A spatial biology approach to interrogate altered cellular interactions in promoting DCIS progression
Primary supervisor: Louise Jones, Queen Mary University of London
Secondary supervisor: Claude Chelala, Queen Mary University of London
Collaborator: Anita Grigoriadis, King’s College London
Project
Ductal Carcinoma in-situ (DCIS) is a non-obligate precursor of breast cancer. It now comprises 20-25% of all new breast cancer diagnoses so represents a significant disease burden. However, DCIS-specific mortality is low: only 1% to 2.6% of women diagnosed with DCIS die of breast cancer within 8 to 10 years. Moreover, it is reported that <50% of DCIS lesions will ever progress to invasive disease. Despite this, standard of care is to treat all DCIS as potentially invasive, with surgery (sometimes with sentinel node biopsy) +/- radiotherapy +/- hormone therapy. For many women, this represents substantial overtreatment, but currently there are no robust biomarkers to distinguish between quiescent and potentially progressive disease.
We, and others, have shown that there are differences in the breast microenvironment that can influence disease progression [1-3]. We recently have identified changes in myoepithelial cells, fibroblasts and immune cells that associate with cancer risk in ‘normal’ breast [4].
Hypothesis and Aims:
We hypothesise that both intrinsic and acquired differences in the ductal microenvironment influence the behaviour of DCIS. These differences affect multiple components of the microenvironment including myoepithelial cells, fibroblasts and immune cells. A multi-omic approach will be taken to capture the breadth of these changes and allow associations with disease stage. This will be combined with functional analyses to demonstrate causality.
The specific aims are to:
- Carry out individual cell population isolation and single cell sequencing (scSeq) on a unique series of fresh DCIS samples to map differences between progressed and non-progressed DCIS
- Validate differentially expressed genes using multiplex immunofluorescence on tissues from these and a wider cohort of cases
- Take key differentially expressed gene(s) to assess functional relevance in vitro
Output:
This project aims to identify key alterations in the DCIS duct microenvironment that are functionally implicated in progression to invasive disease.
The project is complementary to other work in the laboratory, building a ‘signature’ of risk which will allow improved stratification of care for patients with DCIS.
Student experience:
This project will provide experience in cutting-edge laboratory technologies as well as providing training in bioinformatics analysis of molecular data – a skill likely to become highly desirable in precision medicine of the future. The student will be supported both by PIs expert in the field of breast cancer and bioinformatics, as well laboratory scientists providing on-the-ground training and supervision.
References
- Altered microenvironment promotes progression of preinvasive breast cancer: myoepithelial expression of αvβ6 integrin in DCIS identifies high-risk patients and predicts recurrence. Allen MD, Thomas GJ, Clark S, Dawoud MM, Vallath S, Payne SJ, Gomm JJ, Dreger SA, Dickinson S, Edwards DR, Pennington CJ, Sestak I, Cuzick J, Marshall JF, Hart IR, Jones JL. Clin Cancer Res. 2014 Jan 15;20(2):344-57. doi: 10.1158/1078-0432.CCR-13-1504. Epub 2013 Oct 22. PMID: 24150233
- ADAMTS3 restricts cancer invasion in models of early breast cancer progression through enhanced fibronectin degradation. SV Gibson, E Madzharova, AC Tan, MD Allen, U auf dem Keller, JL Jones, EP Carter, RP Grose. Matrix Biology 121, 74-89, 2023. doi: 10.1016/j.matbio.2023.06.005. Epub 2023 Jun 17 PMID: 37336268
- Mechanostimulation of breast myoepithelial cells induces functional changes associated with DCIS progression to invasion. Hayward MK, Allen MD, Gomm JJ, Goulding I, Thompson CL, Knight MM, Marshall JF, Jones JL. NPJ Breast Cancer. 2022 Sep 20;8(1):109. doi: 10.1038/s41523-022-00464-4. PMID: 36127361
- A single-cell atlas enables mapping of homeostatic cellular shifts in the adult human breast. Reed AD, Pensa S, Steif A, Stenning J, Kunz DJ, Porter LJ, Hua K, He P, Twigger AJ, Siu AJQ, Kania K, Barrow-McGee R, Goulding I, Gomm JJ, Speirs V, Jones JL, Marioni JC, Khaled WT. Nat Genet. 2024 Apr;56(4):652-662. doi: 10.1038/s41588-024-01688-9. Epub 2024 Mar 28. PMID: 38548988