TY  - JOUR
A1  - Prieto-Garcia, Cristian
A1  - Tomašković, Ines
A1  - Shah, Varun Jayeshkumar
A1  - Dikic, Ivan
A1  - Diefenbacher, Markus
T1  - USP28: oncogene or tumor suppressor? a unifying paradigm for squamous cell carcinoma
JF  - Cells
N2  - Squamous cell carcinomas are therapeutically challenging tumor entities. Low response rates to radiotherapy and chemotherapy are commonly observed in squamous patients and, accordingly, the mortality rate is relatively high compared to other tumor entities. Recently, targeting USP28 has been emerged as a potential alternative to improve the therapeutic response and clinical outcomes of squamous patients. USP28 is a catalytically active deubiquitinase that governs a plethora of biological processes, including cellular proliferation, DNA damage repair, apoptosis and oncogenesis. In squamous cell carcinoma, USP28 is strongly expressed and stabilizes the essential squamous transcription factor ΔNp63, together with important oncogenic factors, such as NOTCH1, c-MYC and c-JUN. It is presumed that USP28 is an oncoprotein; however, recent data suggest that the deubiquitinase also has an antineoplastic effect regulating important tumor suppressor proteins, such as p53 and CHK2. In this review, we discuss: (1) The emerging role of USP28 in cancer. (2) The complexity and mutational landscape of squamous tumors. (3) The genetic alterations and cellular pathways that determine the function of USP28 in squamous cancer. (4) The development and current state of novel USP28 inhibitors.
KW  - USP28
KW  - SCC
KW  - USP25
KW  - FBXW7
KW  - Tp63
KW  - c-MYC
KW  - ΔNp63
KW  - p53
KW  - cancer
KW  - DUB inhibitor
KW  - squamous
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248409
SN  - 2073-4409
VL  - 10
IS  - 10
ER  - 
TY  - JOUR
A1  - Hartmann, Oliver
A1  - Reissland, Michaela
A1  - Maier, Carina R.
A1  - Fischer, Thomas
A1  - Prieto-Garcia, Cristian
A1  - Baluapuri, Apoorva
A1  - Schwarz, Jessica
A1  - Schmitz, Werner
A1  - Garrido-Rodriguez, Martin
A1  - Pahor, Nikolett
A1  - Davies, Clare C.
A1  - Bassermann, Florian
A1  - Orian, Amir
A1  - Wolf, Elmar
A1  - Schulze, Almut
A1  - Calzado, Marco A.
A1  - Rosenfeldt, Mathias T.
A1  - Diefenbacher, Markus E.
T1  - Implementation of CRISPR/Cas9 Genome Editing to Generate Murine Lung Cancer Models That Depict the Mutational Landscape of Human Disease
JF  - Frontiers in Cell and Developmental Biology
N2  - Lung cancer is the most common cancer worldwide and the leading cause of cancer-related deaths in both men and women. Despite the development of novel therapeutic interventions, the 5-year survival rate for non-small cell lung cancer (NSCLC) patients remains low, demonstrating the necessity for novel treatments. One strategy to improve translational research is the development of surrogate models reflecting somatic mutations identified in lung cancer patients as these impact treatment responses. With the advent of CRISPR-mediated genome editing, gene deletion as well as site-directed integration of point mutations enabled us to model human malignancies in more detail than ever before. Here, we report that by using CRISPR/Cas9-mediated targeting of Trp53 and KRas, we recapitulated the classic murine NSCLC model Trp53fl/fl:lsl-KRasG12D/wt. Developing tumors were indistinguishable from Trp53fl/fl:lsl-KRasG12D/wt-derived tumors with regard to morphology, marker expression, and transcriptional profiles. We demonstrate the applicability of CRISPR for tumor modeling in vivo and ameliorating the need to use conventional genetically engineered mouse models. Furthermore, tumor onset was not only achieved in constitutive Cas9 expression but also in wild-type animals via infection of lung epithelial cells with two discrete AAVs encoding different parts of the CRISPR machinery. While conventional mouse models require extensive husbandry to integrate new genetic features allowing for gene targeting, basic molecular methods suffice to inflict the desired genetic alterations in vivo. Utilizing the CRISPR toolbox, in vivo cancer research and modeling is rapidly evolving and enables researchers to swiftly develop new, clinically relevant surrogate models for translational research.
KW  - non-small cell lung cancer
KW  - CRISPR-Cas9
KW  - mouse model
KW  - lung cancer
KW  - MYC
KW  - JUN
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230949
SN  - 2296-634X
VL  - 9
ER  -