This study is fully supported by the Division of Intramural Research of the National Institute of Nursing Research of the NIH, Bethesda, Maryland.

The current study (NCT00852111) was approved by the Institutional Review Board (IRB) of the National Institutes of Health (NIH). Participants enrolled in this study were 18 years of age or older, diagnosed with non-metastatic prostate cancer with or without prior prostatectomy, and scheduled to receive external beam radiation therapy at the Radiation Oncology Clinic of the NIH Clinical Center. Potential participants were excluded if they had a progressive disease that could cause significant fatigue, had psychiatric dise...

<ol>
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R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quantitative+assessment+of+motor+fatigue+and+strength+in+MS.">Quantitative assessment of motor fatigue and strength in MS.</a> Neurology. 53, 743-743 (1999).</li><li>Hunter, S. K., Critchlow, A., Shin, I. S., Enoka, R. 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Here, we provide three different methods for measuring the physical dimension of CRF. Motor fatigue tests using handheld dynamometers are simple and easily adaptable for clinical use. Since many variations of the test exist in the literature, our goal was to provide standardized methods to administer these tests and decrease the need for extensive in-person trainings for clinicians.
Although the fatigue tests outlined in this study demonstrate good test-retest reliability7</s...

Cancer-related fatigue (CRF) is an prevalent and debilitating symptom that is reported by up to 80% of cancer patients1. The National Comprehensive Cancer Network (NCCN) defines CRF as a persistent sense of physical, emotional, and cognitive exhaustion1. The main differentiating characteristics of CRF are the disproportionality to recent activity and the inability of CRF to be relieved by rest1. As a result, CRF severely impacts patients&#39; participation in daily activities and their health-related quality of life1.
The current assessment of CRF relies primarily on self-report questionnaires2. As a result, symptom severity which is measured using self-reports is subject to recall and reporting biases and can be influenced by the specific questionnaire and cutoff scores used to assess CRF3. As a multidimensional construct, the physical dimension of CRF has been shown to correlate with daily activity changes and a need for daytime naps4, whereas the influence of CRF on physical functioning is less explored. To this date, CRF remains an underdiagnosed and undertreated symptom with no well-defined underlying mechanism or treatment option1. To better understand this debilitating condition, there is an increasing need to measure CRF and its dimensions objectively and quantitatively.
Physical fatigue refers to an inability to maintain the required force during sustained contractile activity5. The subsequent compromised daily functioning as a result of not being able to carry out daily tasks (e.g., carrying grocery bags, lifting and holding an object) greatly affects the health-related quality of life, especially in older adults, and contributes to future injuries6,7. Various tools have been developed to quantify physical impairment including physical performance tests, such as the 6 min walk test (6MWT) and sit-to-stand test (STS), as well as wearable physical activity monitors, such as actigraphy devices and fitness trackers8,9,10. Physical performance tests such as 6MWT and STS are easy to administer and do not require special equipment10. However, the reliability and success of such tests require clinician training and logistical requirements such as a 30 m corridor10. Wearable activity monitors allow for automated data collection and longitudinal symptom monitoring11. However, these activity monitors often need to be worn for multiple days, and patient compliance can be an issue11. In addition, the large amount of data collected using activity monitors can be challenging to process, making it difficult to derive clinically meaningful information11.
The handheld dynamometer, or instrumented handgrip device with computer-assisted data acquisition, is a portable apparatus that measures grip strength. Handheld dynamometry has been used to test motor fatigue and impairment in disease conditions that typically involve the motor system including motor neurons and muscular problems12. Recent work has demonstrated an association between self-reported subjective CRF scores and motor fatigue measured using a handgrip static fatigue test13. Handgrip fatigue tests are particularly suitable for clinical use due to their reliability and time efficiency, requiring a few minutes to complete14,15. Furthermore, handgrip fatigue tests can be pre-programed, ensuring data reproducibility7. Administering the handgrip test requires minimal training on the part of the test administrator and can be easily implemented in a clinical setting given a standardized protocol. Using self-reported fatigue questionnaires in conjunction with the handgrip fatigue test should provide additional tools for clinicians to screen, monitor, and manage fatigue symptoms in cancer patients.
The lack of standardized consensus methods has limited the adoption of the handgrip fatigue test in the clinics16. In this current work, we outline three different methods to use the handheld dynamometer to quantify motor fatigue objectively. The utility of each method should be tested in each cancer population to ensure it accurately distinguishes between fatigued and non-fatigued subjects. We also outline methods to calculate the fatigue index for each handgrip fatigue test. The goal of this work is to provide a comprehensive toolkit to supplement self-reported questionnaires and to standardize CRF physical performance measurement accurately and objectively.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Quantitative Muscle Assessment application (QMA)</td>
			<td>Aeverl Medical</td>
			<td>QMA 4.6</td>
			<td>Data acquisition software. NOTE: other brands/models can be used as long as the software records force over time.</td>
		</tr>
		<tr>
			<td>QMA distribution box</td>
			<td>Aeverl Medical</td>
			<td>DSTBX</td>
			<td>Software distribution box which connects the handgrip to the software.</td>
		</tr>
		<tr>
			<td>Baseline hand dynamometer with analog output</td>
			<td>Aeverl Medical</td>
			<td>BHG</td>
			<td>Instrumented handgrip device with computer assisted data acquisition. NOTE: other brands/models can be used as long as the instrument measures force over time</td>
		</tr>
	</tbody>
</table>

