Research Interest: Functional genomics to study host-pathogen interactions and biological processes
Ph.D.: Georgetown University, Washington, D.C.
Postdoctoral: Northwestern University, Chicago, IL
My lab uses functional genomics to study host-pathogen interactions and biological processes. Functional genomics (in our case, using CRISPR screens) allows for the simultaneous interrogation of the contribution of each gene in the human genome to a particular phenotype. Simply put, this bridges genotype to phenotype on a genome-wide scale in one experiment.
We are interested in studying primary effusion lymphoma (PEL), an aggressive B cell cancer caused by the Kaposi’s sarcoma-associated herpesvirus or human herpesvirus 8 (KSHV/HHV8). PEL tumor cells rely on the constitutive expression of virally encoded genes that globally reprogram host gene expression to create a conducive environment optimal for tumor cell proliferation and survival. We previously performed genome-wide CRISPR/Cas9 screens and identified 210 host genes that are required for tumor cell proliferation and survival. Our over-all goal is to understand the functions of these host genes in B cell lymphoma. Using CRISPR/Cas9, CRISPRi and CRISPRa-based synthetic lethality and rescue screens, we aim to identify functional genetic interactions of these host genes. We anticipate that this unbiased approach will uncover novel and underappreciated insights into the biology of these host genes. We will furthermore leverage these host genetic dependencies by testing the efficacy of small molecule inhibitors against PEL in vitro and in vivo. Lastly, we are developing a CRISPR-Cas13 system to screen for coding and non-coding transcripts from KSHV that are essential for tumor cell proliferation and survival. Together, our research program will provide a better understanding of the oncogenic processes driven by the tumor virus KSHV, uncover new biology of host genes, and develop new therapeutics for this aggressive malignancy.
Full bibliography at Google Scholar
Manzano M*, Gunther T*, Ju H, Nicholas J, Bartom ET, Grundhoff A, Gottwein E. KSHV drives a super-enhancer-mediated survival gene expression program in primary effusion lymphoma. mBio, accepted (*Equal contributions.).
Morrison K, Manzano M, Chung K, Schipma MJ, Bartom ET, Gottwein E. The oncogenic Kaposi’s sarcoma-associated herpesvirus encodes a mimic of the tumor suppressive miR-15/16 family. Cell Reports 29(10):2961-2969.e6. 2019. PMID 31801064.
Patil A, Manzano M, Gottwein E. Genome-wide CRISPR screens reveal genetic mediators of cereblon modulator toxicity in primary effusion lymphoma. Blood Advances 3(14):2105-2117, 2019. PMID 31300418.
Manzano M, Patil A, Waldrop A, Dave S, Behdad A, and Gottwein E. Gene essentiality landscape and druggable oncogenic dependencies in herpesviral primary effusion lymphoma. Nature Communications, 9(1):3263, 2018. PMID 30111820.
Balasubramanian A*, Manzano M*, Teramoto T, Pilankatta R, and Padmanabhan R. High-throughput screening for the identification of small-molecule inhibitors of the flaviviral protease. Antiviral Research 134:6-16, 2016. PMID 27539384 (*Equal contributions)
Manzano M, Forte E, Raja AN, Schipma MJ, and Gottwein E. Divergent target recognition by coexpressed 5′-isomiRs of miR-142-3p and selective viral mimicry. RNA 21(9):1606-1620, 2015. PMID 26137849.
Grosswendt S*, Filipchyk A*, Manzano M, Klironomos F, Schilling M, Herzog M, Gottwein E, and Rajewsky N. Unambiguous identification of miRNA:target site interactions by different types of ligation reactions. Molecular Cell. 54(6):1042-1054, 2014. PMID 24857550 (*Equal contributions)
Zhang W, Nandakumar N, Shi Y, Manzano M, Smith A, Graham G, Gupta S, Vietsch EE, Laughlin SZ, Wadhwa M, Chetram M, Joshi M, Wang F, Kallakury B, Toretsky J, Wellstein A, and Yi C. Downstream of mutant KRAS, the transcription regulator YAP is essential for neoplastic progression to pancreatic ductal adenocarcinoma. Science Signaling 7(324):ra42, 2014. PMID 24803537
Manzano M, Shamulailatpam P, Raja AN, Gottwein E. Kaposi’s sarcoma-associated herpesvirus encodes a mimic of cellular miR-23. Journal of Virology 87(21):11821-11830, 2013. PMID 23986579