Signal transducer and activator of transcription (STAT)3 and STAT5 are important transcription factors that are able to mediate or even drive cancer progression through hyperactivation or gain-of-function mutations. Mutated STAT3 is mainly associated with large granular lymphocytic T-cell leukemia, whereas mutated STAT5B is associated with T-cell prolymphocytic leukemia, T-cell acute lymphoblastic leukemia and γδ T-cell-derived lymphomas. Hyperactive STAT3 and STAT5 are also implicated in various hematopoietic and solid malignancies, such as chronic and acute myeloid leukemia, melanoma or prostate cancer. Classical understanding of STAT functions is linked to their phosphorylated parallel dimer conformation, in which they induce gene transcription. However, the functions of STAT proteins are not limited to their phosphorylated dimerization form. In this review, we discuss the functions and the roles of unphosphorylated STAT3/5 in the context of chromatin remodeling, as well as the impact of STAT5 oligomerization on differential gene expression in hematopoietic neoplasms. The central involvement of STAT3/5 in cancer has made these molecules attractive targets for small-molecule drug development, but currently there are no direct STAT3/5 inhibitors of clinical grade available. We summarize the development of inhibitors against the SH2 domains of STAT3/5 and discuss their applicability as cancer therapeutics.

Malignant pleural mesothelioma (MPM), an aggressive malignancy affecting pleural surfaces, occurs in three main histological subtypes. The epithelioid and sarcomatoid subtypes are characterized by cuboid and fibroblastoid cells, respectively. The biphasic subtype contains a mixture of both. The sarcomatoid subtype expresses markers of epithelial–mesenchymal transition (EMT) and confers the worst prognosis, but the signals and pathways controlling EMT in MPM are not well understood. We demonstrate that treatment with FGF2 or EGF induced a fibroblastoid morphology in several cell lines from biphasic MPM, accompanied by scattering, decreased cell adhesion and increased invasiveness. This depended on the MAP-kinase pathway but was independent of TGFβ or PI3-kinase signaling. In addition to changes in known EMT markers, microarray analysis demonstrated differential expression of MMP1, ESM1, ETV4, PDL1 and BDKR2B in response to both growth factors and in epithelioid versus sarcomatoid MPM. Inhibition of MMP1 prevented FGF2-induced scattering and invasiveness. Moreover, in MPM cells with sarcomatoid morphology, inhibition of FGF/MAP-kinase signaling induced a more epithelioid morphology and gene expression pattern. Our findings suggest a critical role of the MAP-kinase axis in the morphological and behavioral plasticity of mesothelioma.

Rationale: Malignant pleural mesothelioma is an aggressive malignancy characterized by frequent resistance to chemo- and radiotherapy, poor outcome, and limited therapeutic options. Fibroblast growth factors (FGFs) and their receptors are potential targets for cancer therapy, but their significance in mesothelioma has remained largely undefined. Objectives: To investigate the antimesothelioma potential of FGF receptor 1 (FGFR1) inhibition. Methods: Expression of FGFs and their receptors was analyzed in mesothelioma cell lines and tissue specimens. Several cell models were used to investigate FGFR1 inhibition in vitro and in combination with cisplatin and irradiation. Mouse intraperitoneal xenotransplant models were used for in vivo validation. Measurements and Main Results: FGFR1, FGF2, and FGF18 were overexpressed in mesothelioma. Stimulation with FGF2 led to increased cell proliferation, migration, and transition to a more sarcomatoid phenotype in subsets of mesothelioma cell lines. In contrast, inhibition of FGFR1 by a specific kinase inhibitor or a dominant-negative FGFR1 construct led to significantly decreased proliferation, clonogenicity, migration, spheroid formation, and G1 cell cycle arrest in several mesothelioma cell lines, accompanied by apoptosis induction and decreased mitogen-activated protein kinase pathway activity. Reduced tumor growth, proliferation, mitogenic signaling, and apoptosis induction were observed in vivo. Inhibition of FGFR1 synergistically enhanced the cytotoxic effects of ionizing radiation and cisplatin. Conclusions: Our data suggest that the malignant phenotype of mesothelioma cells depends on intact FGF signals, which should be considered as therapeutic targets with a promising chemo- and radiosensitizing potential.