measuring the motor aspect of cancer-related fatigue using a handheld dynamometer

Cancer-related fatigue (CRF) is commonly reported by patients both during and after receiving treatment for cancer. Current CRF diagnoses rely on self-report questionnaires which are subject to report and recall biases. Objective measurements using a handheld dynamometer, or handgrip device, have been shown in recent studies to correlate significantly with subjective self-reported fatigue scores. However, variations of both the handgrip fatigue test and fatigue index calculations exist in the literature. The lack of standardized methods limits the utilization of the handgrip fatigue test in the clinical and research settings. In this study, we provide detailed methods for administering the physical fatigue test and calculating the fatigue index. These methods should supplement existing self-reported fatigue questionnaires and help clinicians assess fatigue symptom severity in an objective and quantitative manner.

Representative force (kg) versus time (s) traces are shown in Figure 1. During the static fatigue test, subjects typically reach maximal strength (Fmax) within 2&#8211;3 s23. Self-reported fatigue in subjects was measured based on previous studies3. The absence of Fmax (&#177;10% MVIC) within 3 s indicates insufficient effort23. To prevent this issue, verbal encouragement should be provided. Both su...

Watch this Scientific Journal Video about Measuring the Motor Aspect of Cancer-Related Fatigue using a Handheld Dynamometer at JoVE.com

Measuring the Motor Aspect of Cancer-Related Fatigue using a Handheld Dynamometer

Simple and accessible methods were developed to measure the motor aspect of cancer-related fatigue objectively and quantitatively. We describe, in detail, ways to administer the physical fatigue test using a simple handgrip device as well as methods to calculate fatigue indices.

Cancer-related fatigue (CRF) is commonly reported by patients both during and after receiving treatment for cancer. Current CRF diagnoses rely on ...

