A Systems Biology Approach to the Tumor Microenvironment Using Zebrafish

ASPIRE Award (2019-2022)

Richard White, MD, PhD, Memorial Sloan Kettering Cancer Center

Richard White, MD, PhD

Understanding how cancer cells interact with non-cancer cells is key to developing treatments that prevent the initiation of metastasis. Currently, model systems that allow researchers to observe and study these interactions in vivo are limited. Dr. Richard White and his group at Memorial Sloan Kettering Cancer Center are developing a zebrafish model to visualize cancer metastasis. Because zebrafish are transparent, the interaction of tumor cells with other cells in their microenvironment can be visualized. To create an accurate representation of human cancer, the team is conducting single-cell and spatial transcriptomic analysis of human tumor specimens and using the knowledge gained to recapitulate the metastatic ecosystem in zebrafish. Building upon the transparency of the organism, the team is using fluorescence imaging of the entire tumor microenvironment as well as CRISPR technology to alter different mediators in the microenvironment to determine which have functional significance. The results of this work will lead to a better understanding of how cancer cells interact with normal tissue cells and potentially uncover new therapeutic targets for preventing or inhibiting cancer cell metastasis.

published research

Baron M, Tagore M, Hunter MV, Kim IS, Moncada R, Yan Y, Campbell NR, White RM, Yanai I. The Stress-Like Cancer Cell State Is a Consistent Component of Tumorigenesis. Cell Syst. 2020.

Lumaquin D, Johns E, Montal E, Weiss JM, Ola D, Abuhashem A, White RM. An in vivo reporter for tracking lipid droplet dynamics in transparent zebrafish. Elife. 2021.

Campbell NR, Rao A, Hunter MV, Sznurkowska MK, Briker L, Zhang M, Baron M, Heilmann S, Deforet M, Kenny C, Ferretti LP, Huang TH, Perlee S, Garg M, Nsengimana J, Saini M, Montal E, Tagore M, Newton-Bishop J, Middleton MR, Corrie P, Adams DJ, Rabbie R, Aceto N, Levesque MP, Cornell RA, Yanai I, Xavier JB, White RM. Cooperation between melanoma cell states promotes metastasis through heterotypic cluster formation. Dev Cell. 2021.

Hunter MV, Moncada R, Weiss JM, Yanai I, White RM. Spatially resolved transcriptomics reveals the architecture of the tumor-microenvironment interface. Nature Commun. 2021.

Weiss JM, Hunter MV, Cruz NM, Baggiolini A, Tagore M, Ma Y, Misale S, Marasco M, Simon-Vermot T, Campbell NR, Newell F, Wilmott JS, Johansson PA, Thompson JF, Long GV, Pearson JV, Mann GJ, Scolyer RA, Waddell N, Montal ED, Huang TH, Jonsson P, Donoghue MTA, Harris CC, Taylor BS, Xu T, Chaligné R, Shliaha PV, Hendrickson R, Jungbluth AA, Lezcano C, Koche R, Studer L, Ariyan CE, Solit DB, Wolchok JD, Merghoub T, Rosen N, Hayward NK, White RM. Anatomic position determines oncogenic specificity in melanoma. Nature. 2022.

Suresh S, Rabbie R, Garg M, Lumaquin D, Huang TH, Montal E, Ma Y, Cruz NM, Tang X, Nsengimana J, Newton-Bishop J, Hunter MV, Zhu Y, Chen K, de Stanchina E, Adams DJ, White RM. Identifying the transcriptional drivers of metastasis embedded within localized melanoma. Cancer Discov. 2022.

Montal E, Lumaquin D, Ma Y, Suresh S, White RM. Modeling the effects of genetic and diet induced obesity on melanoma progression in zebrafish. Dis Model Mech. 2022.

Lumaquin-Yin D, Montal E, Johns E, Baggiolini A, Huang TH, Ma Y, LaPlante C, Suresh S, Studer L, White RM. Lipid droplets are a metabolic vulnerability in melanoma. Nat Commun. 2023.

Zhang H, Hunter MV, Chou J, Quinn JF, Zhou M, White RM, Tansey W. BayesTME: An end-to-end method for multiscale spatial transcriptional profiling of the tissue microenvironment. Cell Syst. 2023.

Tagore M, Hergenreder E, Perlee SC, Cruz NM, Menocal L, Suresh S, Chan E, Baron M, Melendez S, Dave A, Chatila WK, Nsengimana J, Koche RP, Hollmann TJ, Ideker T, Studer L, Schietinger A, White RM. GABA regulates electrical activity and tumor initiation in melanoma. Cancer Discov. 2023.