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Targeting epithelial–stromal crosstalk in metastatic colorectal cancer


Cell Biology of Cancer

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Prof O Sansom , Dr A Campbell No more applications being accepted Funded PhD Project (Students Worldwide)

About the Project

The Cancer Research UK Beatson Institute is one of Europe's leading cancer research centres, supporting cutting-edge work into the molecular mechanisms of cancer development. We provide an outstanding research environment, underpinned by state-of-the-art core services and advanced technologies with special emphasis on imaging, metabolomics and in vivo models.

Colorectal cancer (CRC) is the 4th most common cancer in the UK and the 2nd most common cause of cancer death, with metastatic spread seen as a key cause of mortality. When diagnosed at stage 4, the 5-year survival rate is less than 10 percent, and a significant number of cancers diagnosed at stage 3 recur with predominantly liver metastasis. Currently, surgical interventions are the most effective strategy for improving patient survival, although these are only effective in ~15% of patients with metastatic disease. This problem is made worse by the relative lack of effective chemotherapy in late-stage disease. For this reason, there is a clear need to develop new treatments which are effective in tackling aggressive, metastatic colorectal cancer.

For many years, the development of effective treatments for late-stage colorectal cancer has been hampered by a lack of accurate model systems that reflect human disease (Lannagan et al., 2021; Jackstadt et al., J Path, 2016). Over the last 5 years, we have developed a number of new, highly effective in vivo models that closely mimic the most aggressive forms of human metastatic colorectal cancer, and we have used these to identify potential novel effective therapies (Jackstadt et al., Cancer Cell, 2019). Critically, these cutting-edge models develop intestinal cancers that incorporate the inflammatory, immune and stromal-cell rich microenvironment found in the most aggressive human disease. In order to better understand the process underlying tumour development and progression, we have used advanced genomic and transcriptomic profiling to characterise our models, and we have identified a number of key epithelial pathways, signatures and genes which act to modify the tumour microenvironment, and in doing so, drive the process of metastasis in vivo.

As part of this PhD studentship, you will use CRISPR/Cas9 genome editing technologies, coupled with cutting-edge in vivo and organoid culture technologies, to target epithelial genes or gene programmes that may play a critical role in epithelial-to-stromal crosstalk. You will use approaches including orthotopic transplantation of CRC-derived organoid cultures, and advanced intravital imaging techniques to investigate the impact of targeted genetic alteration upon the metastatic microenvironment and the process of metastatic seeding in vivo. This research will greatly advance our understanding of metastatic colorectal cancer, and may go on to have a significant impact upon late-stage colorectal cancer in patients.

To apply, and for further details on the application process, please visit our website: http://www.beatson.gla.ac.uk/education/phd-students.htmlPlease do not email your CV.


Funding Notes

Studentships are funded for 4 years. The annual stipend will be £19,000.

References

Jackstadt R, van Hooff SR, Leach JD, Cortes-Lavaud X, Lohuis JO, Ridgway RA, Wouters VM, Roper J, Kendall TJ, Roxburgh CS, Horgan PG, Nixon C, Nourse C, Gunzer M, Clark W, Hedley A, Yilmaz OH, Rashid M, Bailey P, Biankin AV, Campbell AD, Adams DJ, Barry ST, Steele CW, Medema JP, Sansom OJ. Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis. Cancer cell. 2019; 36: 19-336.e317.
Jackstadt R, Sansom OJ. Mouse models of intestinal cancer. J Pathol. 2016; 238: 141-51
Lannagan TR, Jackstadt R, Leedham SJ, Sansom OJ. Advances in colon cancer research: in vitro and animal models. Curr Opin Genet Dev. 2021;66:50-56.
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