Cancer related fatigue severely impacts patients health related quality of life. Currently, researchers and clinicians rely on self reported questionnaires to diagnose this debilitating symptom. Methods outlined in this work help to standardize physical fatigue measurement in an accurate and objective manner.This technique is fairly simple and easily adaptable for clinical use. Protocols provided in the current work will decrease the need for in person trainings for clinicians. Demonstrating these procedures will be Jeniece Regan, Sarah Alshawi Josephine Liwang and Jamell Joseph, postback fellows from our lab.In a quiet room, set up a chair with armrests. Turn on the handheld dynamometer. When prompted, press the button to accept the calibration prompt.Ensure the devices resting on a flat surface during calibration. The handle device is sensitive to mechanical force. It is important to handle the device with care.Sit the subject in an upright position, with their feet in full contact with the floor. And hips as far back as the chair supports. Ensure the subject's hip and knee angles are close to 90 degrees.And shoulders are a neutral abduction adduction and neutrally rotated. Ensure the subject's elbow is flexed at 90 degrees and the wrist is unsupported. Instruct the subject to grasp the dynamometer with the dorsal Intermediate phalanges facing forward.Adjust the grip position to the subjects hand size. And then record the grip position. It is important to remember to ensure the proper seating and grip position throughout the tests.Using a standardized script for each subject, explained that for this test, the subject will squeeze as hard as they can for five seconds. It is important to ensure that subjects maintain their maximal voluntary isometric contraction or MVIC during the static fatigue test. Count down three, two, one, Go.On Go, start the program by clicking the Go button on the dynamometer.Repeat the MVIC test twice more for a total of three trials with 30-second rest between trials. Using a standardized script, instruct the subject to exert full effort for the whole 35 seconds of this test. Count down three, two, one, Go.On Go, start the program by clicking the Go button on the dynamometer.For 35 seconds, use a standardized script to encourage the subject to squeeze hard. End the test after 35 seconds. Prepare a transparency overlay for the dynamometer screen.Draw a horizontal line on the transparency that represents the target value, 50%of the subjects MVIC. Draw a second line 10%below the target value. Ensure the subject can see the screen and the 50%MVIC line.Instruct the subject to maintain the target value for as long as possible. Count down three two, one, Go.On Go, start the program by clicking the Go button on the dynamometer. When the force declines by 10%from the target value for more than five seconds, stop the test.Set the metronome to one beat per second. Then start the metronome. Instruct the subject that they will be performing a maximal squeeze every second for a duration of 30 seconds.In time with the metronome, count down three, two, one Go.On Go, start the program by clicking the Go button on the dynamometer. Stop the test after 30 seconds. This study provides three different methods for measuring cancer related fatigue.The dynamometer data can be used to calculate fatigue indices. Static fatigue, index version one represents the difference between the actual force generated and the hypothetical force in the absence of fatigue. Version two represents the decline in force from the first five seconds to the last five seconds.While both versions detect the differences between fatigued and non fatigued subjects, version one resulted in better discrimination and a higher test to retest reliability. Version one is recommended for measuring fatigue in patients with Cancer. For the sub maximal fatigue index, performance is calculated as the total work.Non fatigued subjects exhibited higher endurance and total work performed than fatigued subjects. While this test is typically not used to calculate voter fatigue ability, it is included because it is often used to induce fatigue and it better approximates daily tasks. The dynamic fatigue index represents the decline in the intermittent contractile force from the first five seconds to the last five seconds.It also capture the difference between fatigued and non fatigued subjects. But the difficulty of it adhering to a consistent rhythm, introduces variability. Furthermore, while it has good test retest reliability, in prior studies, it did not demonstrate sufficient discriminative power.Following this procedure, subjective fatigue can be measured using a self report questionnaire. The contribution of physical fatigue to the overall sense of tiredness can be further investigated using this procedure. Furthermore, physical fatigue data can be collected over time to examine longitudinal treatment effects.Clinicians will be be able to objectively measure cancer related fatigue. In addition, researchers will be able to explore possible pathogenic mechanisms that underlies debilitating symptom.

measuring-motor-aspect-cancer-related-fatigue-using-handheld

Research

JoVE Journal

Cancer Research

Ultrasonographic Evaluation of Breast Cancer-related Lymphedema

Lymphedema is one of the most common complications after breast cancer surgery. There are many diagnostic tools for lymphedema, but no standard method yet exists. Progressive Resistance Exercise (PRE) is expected to improve lymphedema without additional swelling. This study showed the therapeutic effects of PRE on lymphedema by using ultrasonography to measure the change in thickness of the muscle and subcutaneous tissue. The thickness of subcutaneous tissue decreased more in the PRE group than in the non-PRE group. Ultrasonography is widely used in many clinics because of its easy accessibility, safety, and inexpensiveness. Ultrasound is one of the best tools for diagnosing and determining treatment efficacy on breast cancer-related lymphedema (BCRL).

This study utilized ultrasonography for diagnosis and follow-up tests to confirm treatment efficacy of Progressive Resistance Exercise (PRE) in breast cancer-related lymphedema (BCRL). Ultrasonography can be applied effectively to ensure diagnosis and treatment of lymphedema.

Lymphedema is one of the most common complications after breast cancer surgery. There are many diagnostic tools for lymphedema, but no standard method yet ...

A Mouse Model of Fatigue Induced by Peripheral Irradiation

Cancer-related fatigue (CRF) is a distressing and costly condition that often affects patients receiving cancer treatments, including radiation therapy. Here we describe a method using targeted peripheral irradiation to induce fatigue-like behavior in mice. With appropriate shielding, the irradiation targets the lower abdominal/pelvic region of the mouse, sparing the brain, in an effort to model radiation treatment received by individuals with pelvic cancers. We deliver an irradiation dose that is sufficient to induce fatigue-like behavior in mice, measured by voluntary wheel-running activity (VWRA), without causing obvious morbidity. Since wheel running is a normal, voluntary behavior in mice, its use should have little confounding effect on other behavioral tests or biological measures. Hence, wheel running can be used as a feasible outcome measure in understanding the behavioral and biological correlates of fatigue. CRF is a complex condition with frequent comorbidities, and likely has causes related both to cancer and its various treatments. The methods described in this paper are useful for investigating radiation-induced changes that contribute to the development of CRF and, more generally, to explore the biological networks that can explain the development and persistence of a peripherally-triggered but centrally-driven behavior like fatigue.

