Do Cutting Kinematics Change as Boys Mature? A Longitudinal Cohort Study of High-School Athletes.

OBJECTIVE: Examine longitudinal changes in trunk, hip, and knee kinematics in maturing boys during an unanticipated cutting task. DESIGN: Prospective cohort study. SETTING: Biomechanical laboratory. PARTICIPANTS: Forty-two high-school male basketball, volleyball, and soccer athletes. ASSESSMENT OF RISK FACTORS: Trunk, hip, and knee range-of-motion (RoM), peak angles, and angles at initial contact during an unanticipated 45 degrees sidestep cutting task were estimated using laboratory-based three-dimensional optoelectronic motion capture. Maturation was classified using a modified Pubertal Maturational Observational Scale (PMOS) into prepubertal, midpubertal, or postpubertal stages. MAIN OUTCOME MEASURES: Trunk total RoM in frontal, sagittal, and transverse planes; peak trunk flexion, right lateral flexion and right rotation angles; hip total RoM in frontal, sagittal, and transverse planes; hip flexion angle at initial contact; peak hip flexion and adduction angles; knee total RoM in frontal, sagittal, and transverse planes; knee flexion angle at initial contact; peak knee flexion and abduction angles. RESULTS: As boys matured, there was a decrease in hip sagittal-plane RoM (49.02 degrees to 43.45 degrees, Benjamini-Hochberg adjusted P = 0.027), hip flexion at initial contact (29.33 degrees to 23.08 degrees, P = 0.018), and peak hip flexion (38.66 degrees to 32.71 degrees, P = 0.046), and an increase in trunk contralateral rotation (17.47 degrees to 25.05 degrees, P = 0.027). CONCLUSIONS: Maturing male athletes adopted a more erect cutting strategy that is associated with greater knee joint loading. Knee kinematic changes that increase knee joint loading were not observed in this cohort.

High mobility group A1 (HMGA1) protein and gene expression correlate with ER-negativity and poor outcomes in breast cancer.

PURPOSE: The high mobility group A1 (HMGA1) chromatin remodeling protein is required for metastatic progression and cancer stem cell properties in preclinical breast cancer models, although its role in breast carcinogenesis has remained unclear. To investigate HMGA1 in primary breast cancer, we evaluated immunoreactivity score (IRS) in tumors from a large cohort of Asian women; HMGA1 gene expression was queried from two independent Western cohorts. METHODS: HMGA1 IRS was generated from breast tumors in Korean women as the product of staining intensity (weak = 1, moderate = 2, strong = 3) and percent positive cells (< 5% = 0, 5-30% = 1, 30-60% = 2, > 60% = 3), and stratified into three groups: low (< 3), intermediate (3-6), high (> 6). We assessed HMGA1 and estrogen receptor (ESR1) gene expression from two large databases (TCGA, METABRIC). Overall survival was ascertained from the METABRIC cohort. RESULTS: Among 540 primary tumors from Korean women (181 ER-negative, 359 ER-positive), HMGA1 IRS was < 3 in 89 (16.5%), 3-6 in 215 (39.8%), and > 6 in 236 (43.7%). High HMGA1 IRS was associated with estrogen receptor (ER)-negativity (χ2 = 12.07; P = 0.002) and advanced nuclear grade (χ2 = 12.83; P = 0.012). In two large Western cohorts, the HMGA1 gene was overexpressed in breast cancers compared to non-malignant breast tissue (P < 0.0001), including Asian, African American, and Caucasian subgroups. HMGA1 was highest in ER-negative tumors and there was a strong inverse correlation between HMGA1 and ESR1 gene expression (Pearson r = - 0.60, P < 0.0001). Most importantly, high HMGA1 predicted decreased overall survival (P < 0.0001) for all women with breast cancer and further stratified ER-positive tumors into those with inferior outcomes. CONCLUSIONS: Together, our results suggest that HMGA1 contributes to estrogen-independence, tumor progression, and poor outcomes. Moreover, further studies are warranted to determine whether HMGA1 could serve as a prognostic marker and therapeutic target for women with breast cancer.

Involuntary hamstring muscle activity reduces passive hip range of motion during the straight leg raise test: a stimulation study in healthy people.

BACKGROUND: Involuntary hamstring muscle activity is present in some people during the straight leg raise test, but it is not known to what extent involuntary muscle activity limits passive joint range of motion. This study aimed to determine whether small amounts of involuntary hamstring activity limit passive hip range of motion during the straight leg raise test in healthy people. METHODS: Thirty healthy subjects were recruited from The University of Sydney. As the hamstring muscles were continuously stimulated to generate 0, 2.5, 5, 7.5 and 10% of knee flexion maximal voluntary contraction force, an investigator blinded to the amount of stimulation performed a straight leg raise test by passively raising the tested leg while keeping the knee extended. The test was stopped when the knee started to flex, at which point hip range of motion was recorded. RESULTS: On average, passive hip range of motion decreased by 0.6° for every 1% increase in knee flexion force caused by muscle activation (95% CI 0.3 to 0.9°, p = 0.0012). Subjects were instructed to fully relax when the straight leg raise test was performed, but a small amount of involuntary muscle activity (median 2.4% of maximal activation) was present during the trial without stimulation. CONCLUSIONS: Small amounts of involuntary hamstring muscles activity reduce passive hip range of motion during the straight leg raise test in healthy people. TRIAL REGISTRATION: The protocol for this study was registered with the Open Science Framework, reference: https://osf.io/fejpf/ . Registered 9 March 2017.

