Understanding the role of TGFbeta signalling in cancer

Programme stream(s): Cancer discovery / underpinning research

Chair: Gareth Inman, University of Dundee, UK
Presenter: Madelon Paauwe, Beatson Institute for Cancer Research, UK
Speaker: Carl-Henrik Heldin, The Ludwig Institute for Cancer Research, UK
Speaker: Caroline Hill, The Francis Crick Institute, UK
Speaker: Joan Seoane, Val D’Hebron Institute of Oncology, Spain

2:00 pm-4:00 pm

Room: Boisdale

TGFb is a pleitropic cytokine that can have profound effects on the development, progression and metastatic spread of tumours acting as a potent tumour suppressor or powerful tumour promoter in a context dependent manner. Understanding, how, where and when TGFb signalling influences these processes is the focus of this session. The regulation and control of TGFb signalling pathway dynamics, the molecular mechanisms underpinning TGFb driven tumour control and the potential of targeting TGFb signalling for tumour therapy will be discussed. This session should appeal to basic scientists, clinical academics, oncologists and the pharmaceutical industry.

Abstract presentation:
Endoglin expression on cancer-associated fibroblasts regulates invasion and stimulates colorectal cancer metastasis – Madelon Paauwe

Inhibition of the pro-tumorigenic effects of TGFbeta in tumor therapy
Speaker: Carl-Henrik Heldin
Affiliation: Uppsala University


Transforming growth factor-beta (TGFbeta) regulates growth, survival and differentiation of most cell types. It signals by binding to type I and type II serine/threonine kinase receptors, leading to activation of Smad molecules that form complexes which act as transcription factors in the nucleus. TGFbeta also activates non-Smad pathways, including Erk1/2, JNK and p38 MAP kinases, Src, phosphatidylinositol 3´-kinase (PI3K), and formation of a soluble intracellular domain of the type I receptor (TbetaRI-ICD). In cancer, TGFbeta is initially a tumor suppressor, but acquires tumor promoting activities at later stages of tumor progression, including induction of epithelial-mesenchymal transition (EMT), which is correlated to increased invasiveness and metastasis. We aim at developing selective TGFbeta inhibitors which inhibit only the tumor promoting effects of TGFbeta. For this purpose, we are identifying the pathways involved, e.g. TbetaRI-ICD, PI3K Erk1/2 MAPK kinases and Src, and the mechanisms whereby TGFbeta induces these pathways. Moreover, we have screened for low molecular weight inhibitors of TGFbeta-induced EMT. Our aim is to explore whether such compounds, or other selective inhibitors of the pro-tumorigenic effects of TGFbeta which we are developing, can be used for improved treatment of patients with advanced cancers.

Deregulated TGF-β signalling in cancer
Speaker: Caroline Hill
Affiliation: The Francis Crick Institute


Deregulated TGF-β signalling has long been known to play a key role in many different types of cancer. We are studying the mechanism of TGF-β signalling to understand better how the pathway is deregulated in cancer, and to pinpoint exactly what roles TGF-β signalling plays in tumour growth and spread. Two recent key findings from my lab have made us re-evaluate the role of TGF-β signalling in cancer. Firstly, we discovered that cells treated acutely with TGF-β become refractory to further stimulation. This means that cells experiencing prolonged chronic TGF-β signalling counterintuitively exhibit very low signalling activity. This suggested that in cancer, where tumours frequently exhibit high levels of TGF-β signalling, the TGF-β pathway might be rewired. I will discuss the results from a loss-of-function screen designed to identify mechanisms that alter the dynamics of TGF-β signalling. Secondly, we have shown that TGF-β not only signals through SMAD2/3, but also through SMAD1/5, the receptor-regulated SMADs that are traditionally thought to be activated by BMP signalling. Importantly, we have shown that both pathways are essential for TGF-β-induced EMT. I will discuss our recent insights into the role of SMAD1/5 signalling in cancer.

Role of TGF-beta in glioblastoma
Speaker: Joan Seoane
Affiliation: Vall d’Hebron University Hospital


During the last decades, the TGF pathway has emerged as a therapeutic target against
cancer. However, TGF has a complex role in cancer. During tumour progression TGF
becomes an oncogenic factor inducing proliferation, angiogenesis, invasion, and
metastasis, as well as suppressing the anti-tumoral immune response. The precise
understanding of the role of TGF in oncogenesis is required in order to design optimal
therapeutic approaches and select the patient population that may benefit from an anti-
TGF therapy. I will present our work related to the role of TGF in glioblastoma
focusing on the impact of TGF on the tumour microenvironment. Our works aims at
providing biomarkers of response to TGF signalling inhibitors through the
understanding of the TGF oncogenic response in glioblastoma.