well as somatic mutations that alter technological chasm existed between the knowledge regulatory activity near cancer driver genes. Wu et al.5 from abundant cell sources in laboratory settings and discovered that extrachromosomal DNA (ecDNA) our ability to infer regulatory landscapes of diseases amplifications harbouring oncogenes represent a pro- from miniscule clinical samples in individual patients. found epigenetic dysregulation. EcDNAs gain a remark- Therefore, it has become clear that a personal genome able advantage in gene expression because ecDNA is not sufficient for personalized medicine. Instead, particles are decompacted. Each ecDNA molecule sup- a personalized regulome, enabled by interrogation of the ports far more copies of RNA transcript than oncogenes regulatory landscape of personal disease, is required for on chromosomes. informed interventions. The impact of personal regulomes is also being felt in cancer therapy. By serially tracking single can- Personal regulome technologies cer cell and T cell clones in individual patients under- Substantial progress in three areas has enabled the crea- going treatment with anti- PD1 checkpoint blockade, tion and interpretation of personal regulomes over the Yost et al.6 discovered that T cells that expand in response past few years. First, sensitive and rapid methods to to checkpoint blockade are recruited from the periphery. map open chromatin, a biochemical hallmark of active The resident T cells are exhausted, an epigenetic state of DNA regulatory elements1, and RNA transcripts in unresponsiveness7. These findings and others8 mandated tens of thousands of single cells have made it possible a re- conception of the ‘hot’ versus ‘cold’ tumour idea in to quickly discern the regulome landscape and hetero- immunotherapy and prompted searches for ways to geneity of cancers. Second, the development of single-cell rein vigorate exhausted T cells. Again, a deep and tempo- multiomics, where multiple types of high- dimensional rally resolved gene regulatory exploration of exhaustion Center for Personal Dynamic data are acquired from the same individual cell, has revealed transcription factors that can be manipulated to Regulomes and Howard allowed simultaneous monitoring multiple steps in the prevent exhaustion and improve T cell’s ability to fight Hughes Medical Institute, gene expression life cycle, from chromatin to RNA and cancer9. Another approach involves ex vivo gene editing Stanford University, 2 10 Stanford, CA, USA. proteins . Third, the advent of genome- scale gene of T cells prior to reinfusion back to patients . Tracking 3 e- mail: howchang@ and epigenome editing via CRISPR–Cas9 technology single- cell gene edits and global transcriptional pro- stanford.edu also enabled functional screening and validation of grammes demonstrated that clinical multi-locus genome https://doi.org/10.1038/ gene regulatory relationships. These technologies editing is feasible, safe and leads to long term change in s41568-021-00381- x make it possible to appreciate the cell types, cell state, T cell fates10. NATURE REVIEWS | CANCER VOLUME 21 | OCTOBER 2021 | 609 0123456789();: COMMENT Customers Cell types diverse, a fact that is not incorporated in most regulome studies. Knowledge of allele- specific structural varia- tion, single nucleotide polymorphisms and transcript Streets Cell states isoforms is essential for understanding the effect of both protein coding and regulatory variants. In addi- Tissue micro- tion, complex structural rearrangements — inversions, Parcels environment deletions and duplications — must be considered. In the case of cancer, competition between highly diverse clones with different somatic genomes defines tumour Elevation Lineage hetero geneity, progression and therapeutic resistance. Methods to link long-range variants in the regulome and Genetic understand their functional consequences are crucial Land usage variants for tackling some of the most pressing human diseases, especially cancer. The remarkable progress over the past few years suggests that ‘personal regulomes’ may become a daily Real world Personal reality in cancer research and clinical practice. The diag- regulomes nosis, classification, risk stratification and therapeutic prioritization of cancer can potentially be made with far greater precision. Cancer treatments such as targeted therapies, immunotherapies and cell therapies may be designed and engineered to hone in on the unique vulnerabilities of each cancer and monitored in real Fig. 1 | Like a GPS map that represents the real Layering insights from regulomes. time. While the field has laid the groundwork for some world in multiple layers, personal regulome technologies extract and integrate multiple insights from a comprehensive snapshot of gene regulation in an individual. Adapted of these technologies, their full realization will require with permission of National Academies Press (US), from National Research Council significant teamwork and iterative development. If suc- (US) Committee on A Framework for Developing a New Taxonomy of Disease. Toward cessful, these potential advances promise substantial Precision Medicine: Building a Knowledge Network for Biomedical Research and a New benefits to patients with cancer. Taxonomy of Disease. Washington (DC), 2011; permission conveyed through Copyright 1. Buenrostro, J. D. et al. Single- cell chromatin accessibility reveals Clearance Center, Inc. principles of regulatory variation. Nature 523, 486–490 (2015). 2. Satpathy, A. T. et al. Transcript- indexed ATAC- seq for precision immune profiling. Nat. Med. 24, 580–590 (2018). 3. Rubin, A. J. et al. Coupled single- cell CRISPR screening and Vision for the future epigenomic profiling reveals causal gene regulatory networks. Cell 176, 361–376 (2019). We have significant opportunities to build on this 4. Corces, M. R. et al. The chromatin accessibility landscape of primary exciting momentum. Single- cell multiomics need to human cancers. Science 362, eaav1898 (2018). 5. Wu, S. et al. Circular ecDNA promotes accessible chromatin and further advance to incorporate protein abundance, high oncogene expression. Nature 575, 699–703 (2019). post- translational modifications and metabolic states 6. Yost, K. E. et al. Clonal replacement of tumor- specific T cells following PD-1 blockade. Nat. Med. 25, 1251–1259 (2019). in cancer. While each individual modality is informa- 7. Satpathy, A. T. et al. Massively parallel single- cell chromatin tive, many current technologies retrieve only one type landscapes of human immune cell development and intratumoral T cell exhaustion. Nat. Biotechnol. 37, 925–936 (2019). of molecular information per assay, like the proverbial 8. Yost, K. E., Chang, H. Y. & Satpathy, A. T. Recruiting T cells in cancer blind men attempting to describe an elephant by touch- immunotherapy. Science 372, 130–131 (2021). 9. Lynn, R. C. et al. c- Jun overexpression in CAR T cells induces ing different portions. In complex human organs that exhaustion resistance. Nature 576, 293–300 (2019). change structure and function from one millimeter to the 10. Stadtmauer, E. A. et al. CRISPR- engineered T cells in patients with refractory cancer. Science 367, eaba7365 (2020). next, assaying physically different pieces of tissue implies the possibility of very different results. This problem is Acknowledgements Supported by NIH RM1- HG007735, R35- CA209919. H.Y.C. is an further compounded in cancer where multiple somatic Investigator of the Howard Hughes Medical Institute. clones exist in close spatial proximity. Spatial regulome Competing interests and in situ profiling methods will likely become increas- H.Y.C. is a co- founder of Accent Therapeutics, Boundless Bio, and is an ingly important. Finally, human genomes are highly advisor of 10x Genomics, Arsenal Biosciences and Spring Discovery. 610 | OCTOBER 2021 | VOLUME 21 www.nature.com/nrc 0123456789();: .