HMGA1 induces FGF19 to drive pancreatic carcinogenesis and stroma formation.

High mobility group A1 (HMGA1) chromatin regulators are upregulated in diverse tumors where they portend adverse outcomes, although how they function in cancer remains unclear. Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors characterized by dense desmoplastic stroma composed predominantly of cancer-associated fibroblasts and fibrotic tissue. Here, we uncover an epigenetic program whereby HMGA1 upregulates FGF19 during tumor progression and stroma formation. HMGA1 deficiency disrupts oncogenic properties in vitro while impairing tumor inception and progression in KPC mice and subcutaneous or orthotopic models of PDAC. RNA sequencing revealed HMGA1 transcriptional networks governing proliferation and tumor-stroma interactions, including the FGF19 gene. HMGA1 directly induces FGF19 expression and increases its protein secretion by recruiting active histone marks (H3K4me3, H3K27Ac). Surprisingly, disrupting FGF19 via gene silencing or the FGFR4 inhibitor BLU9931 recapitulates most phenotypes observed with HMGA1 deficiency, decreasing tumor growth and formation of a desmoplastic stroma in mouse models of PDAC. In human PDAC, overexpression of HMGA1 and FGF19 defines a subset of tumors with extremely poor outcomes. Our results reveal what we believe is a new paradigm whereby HMGA1 and FGF19 drive tumor progression and stroma formation, thus illuminating FGF19 as a rational therapeutic target for a molecularly defined PDAC subtype.

Mastering the Topic, the Message, and the Delivery: Leveraging the Social Marketing Mix to Better Implement Sports Injury Prevention Programs.

SYNOPSIS: Social marketing is successful at tackling global health threats and social change but has not been fully explored in sports injury prevention contexts. The social marketing mix (product, price, place, and promotion) can help create exercise-based injury prevention programs with high-value propositions that will be relevant to their implementation (adoption, adherence, maintenance). To improve the real-world effectiveness of injury prevention programs, we share steps that researchers and sports administrators can take tomorrow to leverage the social marketing mix to encourage downstream consumers, such as coaches, clinicians, parents, and athletes, to implement injury prevention programs. J Orthop Sports Phys Ther 2022;52(2):55-59. doi:10.2519/jospt.2022.10839.

Beginning With the End in Mind: Implementing Backward Design to Improve Sports Injury Rehabilitation Practices.

SYNOPSIS: Current injury-specific return-to-performance rehabilitation programs are not comprehensive, lack intensity, and need better tailoring to the demands of sport. The vast number of rehabilitation and return to sport protocols also reflects a lack of consensus about what the best program looks like, which hinders beginning practitioners from implementing best practices across the spectrum of injuries and sports. Backward design, which has underpinnings in educational research, can facilitate implementation by encouraging practitioners to begin with the end in mind before logically and intentionally working backwards to design transferable and context-specific rehabilitation plans that improve sports injury rehabilitation practices. We discuss and illustrate using case examples how clinicians can apply backward design in best practice sports injury rehabilitation. J Orthop Sports Phys Ther 2022;52(12):770-776. Epub: 7 October 2022. doi:10.2519/jospt.2022.11440.

Non-contact Anterior Cruciate Ligament Injury Epidemiology in Team-Ball Sports: A Systematic Review with Meta-analysis by Sex, Age, Sport, Participation Level, and Exposure Type.

BACKGROUND: Not all anterior cruciate ligament (ACL) injuries are preventable. While some ACL injuries are unavoidable such as those resulting from a tackle, others that occur in non-contact situations like twisting and turning in the absence of external contact might be more preventable. Because ACL injuries commonly occur in team ball-sports that involve jumping, landing and cutting manoeuvres, accurate information about the epidemiology of non-contact ACL injuries in these sports is needed to quantify their extent and burden to guide resource allocation for risk-reduction efforts. OBJECTIVE: To synthesize the evidence on the incidence and proportion of non-contact to total ACL injuries by sex, age, sport, participation level and exposure type in team ball-sports. METHODS: Six databases (MEDLINE, EMBASE, Web of Science, CINAHL, Scopus and SPORTDiscus) were searched from inception to July 2021. Cohort studies of team ball-sports reporting number of knee injuries as a function of exposure and injury mechanism were included. RESULTS: Forty-five studies covering 13 team ball-sports were included. The overall proportion of non-contact to total ACL injuries was 55% (95% CI 48-62, I2 = 82%; females: 63%, 95% CI 53-71, I2 = 84%; males: 50%, 95% CI 42-58, I2 = 86%). The overall incidence of non-contact ACL injuries was 0.07 per 1000 player-hours (95% CI 0.05-0.10, I2 = 77%), and 0.05 per 1000 player-exposures (95% CI 0.03-0.07, I2 = 97%). Injury incidence was higher in female athletes (0.14 per 1000 player-hours, 95% CI 0.10-0.19, I2 = 40%) than male athletes (0.05 per 1000 player-hours, 95% CI 0.03-0.07, I2 = 48%), and this difference was significant. Injury incidence during competition was higher (0.48 per 1000 player-hours, 95% CI 0.32-0.72, I2 = 77%; 0.32 per 1000 player-exposures, 95% CI 0.15-0.70, I2 = 96%) than during training (0.04 per 1000 player-hours, 95% CI 0.02-0.07, I2 = 63%; 0.02 per 1000 player-exposures, 95% CI 0.01-0.05, I2 = 86%) and these differences were significant. Heterogeneity across studies was generally high. CONCLUSION: This study quantifies several key epidemiological findings for ACL injuries in team ball-sports. Non-contact ACL injuries represented over half of all ACL injuries sustained. The proportion of non-contact to total ACL injuries and injury incidence were higher in female than in male athletes. Injuries mostly occurred in competition settings.