We describe a method using targeted peripheral irradiation to induce fatigue-like behavior in mice. The selected non-lethal irradiation dose leads to a week-long reduction in voluntary wheel-running activity.

Cancer-related fatigue (CRF) is a distressing and costly condition that often affects patients receiving cancer treatments, including radiation therapy. ...

A Comprehensive Procedure to Evaluate the In Vitro Performance of the Putative Hemangioblastoma Neovascularization Using the Spheroid Sprouting Assay

The inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene plays a crucial role in the development of hemangioblastomas (HBs) within the human central nervous system (CNS). However, both the cytological origin and the evolutionary process of HBs (including neovascularization) remain controversial, and anti-angiogenesis for VHL-HBs, based on classic HB angiogenesis, have produced disappointing results in clinical trials. One major obstacle to the successful clinical translation of anti-vascular treatment is the lack of a thorough understanding of neovascularization in this vascular tumor. In this article, we present a comprehensive procedure to evaluate in vitro whether classic tumor angiogenesis exists in HBs, as well as its role in HBs. With this procedure, researchers can accurately understand the complexity of HB neovascularization and identify the function of this common form of angiogenesis in HBs. These protocols can be used to evaluate the most promising anti-vascular therapy for tumors, which has high translational potential either for tumors treatment or for aiding in the optimization of the anti-angiogenic treatment for HBs in future translations. The results highlight the complexity of HB neovascularization and suggest that this common form angiogenesis is only a complementary mechanism in HB neovascularization.

A Comprehensive Procedure to Evaluate the In Vitro Performance of the Putative Hemangioblastoma Neovascularization Using the Spheroid Sprouting Assay

This paper presents a comprehensive procedure to evaluate in vitro whether classic tumor angiogenesis exists in hemangioblastomas (HBs) and its role in HBs. The results highlight the complexity of HB-neovascularization and suggest that this common form of angiogenesis is only a complementary mechanism in the HB-neovascularization.

The inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene plays a crucial role in the development of hemangioblastomas (HBs) within the human ...

Modeling Osteosarcoma Using Li-Fraumeni Syndrome Patient-derived Induced Pluripotent Stem Cells

Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer disorder. Patients with LFS are predisposed to a various type of tumors, including osteosarcoma--one of the most frequent primary non-hematologic malignancies in the childhood and adolescence. Therefore, LFS provides an ideal model to study this malignancy. Taking advantage of iPSC methodologies, LFS-associated osteosarcoma can be successfully modeled by differentiating LFS patient iPSCs to mesenchymal stem cells (MSCs), and then to osteoblasts--the cells of origin for osteosarcomas. These LFS osteoblasts recapitulate oncogenic properties of osteosarcoma, providing an attractive model system for delineating the pathogenesis of osteosarcoma. This manuscript demonstrates a protocol for the generation of iPSCs from LFS patient fibroblasts, differentiation of iPSCs to MSCs, differentiation of MSCs to osteoblasts, and in vivo tumorigenesis using LFS osteoblasts. This iPSC disease model can be extended to identify potential biomarkers or therapeutic targets for LFS-associated osteosarcoma.

Here, we present a protocol for the generation of induced pluripotent Stem Cells (iPSCs) from Li-Fraumeni Syndrome (LFS) patient derived fibroblasts, differentiation of iPSCs via mesenchymal stem cells (MSCs) to osteoblasts, and modeling in vivo tumorigenesis using LFS patient-derived osteoblasts.

Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer disorder. Patients with LFS are predisposed to a various type of tumors, including ...

Evaluating the Role of Mitochondrial Function in Cancer-related Fatigue

Fatigue is a common and debilitating condition that affects most cancer patients. To date, fatigue remains poorly characterized with no diagnostic test to objectively measure the severity of this condition. Here we describe an optimized method for assessing mitochondrial function of PBMCs collected from fatigued cancer patients. Using a compact extracellular flux system and sequential injection of respiratory inhibitors, we examined PBMC mitochondrial functional status by measuring basal mitochondrial respiration, spare respiratory capacity, and energy phenotype, which describes the preferred energy pathway to respond to stress. Fresh PBMCs are readily available in the clinical setting using standard phlebotomy. The entire assay described in this protocol can be completed in less than 4 hours without the involvement of complex biochemical techniques. Additionally, we describe a normalization method that is necessary for obtaining reproducible data. The simple procedure and normalization methods presented allow for repeated sample collection from the same patient and generation of reproducible data that can be compared between time points to evaluate potential treatment effects.

