Federico Gaiti

At a Glance

• The focus of our group is to dissect the mechanisms that drive and facilitate cancer evolution
• We study human tissues at single-cell resolution integrating computational (epi)genomics and evolutionary dynamics approaches with analytical/technological innovations
• Our work includes novel computational frameworks and single-cell multi-omics methodologies to decipher the interactions between genome, epigenome, and phenotype in human cancers
• Our ultimate goal is to discover fundamental principles in evolutionary biology of cancer to inform the future design and application of novel therapeutic options to directly address tumor evolution

Short Bio

Dr. Gaiti is a Scientist at the Princess Margaret Cancer Centre, University Health Network, and Assistant Professor in the Dept. of Medical Biophysics at the University of Toronto. He earned his PhD in evolutionary biology and genomics from the University of Queensland (Australia), where he focused on understanding the evolutionary origin of two major players in human gene regulation: long non-coding RNAs and chromatin marks. Through these studies, he developed a deep interest in understanding how a single normal cell becomes malignant by the accumulation of genetic and non-genetic alterations. This motivated him to pursue a career in biomedical research, to specifically understand the underpinnings of evolutionary plasticity of cancer. Dr. Gaiti, therefore, joined Dr. Dan Landau’s laboratory at Weill Cornell Medicine and New York Genome Center. As a postdoctoral fellow, he studied the epigenetic determinants of cancer evolution using novel single-cell multi-omics experimental and computational approaches in blood disorders (leukemia) and brain tumors (glioma). His works has been recognized by prestigious postdoctoral fellowships and awards, including the NIH Pathway to Independence Award (K99/R00), the American Society of Hematology Scholar Award, the Lymphoma Research Foundation Postdoctoral Fellowship, and the Leukemia & Lymphoma Society Award. Dr. Gaiti is now developing and applying these single-cell multi-omics approaches to answer the fundamental question of how malignant cellular states in cancer are jointly determined by genetic and epigenetic alterations. Dr. Gaiti is committed to a career in basic cancer research with translational impact, making discoveries that would offer improved therapeutic options to directly address cancer evolution.

Research Synopsis

Our research focuses on providing novel insights into a central aspect of human biology – somatic evolution of cancer cells. Cancer progression, relapse, and resistance to therapy are the result of an evolutionary optimization process, in which genetic alterations generate diversity. This genetic diversity provides the critical substrate for malignant cells to evolve and adapt to the selective pressures provided by a therapeutic intervention. However, in addition to genetic diversity, there is a whole host of heritable layers of information, like epigenetic layers, that fuel cancer evolution. Thus, the study of cancer requires the integration of multiple heritable dimensions at the resolution of the single cell — the fundamental unit of somatic evolution.

The goal of our research program is to develop and apply computational and experimental genomics and epigenomics approaches for the study of cancer evolution and analysis of single-cell multi-omics data, empowering us to simultaneously interrogate the multi-faceted axes of diversity that drive tumor evolution. From a clinical perspective, the evolutionary plasticity of cancer cells is one of the major reasons for partial therapeutic success in oncology, emphasizing the key challenge associated with attempts at eradicating specific malignant cellular subsets. Understanding of the mechanisms underlying this evolutionary process, which contributes to greater diversity of subpopulations within the cancer, is therefore critical to discover fundamental principles in evolutionary biology and biological regulation of cancer cells and to better inform the future design and application of more effective therapeutic options.

Current efforts in the lab focus on understanding:

1. Role of non-genetic/epigenetic alterations (DNA methylation or chromatin factors) in dictating malignant cell states.
2. The phenotypic plasticity of malignant cell states.
3. The impact of cell extrinsic factors (such as tumor microenvironment) on malignant cell states.

For more information, please visit the Gaiti Lab website.

Recent Publications

Ashouri A, Zhang C, Gaiti F. Decoding Cancer Evolution: Integrating Genetic and Non-Genetic Insights. Genes. 2023 September; 14(10):1856. doi: https://doi.org/10.3390/genes14101856

Chaligne R*, Gaiti F*, Silverbush D*, Schiffman JS*, Weisman HR, Kluegel L, Gritsch S, Deochand S, Gonzalez castro N, Richman AR, Klughammer J, Biancalani T, Muus C, Sheridan C, Alonso A, Izzo F, Park J, Rozenblatt-Rosen O, Regev A, Suva M, Landau DA. Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states. Nature Genetics, 2021. *co-first authors

Gaiti F*, Chaligne R*, Gu H*, Brand RM, Kothen-Hill S, Schulman RC, Grigorev K, Risso D, Kim KT, Pastore A, Huang KY, Alonso A, Sheridan C, Omans ND, Biederstedt E, Clement K, Wang L, Felsenfeld JA, Bhavsar EB, Aryee MJ, Allan JN, Furman R, Gnirke A, Wu CJ, Meissner A, Landau DA. Epigenetic evolution and lineage histories of chronic lymphocytic leukaemia. Nature. 2019 May;569(7757):576-580. doi: 10.1038/s41586-019-1198-z.Epub 2019 May 15. PubMed PMID: 31092926; PubMed Central PMCID: PMC6533116.

