Ding, Kai
(2022)
Multi-omics profiling of breast cancer metastases to identify drivers and mechanisms of endocrine resistance for precision medicine.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Metastatic breast cancer (MBC) is the leading cause of breast cancer (BC) related morbidity and mortality. Treatment resistance and tumor evolution and heterogeneity are major challenges of managing MBC. This thesis set out to investigate MBC evolution and heterogeneity through the lens of multi-omics to uncover drivers and mechanisms of endocrine resistance and guide precision treatment of BC bone metastasis (BoM).
We previously identified the overexpression of FGFR4 in endocrine resistant samples. Further in this thesis, we demonstrated that high FGFR4 predicts poorer survival of patients with ER+ BC and ER suppresses FGFR4 expression. However, FGFR4 cannot drive endocrine resistance in ER+ BC cell lines in vitro. FGFR4 inhibitor had a minimal effect on HER2 non-amplified cell growth but a stronger inhibition of HER2 amplified cell growth and FGFR4 showed the highest expression in HER2-enriched BC, suggesting HER2 expression may be required for FGFR4 function in BC which should be further explored. To verify FGFR4 overexpression post endocrine therapy in vivo and investigate tumor microenvironment (TME) contribution to endocrine resistance, an ER+ SSM3 syngeneic murine homograft model was utilized. Results showed an increase of myeloid cell infiltration post endocrine therapy.
To investigate the potential of multi-omics guided precision MBC treatment, we performed DNA/RNA/single cell RNA (scRNA) analyses of bilateral BoM, with matched primary invasive lobular breast carcinoma and patient derived organoids (PDO). BoM lost estrogen receptor expression, gained BRCA1 (D1834H) mutation, and upregulated multiple targetable cancer hallmark pathways. scRNA analysis uncovered a complicated microenvironment of BoM consisting of multiple epithelial cell subclones communicating extensively with TME. PDO faithfully retained features of originating BoM and were responsive to targeting driver mutations in vitro and in vivo.
In summary, I performed a comprehensive analysis of MBC evolution and heterogeneity in ER+ breast cancer. These studies have identified FGFR4 as a potential driver of endocrine resistance, however, more studies are necessary as its role in breast cancer tumorigenesis might be strictly context dependent. In addition, I have shown that multi-omics profiling of BoM and organoids modeling represent a promising approach for precision medicine for patients with breast cancer.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
28 November 2022 |
| Date Type: |
Publication |
| Defense Date: |
1 June 2022 |
| Approval Date: |
28 November 2022 |
| Submission Date: |
29 August 2022 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
153 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Integrative Systems Biology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Breast cancer, Endocrine resistance, Multi-omics, Patient derived organoids, Precision medicine |
| Date Deposited: |
29 Nov 2022 03:30 |
| Last Modified: |
29 Nov 2022 03:30 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/43682 |
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