GPMLS Distinguished Lecture Series - Professor Carl-Henrik Heldin

Professor Carl-Henrik Heldin will give a lecture in GPMLS Distinguished Lecture Series entitled "Targeting the protumorigenic effects of TGFβ in tumor treatment". Carl-Henrik is a Professor in Molecular Cell Biology at the Department of Medical Biochemistry and Microbiology at Uppsala University and former chair of the Nobel Committee.

His research focuses on the mechanisms of signal transduction by growth regulatory factors, their normal function and role in disease. In particular, platelet-derived growth factor (PDGF), a major mitogen for connective tissue cells, and transforming growth factor β (TGF β), which inhibits the growth of most cell types, are studied. An important goal is to explore the possible clinical utility of signal transduction antagonists.

Carl-Henrik Heldin is a member of several learned societies, including the European Molecular Biology Organization, the Royal Swedish Academy of Sciences, Academia Europea, and American Academy of Arts and Sciences.

He has published more than 440 research articles and 210 reviews and his work has been heavily cited (H-index 142). He has received several scientific awards, including Prix Antoine Lacassagne (1989), K. Fernströms Large Medical Prize (1993), the Pezcoller-American Association for Cancer Research Award (2002) and Anders Jahre´s Large Medical Prize (2019).

The lecture will be held in English.

Abstract:

Transforming growth factor-b (TGFb) is the prototype of a large family of cytokines which consists of more than 30 members, including TGFb isoforms, bone morphogenetic proteins, activins, inhibins and anti-Mullerian hormone. Members of the TGFb family regulate growth, survival and differentiation of most cell types, by binding to type I and type II receptors (TbRI and TbRII, respectively). The receptors are equipped with kinase domains with ability to phosphorylate serine/threonine residues, as well as tyrosine residues. Unique for TGFb signaling is activation of Smad molecules which act as transcription factors in the nucleus, but TGFb also activates non-Smad pathways, including Erk1/2, JNK and p38 MAP-kinases, phosphatidylinositol 3´-kinase (PI3K) and the tyrosine kinase Src, as well as liberation of the intracellular domain of TbRI which is translocated to the nucleus and acts as a transcription factor, driving an invasiveness program (Mu et al. (2011) Nat. Commun, 2, 30; Gudey et al. (2014) Sci.Signal. 7, ra2).

In cancer, TGFb is initially a tumor suppressor since it inhibits cell proliferation and induces apoptosis, but acquires tumor promoting activities at later stages of tumor progression, including induction of epithelial-mesenchymal transition (EMT), which increases invasiveness and metastasis of tumor cells. We aim to develop selective TGFb inhibitors which inhibit only the tumor promoting effects of TGFb. For this purpose, we have identified the mechanisms by which the pathways inducing invasiveness and metastasis are activated. The activation of p38 MAP-kinase (Sorrentino et al. (2008) Nature Cell Biol. 10, 1199-1207) and PI3K (Hamidi et al. (2017) Sci.Signal. 10, eeal4186) are independent of the kinase activities of the receptors, but instead depends of the ubiquitin ligase TRAF6 which binds to TbRI. In contrast, activation of Src depends on phosphorylation of Tyr182 in TbRI by TbRII, providing a docking site for the SH2 domain of Src, thus opening up the catalytic pocket of its kinase domain (Yakymovych el al. (2022) Sci.Signal., 15, eabp9521). Our aim is to explore whether TGFb inhibitors that selectively inhibits the tumor promoting pathways and leaves the tumor suppressing pathways unperturbed, are useful for treatment of patients with advanced cancers.