The McPherson Lab develops single-cell genomic methods to measure genome instability in cancer and understand its role in tumor evolution. We led the implementation of DLP+ single-cell whole-genome sequencing at MSK and are continuing to adapt the protocol to profile rare and difficult to sequence populations. We build computational methods that leverage DLP+ to detect copy number and structural changes in individual cells, reconstruct clonal phylogenies, and resolve genomic heterogeneity. A central aim is to measure chromosomal instability (CIN) as an ongoing process, not just a record of past events. That means identifying which alterations arise in individual cells, which are selected or lost, and how they relate to whole-genome doubling, cell state, and the immune microenvironment. In ovarian cancer, we have used these approaches to reveal the evolutionary and immunomodulatory effects of whole-genome doubling. In multiple myeloma, we are using DLP+ to detect myeloma-defining events in subclones too small for bulk sequencing, distinguish benign precursors from early myeloma, and understand how immune escape enables progression. In osteosarcoma and neuroblastoma, we study ongoing CIN, whole-genome doubling, telomere dysfunction and telomere maintenance, and how they relate to treatment resistance and tumor immune states. The lab also leads analytical development for MSK’s Pediatric Translational Medicine Program, which provides rapid-turnaround research whole-genome and transcriptome sequencing of pediatric tumors.
McPherson A, Vázquez-García I, Myers MA, Al-Rawi DH, Zatzman M, Weiner AC, Freeman S, Mohibullah N, Satas G, Williams MJ, Ceglia N, Norkūnaitė D, Zhang AW, Li J, Lim JLP, Wu M, Choi S, Havasov E, Grewal D, Shi H, Kim M, Schwarz RF, Kaufmann T, Dinh KN, Uhlitz F, Tran J, Wu Y, Patel R, Ramakrishnan S, Kim D, Clarke J, Green H, Ali E, DiBona M, Varice N, Kundra R, Broach V, Gardner GJ, Roche KL, Sonoda Y, Zivanovic O, Kim SH, Grisham RN, Liu YL, Viale A, Rusk N, Lakhman Y, Ellenson LH, Tavaré S, Aparicio S, Chi DS, Aghajanian C, Abu-Rustum NR, Friedman CF, Zamarin D, Weigelt B, Bakhoum SF, Shah SP. Ongoing genome doubling shapes evolvability and immunity in ovarian cancer. Nature. 2025 Aug;644(8078):1078-1087. doi: 10.1038/s41586-025-09240-3. Epub 2025 Jul 16. PMID: 40670783; PMCID: PMC12390843.
Weiner AC, Williams MJ, Shi H, Vázquez-García I, Salehi S, Rusk N, Aparicio S, Shah SP, McPherson A. Inferring replication timing and proliferation dynamics from single-cell DNA sequencing data. Nat Commun. 2024 Oct 1;15(1):8512. doi: 10.1038/s41467-024-52544-7. PMID: 39353885; PMCID: PMC11445576.
Shi H, Williams MJ, Satas G, Weiner AC, McPherson A, Shah SP. Allele-specific transcriptional effects of subclonal copy number alterations enable genotype-phenotype mapping in cancer cells. Nat Commun. 2024 Mar 20;15(1):2482. doi: 10.1038/s41467-024-46710-0. PMID: 38509111; PMCID: PMC10954741.
Ceglia N, Sethna Z, Freeman SS, Uhlitz F, Bojilova V, Rusk N, Burman B, Chow A, Salehi S, Kabeer F, Aparicio S, Greenbaum BD, Shah SP, McPherson A. Identification of transcriptional programs using dense vector representations defined by mutual information with GeneVector. Nat Commun. 2023 Jul 20;14(1):4400. doi: 10.1038/s41467-023-39985-2. PMID: 37474509; PMCID: PMC10359421.
Funnell T, O’Flanagan CH, Williams MJ, McPherson A, McKinney S, Kabeer F, Lee H, Salehi S, Vázquez-García I, Shi H, Leventhal E, Masud T, Eirew P, Yap D, Zhang AW, Lim JLP, Wang B, Brimhall J, Biele J, Ting J, Au V, Van Vliet M, Liu YF, Beatty S, Lai D, Pham J, Grewal D, Abrams D, Havasov E, Leung S, Bojilova V, Moore RA, Rusk N, Uhlitz F, Ceglia N, Weiner AC, Zaikova E, Douglas JM, Zamarin D, Weigelt B, Kim SH, Da Cruz Paula A, Reis-Filho JS, Martin SD, Li Y, Xu H, de Algara TR, Lee SR, Llanos VC, Huntsman DG, McAlpine JN, IMAXT Consortium, Shah SP, Aparicio S. Single-cell genomic variation induced by mutational processes in cancer. Nature. 2022 Dec;612(7938):106-115. doi: 10.1038/s41586-022-05249-0. Epub 2022 Oct 26. PMID: 36289342; PMCID: PMC9712114.
Salehi S, Kabeer F, Ceglia N, Andronescu M, Williams MJ, Campbell KR, Masud T, Wang B, Biele J, Brimhall J, Gee D, Lee H, Ting J, Zhang AW, Tran H, O’Flanagan C, Dorri F, Rusk N, de Algara TR, Lee SR, Cheng BYC, Eirew P, Kono T, Pham J, Grewal D, Lai D, Moore R, Mungall AJ, Marra MA, IMAXT Consortium, McPherson A, Bouchard-Côté A, Aparicio S, Shah SP. Clonal fitness inferred from time-series modelling of single-cell cancer genomes. Nature. 2021 Jul;595(7868):585-590. doi: 10.1038/s41586-021-03648-3. Epub 2021 Jun 23. PMID: 34163070; PMCID: PMC8396073.
Laks E, McPherson A, Zahn H, Lai D, Steif A, Brimhall J, Biele J, Wang B, Masud T, Ting J, Grewal D, Nielsen C, Leung S, Bojilova V, Smith M, Golovko O, Poon S, Eirew P, Kabeer F, Ruiz de Algara T, Lee SR, Taghiyar MJ, Huebner C, Ngo J, Chan T, Vatrt-Watts S, Walters P, Abrar N, Chan S, Wiens M, Martin L, Scott RW, Underhill TM, Chavez E, Steidl C, Da Costa D, Ma Y, Coope RJN, Corbett R, Pleasance S, Moore R, Mungall AJ, Mar C, Cafferty F, Gelmon K, Chia S, CRUK IMAXT Grand Challenge Team, Marra MA, Hansen C, Shah SP, Aparicio S. Clonal Decomposition and DNA Replication States Defined by Scaled Single-Cell Genome Sequencing. Cell. 2019 Nov 14;179(5):1207-1221.e22. doi: 10.1016/j.cell.2019.10.026. PMID: 31730858; PMCID: PMC6912164.
Please visit Dr. McPherson’s faculty page for more publications.
