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Impact Factor

November 2023
Frontiers in Genetics
Unraveling haplotype errors in the DFNA33 locus
Vona B, Regele S, Rad A, Strenzke N, Pater JA, Neumann K, Sturm M, Haack TB, Am Zehnhoff-Dinnesen AG
November 2023
BioRxiv
Efficient and sustained optogenetic control of nervous and cardiac systems
Zerche M, Hunniford V, Alekseev A, El May F, Vavakou A, Siegenthaler D, Hueser MA, Kiehn SM, Garrido-Charles A, Alvanos T, Witzke I, Trenholm S, Macé E, Kusch K, Bruegmann T, Wolf BJ, Mager T, Moser T
November 2023
Biorxiv
Prediction mismatch responses arise as corrections of a predictive spiking code
van Driel K, Rudelt L, Priesemann V, Mikulasch FA
November 2023
Neuropediatrics
Tazarotene and Bexarotene Show Efficacy as In Vitro Therapeutic Agents in Multiple Sulfatase Deficiency
Schlotawa l, Matysiak K, Kettwig M, Ahrens-Nicklas RC, Baud M, Berulava T, Brunetti-Pierri N, Gagne A, Herbst ZM, Maguire JA, Monfregola J, Pena T, Radhakrishnan K, Schröder S, Waxman EA, Ballabio A, Dierks T, Fischer A, French DL, Gelb MH, Gärtner J
November 2023
Brain
Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders
Kaiyrzhanov R, Rad A, Lin SJ, Bertoli-Avella A, Kallemeijn WW, Godwin A, Zaki MS, Huang K, Lau T, Petree C, Efthymiou S, Ghayoor Karimiani E, Hempel M, Normand EA, Rudnik-Schöneborn S, Schatz UA, Baggelaar MP, Ilyas M, Sultan T, Alvi JR, Ganieva M, Fowler B, Aanicai R, Akay Tayfun G, Al Saman A, Alswaid A, Amiri N, Asilova N, Shotelersuk V, Yeetong P, Azam M, Babaei M, Bahrami Monajemi G, Mohammadi P, Samie S, Banu SH, Basto JP, Kortüm F, Bauer M, Bauer P, Beetz C, Garshasbi M, Hameed Issa A, Eyaid W, Ahmed H, Hashemi N, Hassanpour K, Herman I, Ibrohimov S, Abdul-Majeed BA, Imdad M, Isrofilov M, Kaiyal Q, Khan S, Kirmse B, Koster J, Lourenço CM, Mitani T, Moldovan O, Murphy D, Najafi M, Pehlivan D, Rocha ME, Salpietro V, Schmidts M, Shalata A, Mahroum M, Talbeya JK, Taylor RW, Vazquez D, Vetro A, Waterham HR, Zaman M, Schrader TA, Chung WK, Guerrini R, Lupski JR, Gleeson J, Suri M, Jamshidi Y, Bhatia KP, Vona B, Schrader M, Severino M, Guille M, Tate EW, Varshney GK, Houlden H, Maroofian R
November 2023
Nature Structural & Molecular Biology
Structure of the transcribing RNA polymerase II-Elongin complex
Chen Y, Kokic G, Dienemann C, Dybkov O, Urlaub H, Cramer P
November 2023
Clinical Research in Cardiology
Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome
Kutschka I, Bertero E, Wasmus C, Xiao K, Yang L, Chen X, Oshima Y, Fischer M, Erk M, Arslan B, Alhasan L, Grosser D, Ermer KJ, Nickel A, Kohlhaas M, Eberl H, Rebs S, Streckfuss-Bömeke K, Schmitz W, Rehling P, Thum T, Higuchi T, Rabinowitz J, Maack C, Dudek J
November 2023
Cardiovascular Research
Contractility measurements for cardiotoxicity screening with ventricular myocardial slices of pigs
Shi R, Reichardt M, Fiegle DJ, Küpfer LK, Czajka T, Sun Z, Salditt T, Dendorfer A, Seidel T, Bruegmann T
Oktober 2023
Cell
Mammalian oocyes store proteins for the early embryo on cytoplasmic lattices
Ida M.A. Jentoft, Felix J.B. Bäuerlein, Luisa M. Welp, Benjamin H. Cooper, Arsen Petrovic, Chun So, Sarah Mae Penir, Antonio Z. Politi, Yehor Horokhovskyi, Iina Takala, Heike Eckel, Rüdiger Moltrecht, Peter Lénárt, Tommaso Cavazza, Juliane Liepe, Nils Brose, Henning Urlaub, Rubén Fernández-Busnadiego, Melina Schuh
Oktober 2023
Gastroenterology
An NFATc1/SMAD3/cJUN complex restricted to SMAD4-deficient pancreatic cancer guides rational therapies
Hasselluhn MC, Schlösser D, Versemann L, Schmidt GE, Ulisse M, Oschwald J, Zhang Z, Hamdan F, Xiao H, Kopp W, Spitalieri J, Kellner C, Schneider C, Reutlinger K, Nagarajan S, Steuber B, Sastra SA, Palermo CF, Appelhans J, Bohnenberger H, Todorovic J, Kostyuchek I, Ströbel P, Bockelmann A, König A, Ammer-Herrmenau C, Schmidleitner L, Kaulfuß S, Wollnik B, Hahn SA, Neesse A, Singh SK, Bastians H, Reichert M, Sax U, Olive KP, Johnsen SA, Schneider G, Ellenrieder V, Hessmann E

