Elucidating the role of primary and secondary senescence in liver cancer

Dr Kristina Kirschner, Dr Tom Bird, Prof Stuart Forbes

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Labs:
Kirschner Group
Bird Group
Forbes Group
Duration: 4 years from September 2022
Closing Date: 27th May 2022

About us

Applications are invited from outstanding candidates to join a Cancer Research UK funded PhD programme at the Beatson Institute. These are funded by the Cancer Research UK Scotland Centre, a joint initiative between Edinburgh and Glasgow which brings together cancer scientists and clinicians from across the Universities of Edinburgh and Glasgow, delivering outstanding cancer research and improved patient care. The Cancer Research UK PhD programme is integrated into the research activities of the Centre with over 80 principal investigators contributing to this cross-disciplinary programme spanning from fundamental science to translational research. Research projects benefit from state-of-the art facilities for genomics, mass spectrometry, advanced microscopy, single cell technologies, and from advanced computational and informatics capabilities.

Project description

Senescence is a cell cycle arrest state characterised by a pro-tumorigenic secretome. Oncogene activation or exposure to DNA damaging therapy, such as chemotherapy causes accumulation of DNA damage and may trigger senescence. Through the secretion of factors like extracellular matrix proteases and interleukins and chemokines, senescent cells modulate tissue organisation and recruit immune cells, mediating their own clearance. Chronically, however the senescence associated secretory phenotype (SASP) accelerates inflammation and cancer progression. In addition, SASP factors can act in a paracrine fashion to induce secondary senescence in otherwise healthy surrounding cells and tissues (Nelson et al, Aging cell 2012, Bird and Forbes STM 2018). More recently, cell-contact mediated juxtacrine Notch signalling has also been implicated in mediating secondary senescence induction (Teo et al Cell Reports 2019, Hoare et al. Nat Cell Biol 2016). The roles of secondary senescence in-vitro and in-vivo remain elusive since its discovery. We previously

showed that these two senescent populations differ in their gene expression profiles and secretomes (Teo et al 2019), hinting at functional differences in heterogeneous senescence populations. From this we hypothesise that these different senescence forms have distinct roles in cancer with relevance for cancer formation and prevention. We will investigate the role of stromal cell primary and secondary senescence in liver cancer initiation, progression and resistance to chemotherapy in the context of therapy induced senescence.

Aim 1: Elucidate the role of primary and secondary senescence on tumorigenesis in-vitro.

We will elucidate the role of secondary senescence on tumorigenesis in-vitro. Using a co-culture system previously described (Teo et al 2019), we will produce primary senescent fibroblasts and secondary senescent stromal cells and characterise their gene expression and senescence profiles.

We will sort primary and secondary senescent cells for co-culture with liver cancer cell lines to test senescence impact on tumoral properties and response to chemotherapy by senescence profiling on a molecular and cellular level (including single cell RNA-seq).

Aim 2: Elucidate the role of primary and secondary senescence on tumorigenesis in-vivo

To investigate the role of senescence of stromal cells on acute tumorigenesis, we will co-inject senescent cell populations with liver cancer cells into mice characterising tumours, their environment and their response to chemotherapy. To investigate the role of senescence in tumour initiation and progression, we will inject senescent cell populations into the liver of transgenic mouse models susceptible to cancer and characterise precancerous lesions and tumours.

Aim 3: Test senolytics on primary and secondary senescence interacting with cancer cells in-vitro and in-vivo

Senolytics drugs specifically eliminate senescent cells. In the previous in-vitro and in-vivo models, we will test if senolytics counteract the effects of primary and secondary senescence on cancer, using standard chemotherapy with and without senolytics combination therapy.

In conclusion, this project will characterise the responses of secondary and primary senescence to therapy and provide a rationale for using senolytics to target each population as cancer therapy.

Application procedure

Up to 3 studentships are available to start in September 2022 for outstanding applicants with a stipend of £19,000 p/a. These are funded by the CRUK Scotland Centre, a joint initiative between Edinburgh and Glasgow. Successful students will be registered for their degree in either Glasgow or Edinburgh, depending on the project they apply for.

We are looking for students with a very good degree in a Life Sciences subject and an aptitude for experimental work, who are also highly committed to pursuing a PhD and a career in cancer research. You should hold at least an upper second-class degree in a relevant subject and comply with English language requirements.

All applications will be administered centrally via the University of Edinburgh, please apply on the link below - this includes Glasgow-based projects with Glasgow-based supervisors: https://www.star.euclid.ed.ac.uk/public/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=PRPHDCECRC1F&code2=0020

Closing date: 27 May 2022

Interviews are expected to be held week beginning 27 June.

Applications are open to all individuals irrespective of nationality or country of residence.

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