GPMLS öndvegisfyrirlestur - Prófessor Carl-Henrik Heldin

Prófessor Carl-Henrik Heldin mun halda fyrirlestur í öndvegisfyrirlesararöð GPMLS undir yfirskriftinni "Targeting the protumorigenic effects of TGFβ in tumor treatment". Carl-Henrik er prófessor í sameindafrumulíffræði við lífefna- og örverufræðideild Uppsalaháskóla og fyrrum formaður sænsku Nóbelsnefndarinnar. 

Rannsóknaráhugi Carl-Henrik beinist að ferlum að baki boðmiðlunar vaxtarþátta, eðlilegri virkni þeirra og hlutverki í sjúkdómum. Sérstaklega eru rannsakaðir vaxtarþættirnir PDGF, sem er aðal mítógen fyrir bandvefsfrumur, og TGFβ, sem hindrar vöxt flestra frumutegunda. Mikilvægt markmið hópsins er að kanna mögulega klíníska gagnsemi boðmiðlunarblokka.

Heldin er meðlimur í nokkrum lærðum félögum, þar á meðal European Molecular Biology Organization, Konunglegu sænsku vísindaakademíunni, Academia Europea og American Academy of Arts and Sciences. 

Heldin hefur birt meira en 440 rannsóknargreinar og 210 yfirlitsgreinar og mikið hefur verið vitnað í greinar hans (H-index 142). Einnig hefur Carl-Henrik hlotið fjölda vísindaverðlauna, þar á meðal Prix Antoine Lacassagne (1989), K. Fernströms Large Medical Prize (1993), Pezcoller-American Association for Cancer Research Award (2002) og Anders Jahre´s Large Medical Prize (2019). 

Fyrirlestur Carl-Henriks fer fram á ensku.

Ágrip á ensku: 

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.