Our goal was to develop a practical protocol to evaluate mitochondrial dysfunction associated with fatigue in cancer patients. This innovative protocol is optimized for clinical use involving only standard phlebotomy and basic laboratory procedures.

Fatigue is a common and debilitating condition that affects most cancer patients. To date, fatigue remains poorly characterized with no diagnostic test to ...

Measuring Bone Remodeling and Recreating the Tumor-Bone Microenvironment Using Calvaria Co-culture and Histomorphometry

Bone is a connective tissue constituted of osteoblasts, osteocytes, and osteoclasts and a mineralized extracellular matrix, which gives it its strength and flexibility and allows it to fulfill its functions. Bone is continuously exposed to a variety of stimuli, which in pathological conditions can deregulate bone remodeling. To study bone biology and diseases and evaluate potential therapeutic agents, it has been necessary to develop in vitro and in vivo models.
This manuscript describes the dissection process and culture conditions of calvarias isolated from neonatal mice to study bone formation and the bone tumor microenvironment. In contrast to in vitro and in vivo models, this ex vivo model allows preservation of the three-dimensional environment of the tissue as well as the cellular diversity of the bone while culturing under defined conditions to simulate the desired microenvironment. Therefore, it is possible to investigate bone remodeling and its mechanisms, as well as the interactions with other cell types, such as the interactions between cancer cells and bone.
The assays reported here use calvarias from 5-7 day old BALB/C mice. The hemi-calvarias obtained are cultured in the presence of insulin, breast cancer cells (MDA-MB-231), or conditioned medium from breast cancer cell cultures. After analysis, it was established that insulin induced new bone formation, while cancer cells and their conditioned medium induced bone resorption. The calvarial model has been successfully used in basic and applied research to study bone development and cancer-induced bone diseases. Overall, it is an excellent option for an easy, informative, and low-cost assay.

The ex vivo culture of bone explants can be a valuable tool for the study of bone physiology and the potential evaluation of drugs in bone remodeling and bone diseases. The presented protocol describes the preparation and culture of calvarias isolated from newborn mice skulls, as well as its applications.

Bone is a connective tissue constituted of osteoblasts, osteocytes, and osteoclasts and a mineralized extracellular matrix, which gives it its strength ...

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

The rapidly accelerated fibrosarcoma (RAF) family kinases play a central role in cell biology and their dysfunction leads to cancers and developmental disorders. A characterization of disease-related RAF mutants will help us select appropriate therapeutic strategies for treating these diseases. Recent studies have shown that RAF family kinases have both catalytic and allosteric activities, which are tightly regulated by dimerization. Here, we constructed a set of practical and feasible methods to determine the catalytic and allosteric activities and the relative dimer affinity/stability of RAF family kinases and their mutants. Firstly, we amended the classical in vitro kinase assay by reducing the detergent concentration in buffers, utilizing a gentle quick wash procedure, and employing a glutathione S-transferase (GST) fusion to prevent RAF dimers from dissociating during purification. This enables us to measure the catalytic activity of constitutively active RAF mutants appropriately. Secondly, we developed a novel RAF co-activation assay to evaluate the allosteric activity of kinase-dead RAF mutants by using N-terminal truncated RAF proteins, eliminating the requirement of active Ras in current protocols and thereby achieving a higher sensitivity. Lastly, we generated a unique complementary split luciferase assay to quantitatively measure the relative dimer affinity/stability of various RAF mutants, which is more reliable and sensitive compared to the traditional co-immunoprecipitation assay. In summary, these methods have the following advantages: (1) user-friendly; (2) able to carry out effectively without advanced equipment; (3) cost-effective; (4) highly sensitive and reproducible.

In this article, we presented a set of practical and feasible methods for characterizing disease-related mutants of RAF family kinases, which include in vitro kinase assay, RAF co-activation assay, and complementary split luciferase assay.

The rapidly accelerated fibrosarcoma (RAF) family kinases play a central role in cell biology and their dysfunction leads to cancers and developmental ...

