Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer associated mortality with <7% patients surviving for 5 years following diagnosis. This dismal prognosis is associated with late diagnosis, poor patient responsiveness to chemotherapy and a complex heterogeneous tumour microenvironment (TME) with low levels of immune infiltrates. Comprehensive molecular profiling studies have revealed common genetic driver events and have enabled tumour subtyping based on gene expression and mutational profiles whilst also elucidated signalling pathways frequently modulated during disease progression (1).
The transforming growth factor beta (TGFβ) superfamily comprises over 30 related dimeric polypeptide cytokines including the bone morphogenetic proteins (BMPs) the growth and differentiation factors (GDFs), activins, inhibins, nodal and the TGFβs. These factors play fundamental roles during development and in adult tissue homeostasis and can exhibit profound paradoxical roles in tumourigenesis acting as powerful tumour suppressors or tumour promoters in a context dependant manner. The role of TGFβ family signalling in PDAC is particularly striking with ~50% of tumours displaying significant genetic alteration of key signalling components including the TGFβ growth factor receptors TGFBR2, TGFBR1, the activin receptors ACVR2a, ACVR2b, ACVR1b and the common downstream signalling mediator SMAD4 (Cbioportal). Paradoxically elevated levels of activin a (INHBA) have been associated with poor prognosis and may act in tumour cell intrinsic and/or extrinsic manners to promote disease progression (2). Here we will seek to determine the potential tumour suppressive and tumour promoting roles and mechanisms of action of activin signalling in PDAC progression taking a multidisciplinary systematic approach to investigate the contribution of both loss of ACVR2a and gain of INHBA expression on both the tumour and the TME.
The project is part of a competition-based recruitment call by the CRUK Scotland Centre, a joint initiative between Edinburgh and Glasgow. Successful students will start in September 2022 and 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:
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.