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Victoria James - Uncovering how triple negative breast cancer communicates to nearby non-cancer cells in order to mediate treatment resistance 2020 Pilot Grant

Lay summary

Background: Triple negative breast cancer (TNBC) is an aggressive type of breast cancer that accounts for 20% of cases, but disproportionately 83% of deaths compared to other breast cancer types. One reason for this maybe the relationship between the TNBC and the non-cancer cells surrounding it. We and others have found that tumour cells can communicate with non-cancer cells in the surrounding healthy tissue, by sending packets of biological material. When received, the non-cancer cells start to exhibit abnormal behaviors, which subsequently help to support the tumour to grow, spread and resist treatment.
Aims: This study aims to investigate a previously unstudied mechanism of communication between the tumour and the non-cancer cells, to determine if this aids the treatment resistance seen for TNBCs. These findings may allow us to improve the effectiveness of current chemotherapy drugs.
Techniques and Methodology: We will use models of TNBC grown in the lab, based on cancer cells isolated from patients. Testing how tumour cells communicate with noncancer cells that are usually abundant in the tissue that surrounds the tumour within the breast. We previously applied these techniques to determine how prostate cancer spreads and can now leverage the knowledge gained for the benefit of breast cancer patients.
Impact on breast cancer research: In order to more effectively treat TNBC’s we need to understand why the tumours are resistant to treatment. This pilot study will determine if this unstudied mechanism of communication between the TNBC cells and non-cancer cells allows the non-cancer cells to contribute to this resistance to common chemotherapy drugs. The results of this work could lead to the development of drugs that target the abnormal behavior of non-cancer cells that have been in communication with the tumour, allowing chemotherapy drugs already in use to be much more efficient in tackling TNBCs.

Scientific Summary

Background: The tumour microenvironment (TME) is intrinsic to triple negative breast cancer (TNBC) development, contributing to the aggressive nature and drug resistance characteristic of this breast cancer type. Recent evidence supports extracellular vesicles (EVs) as a mechanism of reciprocal communication between TNBC cells and the TME, which can predispose to increased chemotherapeutic resistance. Therefore, we hypothesise that EVs produced by TNBC, re-educate the TME to create a pro-growth environment which mitigates the effects of chemotherapeutics
Aims: Demonstrate TNBC-EVs re-educate TME cell types to produce an environment conducive to support/enhance tumour growth Determine if TNBC-EV re-education of the microenvironment abrogates the effects of chemotherapeutics
Techniques and Methodology: In vitro co-culture models of the TME will be used to determine the effects of EVs isolated from TNBC example cell types HCC1806, MDAMB-231 and controls.
Impact on breast cancer research: Understanding how the TME is modified to support to chemotherapeutic resistance, may lead to improvements in the efficacy of current chemotherapeutics and shape the design of TNBC subtype specific approaches to include the TME

Nottingham Breast Cancer Research Centre (NBCRC)

University of Nottingham
Biodiscovery Institute (Room C214)
University Park
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Nottingham, NG7 2RD