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Abstract RNA-binding proteins have increasingly been identified as important regulators of gene expression given their ability to bind distinct RNA sequences and regulate their fate. Mounting evidence suggests that RNA-binding proteins are involved in the onset and progression of multiple malignancies, prompting increasing interest in their potential for therapeutic intervention. The Musashi RNA binding proteins Musashi-1 and Musashi-2 were initially identified as developmental factors of the nervous system but have more recently been found to be ubiquitously expressed in physiological tissues and may be involved in pathological cell behavior. Both proteins are increasingly investigated in cancers given dysregulation in multiple tumor entities, including in female malignancies. Recent data suggest that the Musashi proteins serve as cancer stem cell markers as they contribute to cancer cell proliferation and therapy resistance, prompting efforts to identify mechanisms to target them. However, as the picture remains incomplete, continuous efforts to elucidate their role in different signaling pathways remain ongoing. In this review, we focus on the roles of Musashi proteins in tumors of the female – breast, endometrial, ovarian and cervical cancer – as we aim to summarize current knowledge and discuss future perspectives.

Abstract Background Endometrial carcinoma is the most common gynecological cancer in Europe. Musashi-1 is known to be a key regulator of endometrial cancer stem cells and a negative prognostic marker. In the present study, we aimed to understand growth and gene expression patterns in endometrial carcinoma after Musashi-1 knockdown in vitro and in vivo. Changes in therapeutic resistance were also assessed. Methods First, we performed analyses to understand Musashi-1 expression patterns using The Cancer Genome Atlas database. We then proceeded to assess effects of small interfering RNA-based Musashi-1 targeting in two endometrial carcinoma cell lines, Ishikawa and KLE. After quantifying baseline changes in cell metabolism, we used MTT tests to assess chemotherapy effects and colony formation assays to understand changes in radioresistance. For mechanistic study, we used quantitative polymerase chain reaction (qPCR) and western blotting of key Musashi-1 target genes and compared results to primary tissue database studies. Finally, xenograft experiments in a mouse model helped understand in vivo effects of Musashi-1 knockdown. Results Musashi-1 is aberrantly expressed in primary tumor tissues. In vitro, silencing of Musashi-1 resulted in a strong decline in cell proliferation and radioresistance, while chemoresistance remained unchanged. Loss of Musashi-1 led to downregulation of telomerase, DNA-dependent protein kinase, the Notch pathway and overexpression of cyclin-dependent kinase inhibitor p21, the latter of which we identified as a key mediator of Msi-1 knockdown-related anti-proliferative signaling. In vivo, the anti-proliferative effect was confirmed, with Msi-1 knockdown tumors being about 40% reduced in size. Conclusions Musashi-1 knockdown resulted in a strong decrease in endometrial cancer proliferation and a loss of radioresistance, suggesting therapeutic potential.

Background and purpose: Glioblastoma (GBM) patients face a strongly unfavorable prognosis despite multimodal therapy regimens. However, individualized mortality prediction remains imprecise. Harnessing routine radiation planning cranial computed tomography (CT) scans, we assessed cervical body composition measures as novel biomarkers for overall survival (OS) in GBM patients. Materials and methods: We performed threshold-based semi-automated quantification of muscle and subcutaneous fat cross-sectional area (CSA) at the levels of the first and second cervical vertebral body. First, we tested this method’s validity by correlating cervical measures to established abdominal body composition in an open-source whole-body CT cohort. We then identified consecutive patients undergoing radiation planning for recent GBM diagnosis at our institution from 2010 to 2020 and quantified cervical body composition on radiation planning CT scans. Finally, we performed univariable and multivariable time-to-event analyses, adjusting for age, sex, body mass index, comorbidities, performance status, extent of surgical resection, extent of tumor at diagnosis, and MGMT methylation. Results: Cervical body composition measurements were well-correlated with established abdominal markers (Spearman’s rho greater than 0.68 in all cases). Subsequently, we included 324 GBM patients in our study cohort (median age 63 years, 60.8% male). 293 (90.4%) patients died during follow-up. Median survival time was 13 months. Patients with below-average muscle CSA or above-average fat CSA demonstrated shorter survival. In multivariable analyses, continuous cervical muscle measurements remained independently associated with OS. Conclusion: This exploratory study establishes novel cervical body composition measures routinely available on cranial radiation planning CT scans and confirms their association with OS in patients diagnosed with GBM.

