A team of researchers around Pia Sommerkamp, who carried out her PhD thesis in the HI-STEM lab and now continues as a Postdoc, now reports alternative polyadenylation (APA) as a new layer of gene regulation. In their study, the team, which involved colleagues at the Max-Planck Institute in Freiburg and at Heidelberg University Hospital, reports APA as a new, so far unrecognized, layer of regulation of HSCs active during homeostasis and in response to emergency situations such as inflammation.

APA is a process that mediates selection of polyadenylation sites in mRNAs. It thereby regulates RNA/protein isoform expression and the length of the untranslated region of the mRNA (3’ UTR). Our study now demonstrates that the RNA regulatory mechanism APA is dynamically regulated within the hematopoietic stem cell and progenitor compartment. We could show that unperturbed APA is essential for proper HSC function. Using a novel sequencing approach to characterize the 3’ UTR in a genome-wide manner, it was possible to determine alternative polyadenylation landscapes (“APAomes”) in resting and activated HSCs, revealing distinct APA profiles and 3’ UTR length patterns. In addition, we show that metabolic reprogramming by APA is a prerequisite for HSC function in emergency situations. In the future, we will investigate whether APA regulation is also active in cancer stem cells, e.g. in leukemia, in order to evaluate possible ways to specifically interfere with this regulation in disease.

The work, which was published in Cell Stem Cell, was co-supervised by Andreas Trumpp from HI-STEM/DKFZ and Nina Cabezas-Wallscheid, HI-STEM Alumni and now a junior group leader at the Max-Planck-Institute of Immunobiology.

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  • Original Publication: Pia Sommerkamp, Sandro Altamura, Simon Renders, Andreas Narr, Luisa Ladel, Petra Zeisberger, Paula Leonie Eiben, Malak Fawaz, Michael A. Rieger, Nina Cabezas-Wallscheid und Andreas Trumpp: Differential alternative polyadenylation landscapes mediate hematopoietic stem cell activation and regulate glutamin metabolism.Cell Stem Cell 2020, DOI: 10.1016/j.stem.2020.03.003
  • DKFZ Press Release (German Version)

The LeukoSyStem consortium, which is coordinated by HI-STEM group leader Simon Haas, investigates leukaemia stem cells in acute myeloid leukaemia (AML). The German Federal Ministry of Education and Research (BMBF) financially supports this collaboration with a total sum of €2.45 M for five years as part of its eMED program on systems medicine. LeukoSystem is a collaboration between junior researchers, namely Dr. Simon Raffel (Heidelberg University Hospital), Lars Velten (CRG Barcelona), Laleh Haghverdi (EMBL Heidelberg) and Simon Haas (HI-STEM gGmbH and German Cancer Research Center (DKFZ)).

The aim of their project is to investigate the cells that are the origin of acute myeloid leukaemia (AML) and thus "get to the root of the problem". The scientists intend to use isolated single cells from patient samples to investigate characteristic markers, mutations, functional data, and metabolic pathways, to gain a better understanding of leukaemia stem cells and their environment in the bone marrow. The collected data will be evaluated comprehensively with the help of computer algorithms specially developed for the purpose.


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Lung metastasis in a breast cancer patient: the arrows indicate fibroblasts (brown) that communicate with metastatic cancer cells. Cell nuclei are stained blue. © Oskarsson, DKFZ/HI-STEM

In order to colonize other organs and grow into metastases, tumor cells that detach from the parent tumor need to manipulate their new microenvironment and create a 'metastatic niche'. Maren Pein and colleagues from the Oskarsson lab within HI-STEM and DKFZ have now discovered that disseminated breast cancer cells evoke phenotypic changes in lung fibroblasts to promote metastasis. This discovery, which is based on a collaboration with clinical partners at the National Center for Tumor Diseases (NCT) and the University Hospital in Heidelberg, plays a key role in better understanding how these dangerous metastases arise.

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Andreas Trumpp © Jutta Jung/DKFZ

On February 19, 2020, Andreas Trumpp, Managing Director of HI-STEM and Division Head at the German Cancer Research Center (DKFZ), will receive the German Cancer Prize in the 'Experimental Research' category for his trailblazing work on identifying cancer stem cells in different types of cancer. The German Cancer Prize, sponsored by the German Cancer Society and the German Cancer Foundation, is one of the most prestigious awards in German oncology. The award ceremony for the researchers will be held at the 34th German Cancer Congress in Berlin.

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