Cancer and Therapy: A look into stemness and the tumour microenvironment

Project: Dissertation

Project Details

Description

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.

Popular science description

In many instances for cancer patients, chemotherapeutics are the only viable options for treatment. There are however, varying effects that it can have on the patients and type of cancer involved. Both the cancer cells and cancer associated fibroblasts (CAFs) can be affected by therapies and propagate the effects to their surroundings, however, depending on the function of each cell, the effect of therapy upon it can vary.
In this study, we investigate the effects that alterations of proteins can have on tumour signalling and cell fate when we examine the role of COMP and a STRIPAK complex component, STRIP1, in breast cancer. Enhanced COMP expression within breast cancer is shown to lead to a poorer prognosis in patients while altering pathways such as Notch, Wnt/ -catenin, and AKT. Consequently, due to these alterations, cancer stem cells (CSCs) increase in the population, being able to evade immune and therapeutic responses and aid in the continued growth of the tumour. In a somewhat similar manner, when STRIP1 is depleted, there is hyperactivation of the GCKIII kinases, leading to cell cycle arrest. Upon treatment with therapy however, these STRIP1-depleted cells better survive the treatment and become more proliferative than wildtype treated cells. The varying effect of therapy on the heterogeneous population of cancer cells conveys the difficulty of identifying proper treatment for patients and the possible eventuality of recurrence.
CAFs similarly play a significant role in the tumour and in therapeutic response, and the identification of new ways to gauge response to therapy is vital. With the difficulty of understanding the functionality of CAFs in the typical 2D culture system, we redeveloped an established 3D coculture model for faster, more high-throughput needs. Within a matter of days, rather than weeks, CAF functionality can be analysed when comparing varying cell lines, cell manipulations, and/or drug treatments. Functionality of CAFs and their effects from therapy is only one aspect of whole role they provide in the tumour microenvironment (TME). CAFs often secrete and deposit material to create the structural extracellular matrix (ECM) which can affect signalling between numerous components. We have identified that CAFs secrete a highly specific chondroitin sulfate, not found in normal tissue outside the placenta. The deposition of this oncofetal chondroitin sulfate (ofCS) is found to increase as cancer progresses. Importantly, the use of a recombinant malarial protein, rVAR2, specifically binding to ofCS, is now providing the prospect to deliver drugs to the specific tumour areas and decreasing unnecessary toxicity to normal cells.
In conclusion, this study describes several aspects of cancer and the tumour microenvironment. We shed light on the difficulty of treatment for cancer patients as their physiological uniqueness and the uniqueness of the tumours pose distinctive characteristics that can respond differently. We emphasize the continued pursuit of personalised therapies due to molecular signatures and even combination therapies to enhance the specified functions of currently used treatments.
StatusFinished
Effective start/end date2018/08/202022/06/09

Free keywords

  • COMP
  • STRIPAK
  • Notch
  • p21
  • oncofetal chondroitin sulfate
  • therapy
  • tumour microenvironment