Laboratorium Sygnalizacji Molekularnej i Komórkowej

Przekaźnictwo sygnałów jest podstawową właściwością żywych organizmów. Bodźce odbierane ze środowiska są przetwarzane i integrowane przez komórki, co prowadzi do zmiany ich morfologii i zachowania. Wadliwe przekaźnictwo sygnału stanowi podstawę wielu chorób, w tym wad rozwoju oraz raka.

W naszym laboratorium badamy różne aspekty sygnalizacji komórkowej, w szczególności  skupiając się na ścieżce Hedgehog. Sygnalizacja Hedgehog odgrywa ważną rolę w rozwoju kończyn, rdzenia kręgowego, serca oraz mózgu. Jej nadmierna aktywacja prowadzi do powstawania wielu nowotworów, w tym najczęstszego raka mózgu u dzieci – medulloblastomy. Celem naszych badań jest ustalenie mechanizmu przekazywania sygnału między receptorem Patched a czynnikami transkrypcyjnymi Gli, które są głównymi efektorami tej ścieżki w jądrze komórkowym. Aby to osiągnąć, korzystamy z wielu metod, w tym modelowania matematycznego, manipulacji genetycznej komórek, obrazowania fluorescencyjnego, proteomiki jakościowej i ilościowej, analiz transkryptomu, mysich modeli raka, oraz manipulacji zarodków kręgowców in vivo. Tak szeroki repertuar technik pozwala nam na wieloaspektowe spojrzenie na podstawowe zagadnienia z zakresu biologii molekularnej i biologii komórki, oraz na odkrywanie nowych elementarnych mechanizmów przekaźnictwa sygnału. Przewidujemy, że nasze badania posłużą do projektowania nowatorskich terapii użytecznych w leczeniu wielu chorób, między innymi nowotworów.

Dr hab. Paweł Niewiadomski
e-mail: p.niewiadomski@cent.uw.edu.pl
telefon: +48 22 55 43693
pokój: 02.104

Research Interests:

Paweł Niewiadomski’s long-term research goal is to understand how signaling pathways regulate transcription of genes in developmental processes and in disease. To this end, his research team is focusing on deciphering the mechanisms that determine transcriptional activity of Gli transcription factors, the main effectors of the Hedgehog signaling pathways. In addition to mechanistic biochemical studies, Paweł’s group also uses “big data” repositories and bioinformatic analyses to find novel promising targets for the treatment of drug-resistant cancers.

 

Current research projects:

Posttranslational modifications of Gli proteins

Gli transcription factors are large oncoproteins (>120kDa) that are heavily modified through phosphorylation, acetylation, ubiquitination, and others. These posttranslational modifications influence what compartments Gli proteins localize in, and affect their ability to activate or repress gene transcription. In cancer, the survival or rate of proliferation of tumor cells is determined by specific enzymatic modifications of Gli proteins. Therefore, enzymes that modify Gli proteins are an attractive target for cancer therapy. Our goal is to identify these enzymes using coimmunoprecipitation coupled with mass spectrometry, followed by RNAi- and CRISPR-based loss-of-function assays of Gli protein activity in vitro and in vivo.

 

Intracellular transport of Gli proteins

Gli proteins are targeted to specific cellular compartments, including the cell nucleus and the primary cilium. The inducible trafficking of Gli transcription factors to these organelles regulates their activity both in healthy development and in disease. Our goal is to elucidate mechanisms that drive Gli proteins into and out of cilia and nuclei with the hope to target these mechanisms in disease processes. To that end, we use molecular cloning, targeted mutagenesis, and microscopy coupled to semi-automated image analysis.

 

Novel therapy targets in cancer

The growth of each malignant tumor is typically driven by a handful of signaling pathways, which determine the proliferation and survival of cancer cells. However, these pathways are wired differently for different cancer types, and sometimes are not homogeneous even in different cells within the same tumor. Only by examining the molecular landscape of each cancer can we identify its “weak spots” that we can target therapeutically. We use the broadly available large datasets of genetic, epigenetic, and transcriptional changes in cancer cells and combine them with data from massive loss-of-function screens on cancer cell lines to devise new ways to kill malignant cells and overcome common mechanisms of antitumor drug resistance. These putative targets are then tested using a variety of experimental approaches – from cell line studies to in vivo experiments.

 

Positions held:

2015-                     Assistant professor/Group leader – Laboratory of Molecular and Cellular Signaling, Centre of New Technologies, University of Warsaw

2013-2015            Postdoc – Nencki Institute of Experimental Biology, Department of Cell Biology, Laboratory of Synaptogenesis

2013:                     Teaching/Research Associate – Medical University of Łódź, School of Medicine, Department of Molecular Cancerogenesis

2010-2012:          Postdoc/Research Associate – laboratory of Rajat Rohatgi MD, PhD, Stanford University.

