Dissecting the role of Activin signalling in Pancreatic Ductal Adenocarcinoma

Professor Jennifer Morton, Dr Alan Serrels, Professor Gareth Inman

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.

Lab websites

https://www.beatson.gla.ac.uk/Invasion-and-Metastasis/jennifer-morton-preclinical-precision-pancreas.html

https://www.ed.ac.uk/inflammation-research/people/associate-members/dr-alan-serrels

https://www.beatson.gla.ac.uk/Cancer-Metabolism-Growth-and-Survival/gareth-inman.html