Investigating metastatic breast cancer patient-derived organoids to identify and validate prospective therapeutic targets

  • Thomas Kedward

Student thesis: Phd

Abstract

30% of patients diagnosed with breast cancer develop metastatic disease, which has no known cure. How to better model late-stage breast cancer is an important question if we are to identify more effective therapies. Recently, many groups have demonstrated the culture of organoids from patient samples which can facilitate discovery of new breast cancer treatments. Organoids recapitulate the original sample they were derived from and so could be a more appropriate breast cancer model. Herein we reported organoids can be cultured from metastatic breast cancer cells derived from ascites or pleural effusions using media supplemented with FGF7/10. This culture condition increased breast cancer stem cell activity which promoted organoid growth. Additionally, the transcriptome, proteome and phosphoproteome was analysed of these metastatic cells to identify therapeutic targets. According to all 3 approaches, samples separated significantly based on if they were derived from ascites or pleural effusions. We observed 2 genes/proteins which were significantly upregulated within each of the ascites samples within each of the 3 datasets; LIMCH1 and TNKS1BP1. Furthermore, the organoids were used to screen the metastatic fluid for factors associated with disease progression, which identified IL-6 as a candidate. We demonstrated IL-6 increased BCSC activity and was related to disease progression and metastasis. Next, we developed an in vivo breast cancer ascites model and confirmed that metastatic fluid increased breast cancer growth within the peritoneum and its metastatic spread. This establishes IL-6 as a late-stage breast cancer therapeutic target and that patients with metastatic fluid with elevated IL-6 concentrations will benefit from anti-IL-6 therapy such as Tocilizumab. In conclusion, we report culture of organoids from cells derived from metastatic fluids. The cells can be analysed using a multiomic approach to identify possible therapeutic targets, which can be validated using organoids cultured from the same patient. Moreover, the organoids can be used to screen the patient’s metastatic fluid for factors regulating disease progression. This establishes a novel approach for modelling and identification of effective therapies for late-stage breast cancer.
Date of Award31 Dec 2022
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorSacha Howell (Supervisor), Robert Clarke (Supervisor), Angelica Santiago-Gomez (Supervisor) & Chiara Francavilla (Supervisor)

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