In Vitro Establishment of a Genetically Engineered Murine Head and Neck Cancer Cell Line using an Adeno-Associated Virus-Cas9 System

The use of primary normal epithelial cells makes it possible to reproducibly induce genomic alterations required for cellular transformation by introducing specific mutations in oncogenes and tumor suppressor genes, using clustered regulatory interspaced short palindromic repeat (CRISPR)-based genome editing technology in mice. This technology allows us to accurately mimic the genetic changes that occur in human cancers using mice. By genetically transforming murine primary cells, we can better study cancer development, progression, treatment, and diagnosis. In this study, we used Cre-inducible Cas9 mouse tongue epithelial cells to enable genome editing using adeno-associated virus (AAV) in vitro. Specifically, by altering KRAS, p53, and APC in normal tongue epithelial cells, we generated a murine head and neck cancer (HNC) cell line in vitro,which is tumorigenic in syngeneic mice. The method presented here describes in detail how to generate HNC cell lines with specific genomic alterations and explains their suitability for predicting tumor progression in syngeneic mice. We envision that this promising method will be informative and useful to study tumor biology and therapy of HNC.

Development of murine models with specific genes mutated in head and neck cancer patients is required for understanding of neoplasia. Here, we present a protocol for in vitro transformation of primary murine tongue cells using an adeno-associated virus-Cas9 system to generate murine HNC cell lines with specific genomic alterations.

The use of primary normal epithelial cells makes it possible to reproducibly induce genomic alterations required for cellular transformation by ...

Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells

Formation of the eIF4F complex has been shown to be the key downstream node for the convergence of signalling pathways that often undergo&#160;oncogenic activation in humans. eIF4F is a cap-binding complex involved in the mRNA-ribosome recruitment phase of translation initiation. In many cellular and pre-clinical model of cancers, the deregulation of eIF4F leads to increased translation of specific mRNA subsets that are involved in cancer proliferation and survival. eIF4F is a hetero-trimeric complex built from the cap-binding subunit eIF4E, the helicase eIF4A and the scaffolding subunit eIF4G. Critical for the assembly of active eIF4F complexes is the protein-protein interaction between eIF4E and eIF4G proteins. In this article, we describe a protocol to measure eIF4F assembly that monitors the status of eIF4E-eIF4G interaction in live cells. The eIF4e:4G cell-based protein-protein interaction assay also allows drug induced changes in eIF4F complex integrity to be accurately and reliably assessed. We envision that this method can be applied for verifying the activity of commercially available compounds or for further screening of novel compounds or modalities that efficiently disrupt formation of eIF4F complex.

Here, we present a protocol to measure eIF4E-eIF4G interaction in live cells that would enable the user to evaluate drug induced perturbation of eIF4F complex dynamics in screening formats.

Formation of the eIF4F complex has been shown to be the key downstream node for the convergence of signalling pathways that often undergo&#160;oncogenic ...

Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis

Many cancers are characterized by chromosomal translocations which result in the expression of oncogenic fusion transcription factors. Typically, these proteins contain an intrinsically disordered domain (IDD) fused with the DNA-binding domain (DBD) of another protein and orchestrate widespread transcriptional changes to promote malignancy. These fusions are often the sole recurring genomic aberration in the cancers they cause, making them attractive therapeutic targets. However, targeting oncogenic transcription factors requires a better understanding of the mechanistic role that low-complexity, IDDs play in their function. The N-terminal domain of EWSR1 is an IDD involved in a variety of oncogenic fusion transcription factors, including EWS/FLI, EWS/ATF, and EWS/WT1. Here, we use RNA-sequencing to investigate the structural features of the EWS domain important for transcriptional function of EWS/FLI in Ewing sarcoma. First shRNA-mediated depletion of the endogenous fusion from Ewing sarcoma cells paired with ectopic expression of a variety of EWS-mutant constructs is performed. Then RNA-sequencing is used to analyze the transcriptomes of cells expressing these constructs to characterize the functional deficits associated with mutations in the EWS domain. By integrating the transcriptomic analyses with previously published information about EWS/FLI DNA binding motifs, and genomic localization, as well as functional assays for transforming ability, we were able to identify structural features of EWS/FLI important for oncogenesis and define a novel set of EWS/FLI target genes critical for Ewing sarcoma. This paper demonstrates the use of RNA-sequencing as a method to map the structure-function relationship of the intrinsically disordered domain of oncogenic transcription factors.

Intrinsically disordered domains are important for oncogenic fusion transcription factor function. To therapeutically target these proteins, a more detailed understanding of the regulatory mechanisms employed by these domains is required. Here, we use transcriptomics to map important structural features of the intrinsically disordered EWS domain in Ewing sarcoma.

Many cancers are characterized by chromosomal translocations which result in the expression of oncogenic fusion transcription factors. Typically, these ...