Uncovering the mechanism of senescence activation in cancer cells
Lead Research Organisation:
Queen Mary University of London
Department Name: Blizard Institute of Cell and Molecular
Abstract
Activating a stable cell cycle arrest in cancer cells (pro-senescence therapy) is emerging as a novel mechanism for tumour suppression. Characteristically, senescent cells secret inflammatory molecules which are universally known as the senescence-associated secretory phenotype (SASP). The composition of these secreted molecules differ from cell type to cell type, however, the SASP profile of senescent cancer cells remains largely unexplored. In addition, robust studies have demonstrated that the SASP of senescent cells can have effects on surrounding cells in a paracrine nature.
Our group can activate senescence in cancer cells through modulation of individual ribosomal proteins. This approach will allow us to explore the SASP composition of senescent cancer cells using cytokine array analysis from conditioned medium. In turn, this information permits us to investigate the potentially beneficial or detrimental paracrine effects of the senescent cancer cell SASP on malignant and normal cells.
Following the induction of senescence in cancer cells, a key underlying question is the consequences for the ribosome's homeostasis. To address this, we will investigate possible differences to the remaining ribosomal components using a gene expression array.
A very recent study proposes that ribosomes are heterogeneous in their composition of ribosomal proteins. This heterogeneity grants the ribosomes selectivity for their transcriptome and subsequent translatome profile. Here, we speculate ribosomal heterogeneity between normal and senescent malignant cell. Consequently, modulations to the ribosome could result in changes to the protein expression profile of senescent cancer cells. Therefore, we seek to analyse the translatome profile of captured ribosome-protected mRNA fragments from normal and senescent malignant cells using ribosomal-seq.
Our investigation will elucidate the SASP composition of senescent cancer cells and determine the possible paracrine effects of this composition. Additionally, this project will demonstrate the resulting effects of modulating ribosomal proteins to induce senescence in cancer cells. Overall, this project will help us to establish the mechanisms and networks of senescence activation in cancer cells.
Our group can activate senescence in cancer cells through modulation of individual ribosomal proteins. This approach will allow us to explore the SASP composition of senescent cancer cells using cytokine array analysis from conditioned medium. In turn, this information permits us to investigate the potentially beneficial or detrimental paracrine effects of the senescent cancer cell SASP on malignant and normal cells.
Following the induction of senescence in cancer cells, a key underlying question is the consequences for the ribosome's homeostasis. To address this, we will investigate possible differences to the remaining ribosomal components using a gene expression array.
A very recent study proposes that ribosomes are heterogeneous in their composition of ribosomal proteins. This heterogeneity grants the ribosomes selectivity for their transcriptome and subsequent translatome profile. Here, we speculate ribosomal heterogeneity between normal and senescent malignant cell. Consequently, modulations to the ribosome could result in changes to the protein expression profile of senescent cancer cells. Therefore, we seek to analyse the translatome profile of captured ribosome-protected mRNA fragments from normal and senescent malignant cells using ribosomal-seq.
Our investigation will elucidate the SASP composition of senescent cancer cells and determine the possible paracrine effects of this composition. Additionally, this project will demonstrate the resulting effects of modulating ribosomal proteins to induce senescence in cancer cells. Overall, this project will help us to establish the mechanisms and networks of senescence activation in cancer cells.
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M009513/1 | 01/10/2015 | 31/03/2024 | |||
| 1754787 | Studentship | BB/M009513/1 | 01/10/2016 | 30/03/2021 | Ugochim Eduputa |
| Description | My project focuses on uncovering the mechanisms by which the genetic knockdown of two ribosomal proteins, RPS3A and RPS7 induces senescence in p16-positive basal like breast cancer model, MDA-MB-468. In the past year, two validated inducible shRNA cell lines targeting the two ribosomal proteins independently, were taken forward to prepare samples for proteomic analysis to determine functional and mechanistic targets which may contribute to senescence induction in the MDA-MB-468 cells. Data analysis have been performed on the proteomics output to validate quality of the samples and identify potential mechanistic targets. |
| Exploitation Route | The mechanistic targets identified from the proteomic analysis can be used in follow up functional studies and validation experiments, to confirm their role in senescence induction in p16-positive MDA-MB-468 cells. Additionally, the cell lines can be used in 3D in vitro studies to investigate the effects of senescent basal-like breast cancer cells within their microenvironment. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | Blizard STARS |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Postgraduate students |
| Results and Impact | Blizard STARS is a widening participation scheme which runs in collaboration with Access aspiration. The work experience scheme aims to create scientific research opportunities for pupils that are interested in furthering their education in STEM degrees. Simultaneously, the scheme proves an opportunity for postgraduate students to engage in science communication with the students and advice them on university life and science degrees where applicable. |
| Year(s) Of Engagement Activity | 2017,2018 |
| URL | https://www.qmul.ac.uk/blizard/about/work-with-us/blizard-stars/ |
| Description | Brilliant club |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Postgraduate students |
| Results and Impact | The Brilliant Club is an award-winning charity that sets out to widen the access of pupils from underrepresented backgrounds progressing to highly-selective universities. They do so by training and mobilising PhD students to share their academic expertise with pupils ranging from KS2-KS5. |
| Year(s) Of Engagement Activity | 2017,2018 |
| URL | https://thebrilliantclub.org/ |