Stefania Massari
STAT proteins as (de)regulators of metabolism in ALCL
Medizinische Universität Wien
Supervisor: Lukas KENNER
Research objective:
Over the past decades, cancer metabolism has emerged as a critical driver of tumorigenesis.
In many cancer types, the metabolic reprogramming underlying cancer onset and progression has been extensively studied. However, its role in anaplastic large cell lymphoma (ALCL) remains poorly understood.
In ALCL, the transcription factors STAT1, STAT3 and STAT5 are known to drive the oncogenic transformation and sustain tumor growth. Recent studies have highlighted their role as metabolic regulators in certain solid tumours and other haematological malignancies, yet their role in orchestrating metabolism in T-cell lymphomas is largely unexplored.
Our preliminary data show that human ALCL cell lines undergo a prominent shift in amino acid metabolism and that STAT protein knockout in splenic cells leads to deregulation of amino acid metabolic gene expression.
In this project, we aim to comprehensively investigate the metabolic reprogramming in ALCL and study the role of the STAT proteins in this process. To achieve this, we will generate an archive of ALK+ and ALK- human ALCL cell lines with knockouts of STAT1/3/5A/5B proteins. In these models, we will evaluate the STAT binding profiles, chromatin accessibility and the transcriptional landscape of metabolic genes, with a particular focus on amino acid metabolic metabolism.
After quantification of individual metabolite levels, we will functionally validate our findings in vitro through targeted modulation of key metabolites and enzymes, and in vivo using an ALK+ patient-derived xenograft (PDX) mouse model.
Expected results:
Our research will dissect the role of key STAT proteins in metabolic reprogramming in ALCL, uncovering their potential as targets for therapeutic intervention. In addition, we will generate a publicly available resource comprising STAT1, STAT3, and STAT5 binding profiles, genome-wide epigenetic landscapes regulated by these factors, chromatin accessibility maps, and associated transcriptional outputs, offering a valuable tool for investigating both metabolic and non-metabolic drivers of the disease.
Planned secondments:
Year 1: MUNI – CEITEC: gaining expertise in analyzing CUT&RUN data
Year 2: MLL Leukaemia lab: Conduct and analyse RNAseq using equipment and expertise available at the MLL lab who will provide specific training.