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Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors driven by populations of cancer stem cells (CSCs). However, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy-resistant niche and identified WDR5 as indispensable for this population. WDR5 is a component of the WRAD complex, which promotes SET1 family-mediated Lys4 methylation of histone H3 (H3K4me), associated with positive regulation of transcription. In GBM CSCs, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, including the POU5F1(OCT4)::SOX2 motif. Use of a SOX2/OCT4 reporter demonstrated that WDR5 inhibitor treatment diminished cells with high reporter activity. Furthermore, WDR5 inhibitor treatment and WDR5 knockdown altered the stem cell state, disrupting CSC in vitro growth and self-renewal, as well as in vivo tumor growth. These findings highlight the role of WDR5 and the WRAD complex in maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers.
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Glioblastoma , Humanos , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Factores de Transcripción , Células Madre Neoplásicas/patología , Péptidos y Proteínas de Señalización Intracelular/genéticaRESUMEN
BACKGROUND: This study aimed to identify patient preferences and outcomes of chest masculinization surgery in patients identifying as nonbinary versus transgender (trans-) males. METHODS: Patients who underwent chest masculinization (2003-2022) were included. Demographics, medical comorbidities, surgical approaches, complications, secondary procedures, and BODY-Q chest module survey responses were compared between cohorts. RESULTS: Three hundred two patients were included. Thirteen percent identified as nonbinary and 87% as trans-male. The most common surgical approach in both groups was double incision with free nipple-areola graft (63% vs 71%, P = 0.33). Nonbinary patients more frequently opted for double incision without free nipple areola graft compared to trans-male patients (18% vs 2.7%, P < 0.001). Other unique surgical requests of nonbinary patients included nipple areola preservation and small breast mound preservation (5.2%) and balance between losing bulk and achieving a more androgynous appearance (5.3%). The survey response rate was 31% (93/302). Both groups reported improved quality of life postoperatively (P = 0.16). Three nonbinary patients elected not to keep their nipple-areola complexes (P = 0.005). Trans-male patients were more likely to report having a male chest as very important for their gender identity (82% vs 95%, P = 0.043). Nonbinary patients were less likely to prefer small nipples (82% vs 95%, P = 0.033) and 18% stated that they preferred no nipples (vs 2.7% trans-male patients, P < 0.001). CONCLUSIONS: Nonbinary patients have distinct surgical preferences regarding nipple-areola complexes. Chest masculinization planning can differ for this group of patients compared to their trans-male counterparts.
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BACKGROUND: Combining multiple surgical procedures into a single operative session is widespread in the field of plastic surgery; however, the implications of this practice are not fully understood. OBJECTIVES: This study compared 30-day complication rates associated with combined plastic surgery procedures with the rates for index procedures. METHODS: This retrospective cohort analysis utilized the Tracking Operations and Outcomes for Plastic Surgeons database from 2016 to 2020 to identify the 3 most frequent combinations of augmentation mammaplasty, reduction mammaplasty, trunk liposuction, mastopexy, and abdominoplasty. RESULTS: The 30-day overall complication rate was 5.0% (1400 of 26,771 patients), with a higher complication rate for combined procedures compared with index (7.6% vs 4.2%, adjusted odd ratio [aOR], 1.91 [95% CI, 1.61-2.27], P < .001). There were no significant differences in complication rates for abdominoplasty or mastopexy combinations compared with index. Complication rates for reduction mammaplasty combinations compared with index were not statistically different after controlling for demographics (aOR, 1.02 [95% CI, 0.61-1.64], P = .93). Higher rates of minor and major complications were observed for combinations of trunk liposuction (aOR, 4.84 [95% CI, 3.31-7.21), P < .001) and augmentation mammaplasty (aOR, 1.60 [95% CI 1.13-2.22], P = .007) compared with index. CONCLUSIONS: Combinations with trunk liposuction or augmentation mammaplasty present with increased risk of complications compared with index, controlling for demographics. Abdominoplasty and mastopexy may be combined with other plastic surgery procedures without increased risk to patients. The complication risk of reduction mammaplasty combinations is mediated by other variables, suggesting the need for shared surgical decision-making when recommending these combinations to patients.
