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Delineating Phenotypic Plasticity in Breast Cancer

Vulin, Milica. Delineating Phenotypic Plasticity in Breast Cancer. 2021, Doctoral Thesis, University of Basel, Faculty of Science.

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Abstract

Phenotypic plasticity describes the reversible switch of cellular states. Cancer cells are characterized by high phenotypic plasticity, endowing them with the ability to metastasize and resist to therapies. In breast cancer, triple-negative is the subtype with high cellular plasticity resulting in higher aggressiveness and poor prognosis compared to other subtypes. Whether plasticity poses a vulnerability to cancer cells remains elusive. The underlying molecular mechanisms are also poorly understood. To identify such fundamental mechanisms of plasticity is paramount for detecting vulnerabilities of this currently incurable disease.
In the first project, I asked whether cancer cell plasticity can be exploited to differentiate triple-negative breast cancer. Using a high-throughput reporter drug screen with 9,501 compounds, we identify three polo-like kinase 1 (PLK1) inhibitors as major inducers of estrogen receptor (ER) protein expression and downstream activity, a major differentiation marker of the breast. PLK1 inhibition upregulates cell differentiation programs paralleled by increased DNA damage, mitotic arrest and ultimately cell death. Notably, cells surviving PLK1 inhibition have decreased tumorigenic potential, and targeting PLK1 in already established tumours reduces tumour growth, both in cell line and patient-derived xenograft models. In addition, genes upregulated upon PLK1 inhibition are correlated with those expressed in normal breast tissue and confer better overall survival in breast cancer patients. Our results indicate that differentiation therapy based on PLK1 inhibition might be an alternative strategy to treat triple-negative breast cancer.
In the second project, I aimed to identify fundamental plasticity programs important for metastatic colonisation, the last and fatal step of tumour progression. In this regard, we compared expression profiles of breast cancer metastases to primary tumours and focused on metabolic genes conferring higher metastatic potential to cancer cells. We show that the metabolic protein nicotinamide N-methyltransferase (NNMT) is a factor in early metastatic colonisation of triple-negative breast cancer. NNMT stimulates an epigenetic program that drives stromal mimicry via cancer cell-intrinsic secretion of extracellular matrix (ECM) components. Such ECM deposition is critical in the engraftment of breast cancer cells in distant organs. Depletion of NNMT profoundly impairs metastases formation as well as the expression of collagens and the collagen processing machinery in cancer cells. Mechanistically, NNMT depletion results in a methyl overflow that increases H3K9me3 and DNA cytosine methylation at the promoter of PR/SET Domain 5 (PRDM5), a potent inducer of collagen gene transcription. Moreover, NNMT ablation increases DNA cytosine methylation at the promoters of collagen genes. Altogether, increased H3K9me3 and DNA methylation result in a locked epigenetic state that represses the expression of ECM components. The second study reveals a major effect of NNMT and methyl shortage in promoting metastatic colonisation via cancer cell intrinsic stromal mimicry, and thereby uncovers a novel plasticity program during metastatic progression.
Advisors:Christofori, Gerhard M. and Bentires-Alj, Mohamed and Khaled, Walid
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Tumor Biology (Christofori)
UniBasel Contributors:Christofori, Gerhard M. and Bentires-Alj, Mohamed
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14570
Thesis status:Complete
Number of Pages:184
Language:English
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss145701
edoc DOI:
Last Modified:15 Feb 2022 11:01
Deposited On:18 Jan 2022 11:35

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