2005-2009:          Postdoc – laboratory of James A. Waschek, PhD, David Geffen School of Medicine at UCLA

2005:                     Teaching/Research Assistant – Medical University of Łódź, School of Medicine, Department of Pharmacology

2003-2005:          Teaching Assistant – University of Łódź, Department of Mathematics

2001-2004:          Doctoral student – Medical University of Łódź in cooperation with the Department of Biogenic Amines (currently Center of Medical Biology), Polish Academy of Sciences

 

Education:

1996-2001:          MSc in Pharmacy, School of Pharmacy, Medical University of Łódź, Poland

1999/2000:          School of Pharmacy, Université Claude Bernard, Lyon, France – seven-month-long Erasmus/Socrates scholarship.

2001-2004:          PhD in Pharmaceutical Sciences, Department of Pharmacodynamics, Medical University of Łódź, under the supervision of Prof. Jolanta B. Zawilska, PhD

1998-2003:          MSc in Mathematics (specialty: Informatics), University of Łódź

 

 

Selected publications:

Coni S, Mancuso AB, Di Magno L, Sdruscia G, Manni S, Serrao SM, Rotili D, Spiombi E, Bufalieri F, Petroni M, Kusio-Kobialka M, De Smaele E, Ferretti E, Capalbo C, Mai A, Niewiadomski P, Screpanti I, Di Marcotullio L, Canettieri G. “Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma.” Scientific Reports 7:44079 (2017)

 

Waschek JA, Cohen JR, Chi GC, Proszynski TJ, Niewiadomski P. “PACAP Promotes Matrix-Driven Adhesion of Cultured Adult Murine Neural Progenitors.” ASN Neuro. 9(3):1759091417708720 (2017)

 

Niewiadomski P*, Kong JH, Ahrends R, Ma Y, Humke EW, Khan S, Teruel MN, Novitch BG, Rohatgi R, “Gli protein activity is controlled by multisite phosphorylation in vertebrate hedgehog signaling.”, Cell Reports 6: 168-81 (2014).

* first and co-corresponding author

 

Niewiadomski P, Zhujiang A, Youssef M, Waschek JA, “Interaction of PACAP with Sonic hedgehog reveals complex regulation of the hedgehog pathway by PKA.”, Cellular Signaling, 25: 2222-30 (2013).

 

Lin Y, Niewiadomski P**, Lin B**, Nakamura H**, Phua SC, Jiao J, Levchenko A, Inoue T, Rohatgi R, Inoue T, “Chemically-inducible diffusion trap at primary cilia (C-IDTc) reveals molecular sieve-like barrier”, Nature Chemical Biology,  9: 437-43 (2013).

** equal contribution

 

Hirose M**, Niewiadomski P**, Tse G, Chi GC, Dong H, Lee A, Carpenter EM, Waschek JA., “Pituitary adenylyl cyclase-activating peptide counteracts hedgehog-dependent motor neuron production in mouse embryonic stem cell cultures.”, Journal of Neuroscience Research, 89: 1363-74 (2011).

** equal contribution

 

Kim WK, Meliton V, Park KW, Hong C, Tontonoz P, Niewiadomski P, Waschek JA, Tetradis S, Parhami F., “Negative regulation of Hedgehog signaling by liver X receptors.” Molecular Endocrinology, 23: 1532-43 (2009).

 

Lelievre V, Seksenyan A, Nobuta H, Yong WH, Chhith S, Niewiadomski P, Cohen JR, Dong H, Flores A, Liau LM, Kornblum HI, Scott MP, Waschek JA. “Disruption of the PACAP gene promotes medulloblastoma in ptc1 mutant mice.”, Developmental Biology, 313: 359-70 (2008).


Rola rzęski pierwotnej w aktywacji czynników transkrypcyjnych Gli w sygnalizacji Hedgehog

Kierownik projektu: Okres: 2015 - 2020
Finansowanie: SONATA BIS, NCN
Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma.
Coni, S., Mancuso, A. B., Di Magno, L., Sdruscia, G., Manni, S., Serrao, S. M., Rotili, D., Spiombi, E., Bufalieri, F., Petroni, M. & Kusio-Kobialka M. ; De Smaele, E.; Ferretti, E.; Capalbo, C.; Mai, A.; Niewiadomski, P.; Screpanti, I.; Di Marcotullio, L.; Canettieri, G. (2017).
Scientific Reports, 7, p.44079.
PACAP Promotes Matrix-Driven Adhesion of Cultured Adult Murine Neural Progenitors.
Waschek, J. A., Cohen, J. R., Chi, G. C., Proszynski, T. J., & Niewiadomski, P. (2017).
ASN neuro, 9(3), 1759091417708720.