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BACKGROUND: Breast cancer (BC) is the most common cancer in women and the leading cause of cancer-associated mortality in women. In particular, triple-negative BC (TNBC) has the highest rate of mortality due in large part to the lack of targeted treatment options for this subtype. Thus, there is an urgent need to identify new molecular targets for TNBC treatment. RALA and RALB are small GTPases implicated in growth and metastasis of a variety of cancers, although little is known of their roles in BC. METHODS: The necessity of RALA and RALB for TNBC tumor growth and metastasis were evaluated in vivo using orthotopic and tail-vein models. In vitro, 2D and 3D cell culture methods were used to evaluate the contributions of RALA and RALB during TNBC cell migration, invasion, and viability. The association between TNBC patient outcome and RALA and RALB expression was examined using publicly available gene expression data and patient tissue microarrays. Finally, small molecule inhibition of RALA and RALB was evaluated as a potential treatment strategy for TNBC in cell line and patient-derived xenograft (PDX) models. RESULTS: Knockout or depletion of RALA inhibited orthotopic primary tumor growth, spontaneous metastasis, and experimental metastasis of TNBC cells in vivo. Conversely, knockout of RALB increased TNBC growth and metastasis. In vitro, RALA and RALB had antagonistic effects on TNBC migration, invasion, and viability with RALA generally supporting and RALB opposing these processes. In BC patient populations, elevated RALA but not RALB expression is significantly associated with poor outcome across all BC subtypes and specifically within TNBC patient cohorts. Immunohistochemical staining for RALA in patient cohorts confirmed the prognostic significance of RALA within the general BC population and the TNBC population specifically. BQU57, a small molecule inhibitor of RALA and RALB, decreased TNBC cell line viability, sensitized cells to paclitaxel in vitro and decreased tumor growth and metastasis in TNBC cell line and PDX models in vivo. CONCLUSIONS: Together, these data demonstrate important but paradoxical roles for RALA and RALB in the pathogenesis of TNBC and advocate further investigation of RALA as a target for the precise treatment of metastatic TNBC.
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Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Proteínas de Unión al GTP ral/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Supervivencia Celular/efectos de los fármacos , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Ratones , Metástasis de la Neoplasia , Paclitaxel/uso terapéutico , Pronóstico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas de Unión al GTP ral/antagonistas & inhibidores , Proteínas de Unión al GTP ral/genéticaRESUMEN
Amphibian metamorphosis is driven by thyroid hormone (TH). We used prometamorphic tadpoles and a cell line of the African clawed frog (Xenopus laevis) to examine immediate effects of dioxin exposure on TH. Gene expression patterns suggest cross-talk between the thyroid hormone receptor (TR) and aryl hydrocarbon receptor (AHR) signaling pathways. In XLK-WG cells, expression of Cytochrome P450 1A6 (cyp1A6), an AHR target, was induced 1000-fold by 100 nM TCDD (2, 3, 7, 8 tetrachlorodibenzo-p-dioxin). Krüppel-Like Factor 9 (klf9), the first gene induced in a cascade of TH responses tied to metamorphosis, was upregulated over 5-fold by 50 nM triiodothyronine (T3) and 2-fold by dioxin. Co-exposure to T3 and TCDD boosted both responses, further inducing cyp1A6 by 75% and klf9 about 60%. Additional canonical targets of each receptor, including trßa and trßb (TR) and udpgt1a (AHR) responded similarly. Induction of TH targets by TCDD in XLK-WG cells predicts that exposure could speed metamorphosis. We tested this hypothesis in two remodeling events: tail resorption and hind limb growth. Resorption of ex vivo cultured tails was accelerated by 10 nM T3, while a modest increase in resorption by 100 nM TCDD lacked statistical significance. Hind limbs doubled in length over four days following 1 nM T3 treatment, but limb length was unaffected by 100 nM TCDD. TCDD co-exposure reduced the T3 effect by nearly 40%, despite TCDD induction of klf9 in whole tadpoles, alone or with T3. These results suggest that tissue-specific TCDD effects limit or reverse the increased metamorphosis rate predicted by klf9 induction.
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Disruptores Endocrinos/toxicidad , Larva/efectos de los fármacos , Metamorfosis Biológica/efectos de los fármacos , Dibenzodioxinas Policloradas/toxicidad , Hormonas Tiroideas/metabolismo , Animales , Técnicas de Cultivo de Célula , Línea Celular , Larva/metabolismo , Metamorfosis Biológica/genética , Receptor Cross-Talk/efectos de los fármacos , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hormona Tiroidea/genética , Receptores de Hormona Tiroidea/metabolismo , Transducción de Señal/efectos de los fármacos , Hormonas Tiroideas/farmacología , Triyodotironina/metabolismo , Triyodotironina/farmacología , Xenopus laevisRESUMEN
The development and implementation of a scientific outreach activity comes with a number of challenges. A successful outreach event must match the sophistication of content to the audience, be engaging, expand the knowledge base for participants, and be inclusive for a diverse audience. Ideally, a successful event will also convey the importance of scientific outreach for future scientists and citizens. In this paper, we present a simple, hands-on guide to a scientific outreach event targeted to kindergarten learners. This activity also pursued a second goal: the inclusion of undergraduate students in the development and delivery of the event. We provided a detailed set of four activities, focusing on the blind Mexican cavefish, which were enthusiastically received by kindergarten audiences. The engagement of undergraduate students in the development of this activity encouraged public outreach involvement and fostered new scientific and communication skills. The format of the outreach event we describe is flexible. We provide a set of guidelines and suggestions for adapting this approach to other biological topics. The activity and approach we describe enables the implementation of effective scientific outreach, using active learning approaches, which benefits both elementary school learners and undergraduate students.