Cancer and Therapy: A look into stemness and the tumour microenvironment
Rodriguez, Carmen LU
(2022)
In Lund University, Faculty of Medicine Doctoral Dissertation Series
- Abstract
- Therapy is the often-used treatment for cancer patients, even those that undergo resection surgery. While milestones have been surpassed throughout the decades for a number of cancer types, there are those that comprise of characteristics limiting effectiveness of treatments. For these, such as some breast and pancreatic cancers, other pursuits must be explored to identify avenues for beneficial therapies.
In this study, we explore mechanisms in breast cancer cells that potentially lead to recurrence. Alterations in both COMP and the STRIPAK complex are able to further affect cellular processes leading to recurrence capability in different ways. Over-expression of COMP leads to activation of Notch which affects both Wnt/β-catenin and... (More) - Therapy is the often-used treatment for cancer patients, even those that undergo resection surgery. While milestones have been surpassed throughout the decades for a number of cancer types, there are those that comprise of characteristics limiting effectiveness of treatments. For these, such as some breast and pancreatic cancers, other pursuits must be explored to identify avenues for beneficial therapies.
In this study, we explore mechanisms in breast cancer cells that potentially lead to recurrence. Alterations in both COMP and the STRIPAK complex are able to further affect cellular processes leading to recurrence capability in different ways. Over-expression of COMP leads to activation of Notch which affects both Wnt/β-catenin and AKT pathways, already affected by COMP. The resulting effect is the rise in stem-like cells within the COMP-overexpressing population, able to propagate further even when in limited quantities. Similarly, depletion in the STRIPAK component STRIP1 affects activation of GCKIII kinases and cell cycle disruption through elevated expression of cyclin dependent kinase inhibitors p21 and p27, enhanced levels of which lead to a protective effect from therapeutic treatments and increased proliferation. Both of these altered proteins lead to the eventual ability of cancer cell recurrence.
The tumour microenvironment (TME) contains several other cell types apart from cancer cells which play a role not only in the regulation of the environment but in response to treatments. Cancer associated fibroblasts (CAFs) are vital in their role to affect the TME through manipulation of the structural components and through secreted factors. In attempting to understanding ways to gauge therapeutic response to treatment, a 3D coculture model was established for quick, high throughput analysis of treatment on CAF functionality and subsequent effect on invasion capability. As a component of the TME, a highly specific chondroitin sulfate was investigated as a likely drug target for the purposes of stromal targeting within breast and pancreatic cancers. Through high specificity, targeted treatment can overcome the unfortunate side effects to normal tissue.
In this compiled work, we elaborate on the effect of protein expression alterations and their resulting effect on recurrence capability of cells. We explore signalling alterations resulting in cancer stem cells as well as cell cycle arrest and cell fate determination. Other TME components are investigated for the purpose of anti-stromal therapy as a method to bypass the desmoplastic reaction within certain tumour types. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/fe930373-d3bf-4893-9b98-38414be765b2
- author
- Rodriguez, Carmen
LU
- supervisor
-
- Kristian Pietras LU
- Anna Blom LU
- opponent
-
- Professor O'Neill, Eric, University of Oxford
- organization
- publishing date
- 2022
- type
- Thesis
- publication status
- published
- subject
- keywords
- COMP, STRIPAK, Notch, p21, oncofetal chondroitin sulfate, therapy, tumour microenvironment
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2022:87
- pages
- 86 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Sharience, The Spark, Medicon Village, Scheeletorget 1 i Lund
- defense date
- 2022-06-09 09:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-248-9
- language
- English
- LU publication?
- yes
- id
- fe930373-d3bf-4893-9b98-38414be765b2
- date added to LUP
- 2022-05-19 09:11:03
- date last changed
- 2022-06-29 14:38:32
@phdthesis{fe930373-d3bf-4893-9b98-38414be765b2,
abstract = {{Therapy is the often-used treatment for cancer patients, even those that undergo resection surgery. While milestones have been surpassed throughout the decades for a number of cancer types, there are those that comprise of characteristics limiting effectiveness of treatments. For these, such as some breast and pancreatic cancers, other pursuits must be explored to identify avenues for beneficial therapies.<br/>In this study, we explore mechanisms in breast cancer cells that potentially lead to recurrence. Alterations in both COMP and the STRIPAK complex are able to further affect cellular processes leading to recurrence capability in different ways. Over-expression of COMP leads to activation of Notch which affects both Wnt/β-catenin and AKT pathways, already affected by COMP. The resulting effect is the rise in stem-like cells within the COMP-overexpressing population, able to propagate further even when in limited quantities. Similarly, depletion in the STRIPAK component STRIP1 affects activation of GCKIII kinases and cell cycle disruption through elevated expression of cyclin dependent kinase inhibitors p21 and p27, enhanced levels of which lead to a protective effect from therapeutic treatments and increased proliferation. Both of these altered proteins lead to the eventual ability of cancer cell recurrence.<br/>The tumour microenvironment (TME) contains several other cell types apart from cancer cells which play a role not only in the regulation of the environment but in response to treatments. Cancer associated fibroblasts (CAFs) are vital in their role to affect the TME through manipulation of the structural components and through secreted factors. In attempting to understanding ways to gauge therapeutic response to treatment, a 3D coculture model was established for quick, high throughput analysis of treatment on CAF functionality and subsequent effect on invasion capability. As a component of the TME, a highly specific chondroitin sulfate was investigated as a likely drug target for the purposes of stromal targeting within breast and pancreatic cancers. Through high specificity, targeted treatment can overcome the unfortunate side effects to normal tissue.<br/>In this compiled work, we elaborate on the effect of protein expression alterations and their resulting effect on recurrence capability of cells. We explore signalling alterations resulting in cancer stem cells as well as cell cycle arrest and cell fate determination. Other TME components are investigated for the purpose of anti-stromal therapy as a method to bypass the desmoplastic reaction within certain tumour types.}},
author = {{Rodriguez, Carmen}},
isbn = {{978-91-8021-248-9}},
issn = {{1652-8220}},
keywords = {{COMP; STRIPAK; Notch; p21; oncofetal chondroitin sulfate; therapy; tumour microenvironment}},
language = {{eng}},
number = {{2022:87}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Cancer and Therapy: A look into stemness and the tumour microenvironment}},
url = {{https://lup.lub.lu.se/search/files/118672022/Cancer_and_Therapy_A_look_into_stemness_and_the_tumour_microenvironment_Electronic.pdf}},
year = {{2022}},
}