Objectives: Informal caregivers often experience a restriction in occupational balance. The self-reported questionnaire on Occupational Balance in Informal Caregivers (OBI-Care) is a measurement instrument to assess occupational balance in informal caregivers. Measurement properties of the German version of the OBI-Care had previously been assessed in parents of preterm infants exclusively. Thus, the aim of this study was to examine the measurement properties of the questionnaire in a mixed population of informal caregivers. Methods: A psychometric study was conducted, applying a multicenter cross-sectional design. Measurement properties (construct validity, internal consistency, and interpretability) of each subscale of the German version of the OBI-Care were examined. Construct validity was explored by assessing dimensionality, item fit and overall fit to the Rasch model, and threshold ordering. Internal consistency was examined with inter-item correlations, item-total correlations, Cronbach’s alpha, and person separation index. Interpretability was assessed by inspecting floor and ceiling effects. Results: A total of 196 informal caregivers, 171 (87.2%) female and 25 (12.8%) male participated in this study. Mean age of participants was 52.27 (±12.6) years. Subscale 1 was multidimensional, subscale 2 and subscale 3 were unidimensional. All items demonstrated item fit and overall fit to the Rasch model and displayed ordered thresholds. Cronbach’s Alpha and person separation index values were excellent for each subscale. There was no evidence of ceiling or floor effects. Conclusions: We identified satisfying construct validity, internal consistency, and interpretability. Thus, the findings of this study support the application of the German version of the OBI-Care to assess occupational balance in informal caregivers.

T-cell leukemias and lymphomas (TCL) form a heterogeneous group of rare and often aggressive malignancies. Because of the rarity and heterogeneity of TCL subtypes, clinical trials are challenging to conduct, making pharmacogenomic studies in cell line panels critical for the discovery of targeted therapeutics. The scarcity of data repositories with integrated multiomics and drug screening data hinders the preclinical evaluation of drug vulnerabilities and the identification of molecular markers predictive of responses to monotherapies and combinations. To address this gap, we conducted comprehensive pharmacogenomic profiling on a panel of 38 TCL cell lines, representing major clinical TCL subtypes to capture the molecular and phenotypic diversity. The TCL-38 multiomics data resource includes harmonized genetic, molecular, and epigenetic profiles, with comprehensive annotations and standardized drug response assessment of each cell line. This resource, together with machine learning predictions, was leveraged to identify TCL subtype–specific therapeutic vulnerabilities, including single-agent sensitivities and synergistic drug combinations, which were linked to genetic or epigenetic features as potential predictive biomarkers. This integrated and openly available resource (https://aittokallio.group/tcl38) could help advance the currently limited treatment options for patients with TCL. Significance: Integrated and harmonized multiomics analyses and drug screening across a heterogeneous panel of T-cell leukemias and lymphomas provide a resource to uncover drug targets and predictive biomarkers to improve patient outcomes.

Transcription as the key step in gene expression is a highly regulated process. The speed of transcription elongation depends on the underlying gene sequence and varies on a gene by gene basis. The reason for this sequence dependence is not known in detail. Recently, our group studied the cross talk between the nascent RNA and the transcribing RNA polymerase by screening the Escherichia coli genome for RNA sequences with high affinity to RNA Pol by performing genomic SELEX. This approach led to the identification of RNA polymerase-binding APtamers termed “RAPs”. RAPs can have positive and negative effects on gene expression. A subgroup is able to downregulate transcription via the activity of the termination factor Rho. In this study, we used a similar SELEX setup using yeast genomic DNA as source of RNA sequences and highly purified yeast RNA Pol II as bait and obtained almost 1300 yeast-derived RAPs. Yeast RAPs are found throughout the genome within genes and antisense to genes, they are overrepresented in the non-transcribed strand of yeast telomeres and underrepresented in intergenic regions. Genes harbouring a RAP are more likely to show lower mRNA levels. By determining the endogenous expression levels as well as using a reporter system, we show that RAPs located within coding regions can reduce the transcript level downstream of the RAP. Here we demonstrate that RAPs represent a novel type of regulatory RNA signal in Saccharomyces cerevisiae that act in cis and interfere with the elongating transcription machinery to reduce the transcriptional output.