Dissecting the role of Activin signalling in Pancreatic Ductal Adenocarcinoma
Prof Gareth Inman & Prof Jen Morton
Labs: Growth Factor Signalling and Squamous Cancers & Preclinical Pancreatic Cancer
Duration: 4 years, starting October 2025
Closing Date: Monday 25 November 2024
Interviews for this position will take place January/February 2025
Background
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).
Research Question
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.
Skills/Techniques that will be gained
In this project we bring together a cross city supervisory team with complimentary internationally renowned expertise in pancreatic cancer (Prof Jen Morton, Dr Alan Serrels, University of Edinburgh and collaborators), TGFβ superfamily signalling (Inman) and study of the TME (Serrels, Morton). We have already generated mice harbouring the floxed allele of Acvr2a and crossed these mice to the KrasLSL-G12D/+;Pdx1–Cre PDAC model to measure effects of deletion of Acvr2a on early tumour initiation and to the KrasLSL-G12D/+;Trp53LSL-R172H/+;Pdx1–Cre mice to measure effects on tumour progression and metastasis (Morton lab). Initial analysis of these cohorts reveals a tumour suppressive role of ACVR2a in this context. Here we will take a deep phenotyping approach to understand the biological basis of these findings employing bulk RNAseq, spatial transcriptomics and multiplexed immunohistochemistry on tumour tissues isolated from these cohorts. We will also investigate tumour cell intrinsic effects of activin signalling in-vitro using ligand stimulation and inhibition coupled with overexpression, and Crispr/Cas9 mediated knockout of ACVR2a and INHBA measuring effects on cell proliferation, survival, migration and invasion employing a suite of human and mouse syngeneic PDAC cell lines (Inman and Serrels lab). We will explore downstream mediators of the biological effects using RNAseq. Using syngeneic transplantation studies we will further investigate the consequences of activin signalling modulation on the TME in-vivo with particular focus on the immune landscape using spatial transcriptomics and digital and molecular pathology (Inman/Serrels/Morton lab) and advanced intravital imaging techniques (Serrels lab) and compare observations with those made in the genetically engineered models described above (Morton lab). Students will receive expert tuition in bioinformatics (Prof Crispin Miller, CRUK SI, collaborator) to enable integration of their multimodal datasets by working closely with dedicated bioinformaticians in the host laboratories and Institutes.
For questions regarding the application process, PhD programme/studentships at the CRUK Scotland Institute or any other queries, please contact phdstudentships@beatson.gla.ac.uk.
Closing date: Monday 25 November 2024
Applications are open to all individuals irrespective of nationality or country of residence.
Relevant Publications
1. Connor AA, Gallinger S. Pancreatic cancer evolution and heterogeneity: integrating omics and clinical data. Nat Rev Cancer. 2022 Mar;22(3):131-142.
2. Qiu W, Kuo CY, Tian Y, Su GH. Dual Roles of the Activin Signaling Pathway in Pancreatic Cancer. Biomedicines. 2021 Jul 14;9(7):821.
3. Astuti Y, Raymant M, Quaranta V, Clarke K, Abudula M, Smith O, Bellomo G, Chandran-Gorner V, Nourse C, Halloran C, Ghaneh P, Palmer D, Jones RP, Campbell F, Pollard JW, Morton JP, Mielgo A, Schmid MC. Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis. Nat Cancer. 2024 Feb 14. doi: 10.1038/s43018-024-00731-2
4. Canel M, Sławińska AD, Lonergan DW, Kallor AA, Upstill-Goddard R, Davidson C, von Kriegsheim A, Biankin AV, Byron A, Alfaro J, Serrels A. FAK suppresses antigen processing and presentation to promote immune evasion in pancreatic cancer. Gut. 2023 Dec 7;73(1):131-155
5. Bailey P, Ridgway RA, Cammareri P, Treanor-Taylor M, Bailey UM, Schoenherr C, Bone M, Schreyer D, Purdie K, Thomson J, Rickaby W, Jackstadt R, Campbell AD, Dimonitsas E, Stratigos AJ, Arron ST, Wang J, Blyth K, Proby CM, Harwood CA, Sansom OJ, Leigh IM, Inman GJ. Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression. Nat Commun. 2023 Aug 25;14(1):5211