Mariela Cortés-López*, Paulina Chamely*, Allegra G. Hawkins*, Robert F. Stanley*, Ariel D. Swett, Saravanan Ganesan, Tarek H. Mouhieddine, Xiaoguang Dai, Lloyd Kluegel, Celine Chen, Kiran Batta, Nili Furer, Rahul S. Vedula, John Beaulaurier, Alexander W. Drong, Scott Hickey, Neville Dusaj, Gavriel Mullokandov, Adam M. Stasiw, Jiayu Su, Ronan Chaligné, Sissel Juul, Eoghan Harrington, David A. Knowles, Catherine J. Potenski, Daniel H. Wiseman, Amos Tanay, Liran Shlush, Robert C. Lindsley, Irene M. Ghobrial, Justin Taylor, Omar Abdel-Wahab, Federico Gaiti^#, Dan A. Landau^#. Single-cell multi-omics defines the cell-type-specific impact of splicing aberrations in human hematopoietic clonal outgrowths, Cell Stem Cell, 2023.

Pastore A*, Gaiti F*, Lu SX, Brand RM, Kulm S, Chaligne R, Gu H, Huang KY, Stamenova EK, Béguelin W, Jiang Y, Schulman RC, Kim KT, Alonso A, Allan JN, Furman RR, Gnirke A, Wu CJ, Melnick AM, Meissner A, Bernstein BE, Abdel-Wahab O, Landau DA. Corrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL. Nat Commun. 2019 Apr 23;10(1):1874. doi: 10.1038/s41467-019-09645-5. PubMed PMID: 31015400; PubMed Central PMCID: PMC6478836.

Gu H*, Raman AT*, Wang X, Gaiti F, Chaligne R, Mohammad AW, Arczewska A, Smith ZD, Landau DA, Aryee MJ, Meissner A, Gnirke A. Smart-RRBS for single-cell methylome and transcriptome analysis. Nat Protoc. 2021 Jul 9;. doi: 10.1038/s41596-021-00571-9. [Epub ahead of print] Review. PubMed PMID: 34244697.

Zviran A*, Schulman RC*, Shah M*, Hill STK, Deochand S, Khamnei CC, Maloney D, Patel K, Liao W, Widman AJ, Wong P, Callahan MK, Ha G, Reed S, Rotem D, Frederick D, Sharova T, Miao B, Kim T, Gydush G, Rhoades J, Huang KY, Omans ND, Bolan PO, Lipsky AH, Ang C, Malbari M, Spinelli CF, Kazancioglu S, Runnels AM, Fennessey S, Stolte C, Gaiti F, Inghirami GG, Adalsteinsson V, Houck-Loomis B, Ishii J, Wolchok JD, Boland G, Robine N, Altorki NK, Landau DA. Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring. Nat Med. 2020 Jul;26(7):1114-1124. doi: 10.1038/s41591-020-0915-3. Epub 2020 Jun 1. PubMed PMID: 32483360; PubMed Central PMCID: PMC8108131.

Izzo F*, Lee SC*, Poran A, Chaligne R, Gaiti F, Gross B, Murali RR, Deochand SD, Ang C, Jones PW, Nam AS, Kim KT, Kothen-Hill S, Schulman RC, Ki M, Lhoumaud P, Skok JA, Viny AD, Levine RL, Kenigsberg E, Abdel-Wahab O, Landau DA. DNA methylation disruption reshapes the hematopoietic differentiation landscape. Nat Genet. 2020 Apr;52(4):378-387. doi: 10.1038/s41588-020-0595-4. Epub 2020 Mar 23. PubMed PMID: 32203468; PubMed Central PMCID: PMC7216752.

Gaiti F, Jindrich K, Fernandez-Valverde SL, Roper KE, Degnan BM, Tanurdžić M. Landscape of histone modifications in a sponge reveals the origin of animal cis-regulatory complexity. Elife. 2017 Apr 11;6. doi: 10.7554/eLife.22194. PubMed PMID: 28395144; PubMed Central PMCID: PMC5429095.

Gaiti F, Fernandez-Valverde SL, Nakanishi N, Calcino AD, Yanai I, Tanurdzic M, Degnan BM. Dynamic and Widespread lncRNA Expression in a Sponge and the Origin of Animal Complexity. Mol Biol Evol. 2015 Sep;32(9):2367-82. doi: 10.1093/molbev/msv117. Epub 2015 May 14. PubMed PMID: 25976353; PubMed Central PMCID: PMC4540969.

Wong ES, Zheng D, Tan SZ, Bower NL, Garside V, Vanwalleghem G, Gaiti F, Scott E, Hogan BM, Kikuchi K, McGlinn E, Francois M, Degnan BM. Deep conservation of the enhancer regulatory code in animals. Science. 2020 Nov 6;370(6517). doi: 10.1126/science.aax8137. PubMed PMID: 33154111.