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Cancer Evolution under Chemotherapy Treatment

Uno, Kaname LU orcid (2024) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Background:
Chemotherapy resistance is a critical issue in oncology, being responsible for the majority of deaths in modern cancer care. My PhD work has focused on two cancer types where such drug resistance is a major clinical issue: epithelial ovarian cancer (EOC) and Wilms tumor (WT). Most EOC is sensitive to the initial platinum-based chemotherapy, but gradually becomes resistant. Although the prognosis of patients with WT is favorable, diffuse anaplasia (DA) WT is a subtype resistant to chemotherapy and associated with poor prognosis. The main theme of my thesis is how these cancer types react and adapt to chemotherapy treatment.
Methods and Results:
My thesis is based on four original articles. In paper I, we... (More)
Background:
Chemotherapy resistance is a critical issue in oncology, being responsible for the majority of deaths in modern cancer care. My PhD work has focused on two cancer types where such drug resistance is a major clinical issue: epithelial ovarian cancer (EOC) and Wilms tumor (WT). Most EOC is sensitive to the initial platinum-based chemotherapy, but gradually becomes resistant. Although the prognosis of patients with WT is favorable, diffuse anaplasia (DA) WT is a subtype resistant to chemotherapy and associated with poor prognosis. The main theme of my thesis is how these cancer types react and adapt to chemotherapy treatment.
Methods and Results:
My thesis is based on four original articles. In paper I, we investigated the definition of platinum-resistance in EOC as a function of platinum distribution using laser-ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). To predict platinum-resistance before recurrence, we analyzed EOC samples after platinum-based chemotherapy. LA-ICP-MS visualized two different platinum distribution patterns, which could be related to clinical differences in platinum-response and recurrence pattern. In papers II-III, we investigated how EOC cells metastasized through ascites as spheroids, conglomerates of EOC cells and mesothelial cells. The spheroids had high ability of invasion. The CSPG4 protein was found to play an important role to spheroid formation and invasion. RNA-sequencing showed that EOC cells altered the gene profile in mesothelial cells at spheroid formation and induced more aggressive characteristics. Finally, in study IV, we investigated the causes of chemotherapy resistance in DA WT and when and how DA emerged from a background of non-anaplastic WT tissue. We found that DA WT cells maintained proliferation in spite of having a high burden of double stranded DNA breaks and chromosomal copy number aberrations. We found that WT cells progressed towards DA, first by increased levels of proliferation, DNA damage, and morphological nuclear unrest, followed by homozygous inactivation/loss of the TP53 gene and the emergence of full-scale morphological anaplasia.
Conclusion:
Visualization of platinum in EOC tissue provides important clues to predicting platinum-resistance before recurrence. EOC cells are present as aggregated spheroids with mesothelial cells. These spheroids have a high invasive ability and are resistant to chemotherapy. EOC cells alters the tumor microenvironment through spheroid formation in ascites. In WT, one cause of chemotherapy resistance seems to be the ability of the cancer cells to continue to grow despite a high burden of DNA damage, a state strongly connected to TP53 mutation in full-scale anaplasia.
(Less)
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author
supervisor
opponent
  • Assistant Professor Herold, Nikolas, Karolinska Institute, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
keywords
ovarian cancer, Wilms tumor, chemotherapy resistance, ascites, spheroids, diffuse anaplasia
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2024:20
pages
69 pages
publisher
Lund University, Faculty of Medicine
defense location
Conference Hall at Medical Research Building No.3, Department of Medicine, Nagoya University, 65, Tsurumai-cho, Showa, Nagoya, Japan. Join by Zoom: https://us06web.zoom.us/meeting/register/tZUsdO2qpz8sGd1AmZQE9UHzkafutgb5MEZM
defense date
2024-01-18 9:00:00
ISSN
1652-8220
ISBN
978-91-8021-513-8
language
English
LU publication?
yes
id
c1d84972-f9ea-4f01-ae23-6641c7fed31e
date added to LUP
2023-12-20 15:04:39
date last changed
2023-12-29 09:32:13
@phdthesis{c1d84972-f9ea-4f01-ae23-6641c7fed31e,
  abstract     = {{Background: <br/>Chemotherapy resistance is a critical issue in oncology, being responsible for the majority of deaths in modern cancer care. My PhD work has focused on two cancer types where such drug resistance is a major clinical issue: epithelial ovarian cancer (EOC) and Wilms tumor (WT). Most EOC is sensitive to the initial platinum-based chemotherapy, but gradually becomes resistant. Although the prognosis of patients with WT is favorable, diffuse anaplasia (DA) WT is a subtype resistant to chemotherapy and associated with poor prognosis. The main theme of my thesis is how these cancer types react and adapt to chemotherapy treatment.<br/>Methods and Results: <br/>My thesis is based on four original articles. In paper I, we investigated the definition of platinum-resistance in EOC as a function of platinum distribution using laser-ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). To predict platinum-resistance before recurrence, we analyzed EOC samples after platinum-based chemotherapy. LA-ICP-MS visualized two different platinum distribution patterns, which could be related to clinical differences in platinum-response and recurrence pattern. In papers II-III, we investigated how EOC cells metastasized through ascites as spheroids, conglomerates of EOC cells and mesothelial cells. The spheroids had high ability of invasion. The CSPG4 protein was found to play an important role to spheroid formation and invasion. RNA-sequencing showed that EOC cells altered the gene profile in mesothelial cells at spheroid formation and induced more aggressive characteristics. Finally, in study IV, we investigated the causes of chemotherapy resistance in DA WT and when and how DA emerged from a background of non-anaplastic WT tissue. We found that DA WT cells maintained proliferation in spite of having a high burden of double stranded DNA breaks and chromosomal copy number aberrations. We found that WT cells progressed towards DA, first by increased levels of proliferation, DNA damage, and morphological nuclear unrest, followed by homozygous inactivation/loss of the TP53 gene and the emergence of full-scale morphological anaplasia.<br/>Conclusion: <br/>Visualization of platinum in EOC tissue provides important clues to predicting platinum-resistance before recurrence. EOC cells are present as aggregated spheroids with mesothelial cells. These spheroids have a high invasive ability and are resistant to chemotherapy. EOC cells alters the tumor microenvironment through spheroid formation in ascites. In WT, one cause of chemotherapy resistance seems to be the ability of the cancer cells to continue to grow despite a high burden of DNA damage, a state strongly connected to TP53 mutation in full-scale anaplasia.<br/>}},
  author       = {{Uno, Kaname}},
  isbn         = {{978-91-8021-513-8}},
  issn         = {{1652-8220}},
  keywords     = {{ovarian cancer; Wilms tumor; chemotherapy resistance; ascites; spheroids; diffuse anaplasia}},
  language     = {{eng}},
  number       = {{2024:20}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Cancer Evolution under Chemotherapy Treatment}},
  url          = {{https://lup.lub.lu.se/search/files/167152358/Kaname_s_thesis_book.docx}},
  year         = {{2024}},
}