Authors

Hasselluhn MC, Schlösser D, Versemann L, Schmidt GE, Ulisse M, Oschwald J, Zhang Z, Hamdan F, Xiao H, Kopp W, Spitalieri J, Kellner C, Schneider C, Reutlinger K, Nagarajan S, Steuber B, Sastra SA, Palermo CF, Appelhans J, Bohnenberger H, Todorovic J, Kostyuchek I, Ströbel P, Bockelmann A, König A, Ammer-Herrmenau C, Schmidleitner L, Kaulfuß S, Wollnik B, Hahn SA, Neesse A, Singh SK, Bastians H, Reichert M, Sax U, Olive KP, Johnsen SA, Schneider G, Ellenrieder V, Hessmann E

Journal

Gastroenterology

Citation

Gastroenterology. 2023 Oct 30:S0016-5085(23)05202-2

Abstract

Background and aims: The highly heterogeneous cellular and molecular makeup of pancreatic ductal adenocarcinoma (PDAC) not only fosters exceptionally aggressive tumor biology but contradicts the current concept of one size fits all therapeutic strategies to combat PDAC. Therefore, we aimed to exploit the tumor biological implication and the therapeutic vulnerabilities of a clinically relevant molecular PDAC subgroup characterized by SMAD4 deficiency and high expression of the Nuclear Factor of Activated T-cells (SMAD4-/-/NFATc1High).

Methods: Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4-/-/NFATc1High cancers. In vitro and in vivo oncogenic transcription factor complex formation was studied by immunoprecipitation, proximity ligation assays, and validated cross model and species. The impact of the SMAD4 status on therapeutically targeting canonical KRAS signaling was mechanistically deciphered and corroborated by genome-wide gene expression analysis and genetic perturbation experiments, respectively. Validation of a novel tailored therapeutic option was conducted in patient-derived organoids and cells and transgenic as well as orthotopic PDAC models.

Results: Our findings determine the tumor biology of an aggressive and chemotherapy-resistant SMAD4-/-/NFATc1High subgroup. Mechanistically, we identify SMAD4 deficiency as a molecular prerequisite for the formation of an oncogenic NFATc1/SMAD3/cJUN transcription factor complex, which drives the expression of RRM1/2. RRM1/2 replenishes nucleoside pools that directly compete with metabolized gemcitabine for DNA strand incorporation. Disassembly of the NFATc1/SMAD3/cJUN complex by mitogen-activated protein kinase signaling inhibition (MEKi) normalizes RRM1/2 expression and synergizes with gemcitabine treatment in vivo to reduce the proliferative index.

Conclusion: Our results suggest that PDAC characterized by SMAD4 deficiency and oncogenic NFATc1/SMAD3/cJUN complex formation exposes sensitivity to a MEKi/gemcitabine combination therapy.

Keywords: MEK inhibition; NFATc1; RRM1/2; pancreatic cancer; stratification.

 

DOI

10.1053/j.gastro.2023.10.026

Pubmed Link

 

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