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A DPhil project available with Richard White and Yang Shi, Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford

Laboratories

The student will be jointly mentored by two supervisors, Prof Richard White and Prof Yang Shi. The White lab, currently in Memorial Sloan Kettering but shortly moving to Ludwig Oxford, uses the zebrafish to study developmental and microenvironmental programs in cancer. The Shi lab studies how epigenetic factors regulate normal and malignant cells.

Project

Although cancers are highly mutated, it is factors above and beyond those mutations that allow a tumor to form. These factors include epigenetic gene programs embedded within the cell of origin (Baggiolini, et al, Science 2021). Recent work from the White lab has demonstrated that the anatomic position of the cell is a major determinant of why cells respond to certain oncogenes (Weiss, et al, Nature 2022). What regulates positional identity in cancer remains poorly understood. We aim to uncover the epigenetic mechanisms that regulate positional identity in melanoma, one of the most common human cancers. Understanding these anatomic gene programs has important implications for the treatment of these cancers at different sites.

Training

This project will utilize a combination of cell lines and a zebrafish model of melanoma[YS1] . The zebrafish allows for rapid genetic manipulation and highly sensitive imaging in the transparent casper strain (White, et al, Cell Stem Cell 2008). We will use informatic approaches including single-cell RNA and epigenetic profiling to identify genes enriched in specific anatomic sites. These may include proteins that alter epigenetic state through DNA, mRNA, non-coding RNA or histone modifications. These will then be tested in vivo using zebrafish and downstream mechanisms evaluated using human cell lines and tissue specimens. The student will be trained in modern molecular biology and epigenetic techniques, cell culture, zebrafish models, quantitative imaging and bioinformatics. The student will benefit from the combined expertise of the White lab (zebrafish models, genetic techniques, imaging) and the Shi lab (epigenetics and epitranscriptomics).

References

  • Baggiolini A+, Callahan SJ+, Montal E, Weiss JM, Trieu T, Tagore MM, Tischfield SE, Walsh RM, Suresh S, Fan Y, Campbell NR, Perlee SC, Saurat N, Hunter MV, Simon-Vermot T, Huang TH, Ma Y, Hollmann T, Tickoo SK, Taylor BS, Khurana E, Koche RP, Studer L*, White RM*.  +co-authors, *co-corresponding authors. Developmental chromatin programs determine oncogenic competence in melanoma. Science 2021 Sep 3;373(6559):eabc1048.
  • Weiss JM, Hunter MV, Tagore M, Ma Y, Misale S, 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 T, Jonsson P, Donoghue MTA, Harris CC, Taylor BS, Ariyan CE, Solit DB, Wolchok JD, Merghoub T, Rosen N, Lezcano-Lopez C, Hayward NK, White RM (2021). Anatomic position determines oncogenic specificity in melanoma. Nature. 2022 Apr;604(7905):354-361
  • White RM, Sessa A, Burke C, Bowman T, LeBlanc J, Ceol C, Bourque C, Dovey M, Goessling W, Burns CE, Zon LI.  Transparent adult zebrafish as a tool for in vivo transplantation analysis. Cell Stem Cell. 2008 Feb 7;2(2): 183-9.