Abstract Background Mortality risk prediction in patients undergoing pneumonectomy for non‐small cell lung cancer (NSCLC) remains imperfect. Here, we aimed to assess whether sarcopenia on routine chest computed tomography (CT) independently predicts worse cancer‐specific (CSS) and overall survival (OS) following pneumonectomy for NSCLC. Methods We included consecutive adults undergoing standard or carinal pneumonectomy for NSCLC at Massachusetts General Hospital and Heidelberg University from 2010 to 2018. We measured muscle cross‐sectional area (CSA) on CT at thoracic vertebral levels T8, T10, and T12 within 90 days prior to surgery. Sarcopenia was defined as T10 muscle CSA less than two standard deviations below the mean in healthy controls. We adjusted time‐to‐event analyses for age, body mass index, Charlson Comorbidity Index, forced expiratory volume in 1 second in % predicted, induction therapy, sex, smoking status, tumor stage, side of pneumonectomy, and institution. Results Three hundred and sixty‐seven patients (67.4% male, median age 62 years, 16.9% early‐stage) underwent predominantly standard pneumonectomy (89.6%) for stage IIIA NSCLC (45.5%) and squamous cell histology (58%). Sarcopenia was present in 104 of 367 patients (28.3%). Ninety‐day all‐cause mortality was 7.1% (26/367). After a median follow‐up of 20.5 months (IQR, 9.2–46.9), 183 of 367 patients (49.9%) had died. One hundred and thirty‐three (72.7%) of these deaths were due to lung cancer. Sarcopenia was associated with shorter CSS (HR 1.7, p = 0.008) and OS (HR 1.7, p = 0.003). Conclusions This transatlantic multicenter study confirms that sarcopenia on preoperative chest CT is an independent risk factor for CSS and OS following pneumonectomy for NSCLC.

Effectively targeting cancer stem cells, a subpopulation of tumorigenic, aggressive, and radioresistant cells, holds therapeutic promise. However, the effects of the microRNA miR-142-3p, a small endogenous regulator of gene expression on breast cancer stem cells, have not been investigated. This study identifies the influence of miR-142-3p on mammary stemness properties and breast cancer radioresistance to establish its role in this setting. miR-142-3p precursor transfection was performed in MDA-MB-468, HCC1806, and MCF-7 cells, and stem cell markers CD44, CD133, ALDH1 activity and mammosphere formation were measured. β-catenin, the canonical wnt signaling effector protein, was quantified by Western blots and cell fluorescence assays both in miR-142-3p–overexpressing and anti–miR-142-3p–treated cells. Radiation response was investigated by colony formation assays. Levels of BRCA1, BRCA2, and Bod1 in miR-142-3p–overexpressing cells as well as expression of miR-142-3p, Bod1, KLF4, and Oct4 in sorted CD44 + /CD24 –/low cells were determined by quantitative polymerase chain reaction. miR-142-3p overexpression resulted in a strong decline in breast cancer stem cell characteristics with a decrease in CD44, CD133, ALDH1, Bod1, BRCA2, and mammosphere formation as well as reduced survival after irradiation. miR-142-3p expression was strongly reduced in sorted CD44 + /CD24 –/low stem cells, while Bod1, Oct4, and KLF4 were overexpressed. β-catenin levels strongly decreased after miR-142-3p overexpression, but not after anti–miR-142-3p treatment. We conclude that miR-142-3p downregulates cancer stem cell characteristics and radioresistance in breast cancer, mediated by a reduced role of β-catenin in miR-142-3p–overexpressing cells. miR-142-3p might therefore help to target cancer stem cells.