Exploration of Circadian Dysregulation in Cancer
Lead Research Organisation:
University of Warwick
Department Name: Warwick Medical School
Abstract
Programme overview:
This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address hypothesis-led biomedical research questions. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice.
Project:
On earth, the environment changes in a significant and predictable manner every 24 hours. Most organisms have evolved biological timing mechanisms in order to anticipate and respond to the changes brought by day and night. This so-called circadian clock leads to significant daily modulation in the expression of more than a third of genes.
Disruption to the circadian clock has been demonstrated to increase cancer risk in experimental models and epidemiological data. For example, in a murine breast cancer model, mice subjected to one inverted light/dark cycle per week, equivalent to working one night shift, developed breast cancer sooner than the control group. However, the mechanism by which the cellular clock regulates tumourigenesis remains to be fully elucidated.
Thus, I will investigate the contribution of the circadian timing system to tumorigenesis in a 3D "living" matrix, the chicken embryonic CAM model. Unlike a plastic 2D cell culture plate, the CAM will provide tumour samples from mouse and human tumours with a rhythmic environment, more closely mimicking the in vivo situation. The influence of the tumour microenvironment, CAM and embryo clock, and external stimuli including temperature and light exposure on the tumour grafts will be assessed via multiple approaches. Bioluminescence imaging of chicken embryos and tumours that express circadian real-time reporter constructs will provide continuous data to assess clock function. Meanwhile, next generation sequencing will be used to probe the heterogeneity of the molecular clocks of different cell populations within the tumour and its microenvironment. Together, these approaches will provide novel insights that will help elucidate molecular detail concerning the role of circadian clocks in cancer.
This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address hypothesis-led biomedical research questions. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice.
Project:
On earth, the environment changes in a significant and predictable manner every 24 hours. Most organisms have evolved biological timing mechanisms in order to anticipate and respond to the changes brought by day and night. This so-called circadian clock leads to significant daily modulation in the expression of more than a third of genes.
Disruption to the circadian clock has been demonstrated to increase cancer risk in experimental models and epidemiological data. For example, in a murine breast cancer model, mice subjected to one inverted light/dark cycle per week, equivalent to working one night shift, developed breast cancer sooner than the control group. However, the mechanism by which the cellular clock regulates tumourigenesis remains to be fully elucidated.
Thus, I will investigate the contribution of the circadian timing system to tumorigenesis in a 3D "living" matrix, the chicken embryonic CAM model. Unlike a plastic 2D cell culture plate, the CAM will provide tumour samples from mouse and human tumours with a rhythmic environment, more closely mimicking the in vivo situation. The influence of the tumour microenvironment, CAM and embryo clock, and external stimuli including temperature and light exposure on the tumour grafts will be assessed via multiple approaches. Bioluminescence imaging of chicken embryos and tumours that express circadian real-time reporter constructs will provide continuous data to assess clock function. Meanwhile, next generation sequencing will be used to probe the heterogeneity of the molecular clocks of different cell populations within the tumour and its microenvironment. Together, these approaches will provide novel insights that will help elucidate molecular detail concerning the role of circadian clocks in cancer.
Organisations
People |
ORCID iD |
| Robert Dallmann (Primary Supervisor) | |
| Laura Usselmann (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/N014294/1 | 01/10/2016 | 30/09/2025 | |||
| 1789397 | Studentship | MR/N014294/1 | 03/10/2016 | 31/03/2021 | Laura Usselmann |