Epidemiology of gradual-onset knee injuries in team ball-sports: A systematic review with meta-analysis of prevalence, incidence, and burden by sex, sport, age, and participation level.

OBJECTIVES: To systematically evaluate the literature and estimate the prevalence, incidence, and burden of gradual-onset knee injuries in team ball-sports. DESIGN: Systematic review with meta-analysis. METHODS: Six databases (MEDLINE, EMBASE, Web of Science, CINAHL, SPORTDiscus, SCOPUS) were searched from inception to June 2021. Cohort studies of team ball-sports reporting the number of gradual-onset knee injuries were included. Study quality was assessed using a modified Newcastle-Ottawa scale. Studies were pooled using a Freeman-Tukey Double arcsine transformation (prevalence) and a Poisson random effects regression model (incidence, burden). RESULTS: Forty-nine studies that captured gradual-onset knee injuries (unclassified, patellofemoral pain, tendinopathies, and iliotibial band friction syndrome) across 15 team ball-sports were included. For unclassified gradual-onset knee injuries, prevalence was 4 % (95 % Confidence Interval (CI) 2 % to 7 %, I2 = 96 %), incidence was 0.32 per 1000 player-hours (95 % CI 0.25 to 0.43, I2 = 88 %), and burden was 3.24 days lost per 1000 player-hours (95 % CI 1.95 to 5.37, I2 = 99 %). For patellofemoral pain, prevalence was 6 % (95 % CI 1 % to 13 %, I2 = 93 %), and incidence was 0.07 per 1000 player-hours (95 % CI 0.04 to 0.12, I2 = 67 %). For tendinopathies, prevalence was 1 % (95 % CI 0 % to 2 %, I2 = 68 %), incidence was 0.07 per 1000 player-hours (95 % CI 0.04 to 0.11, I2 = 76 %), and burden was 2.14 days lost per 1000 player-hours (95 % CI 1.23 to 3.71, I2 = 92 %). CONCLUSIONS: Estimates of prevalence, incidence and burden generated from this systematic review quantify the extent of gradual-onset knee injuries in team ball-sports. Further research is required to assess whether age, sport, and participation level are predictors of gradual-onset knee injuries.

Trunk Biomechanics in Individuals with Knee Disorders: A Systematic Review with Evidence Gap Map and Meta-analysis.

BACKGROUND: The trunk is the foundation for transfer and dissipation of forces throughout the lower extremity kinetic chain. Individuals with knee disorders may employ trunk biomechanical adaptations to accommodate forces at the knee or compensate for muscle weakness. This systematic review aimed to synthesize the literature comparing trunk biomechanics between individuals with knee disorders and injury-free controls. METHODS: Five databases were searched from inception to January 2022. Observational studies comparing trunk kinematics or kinetics during weight-bearing tasks (e.g., stair negotiation, walking, running, landings) between individuals with knee disorders and controls were included. Meta-analyses for each knee disorder were performed. Outcome-level certainty was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), and evidence gap maps were created. RESULTS: A total of 81 studies investigating trunk biomechanics across six different knee disorders were included (i.e., knee osteoarthritis [OA], total knee arthroplasty [TKA], patellofemoral pain [PFP], patellar tendinopathy [PT], anterior cruciate ligament deficiency [ACLD], and anterior cruciate ligament reconstruction [ACLR]). Individuals with knee OA presented greater trunk flexion during squatting (SMD 0.88, 95% CI 0.58-1.18) and stepping tasks (SMD 0.56, 95% CI 0.13-.99); ipsilateral and contralateral trunk lean during walking (SMD 1.36; 95% CI 0.60-2.11) and sit-to-stand (SMD 1.49; 95% CI 0.90-2.08), respectively. Greater trunk flexion during landing tasks in individuals with PFP (SMD 0.56; 95% CI 0.01-1.12) or ACLR (SMD 0.48; 95% CI 0.21-.75) and greater ipsilateral trunk lean during single-leg squat in individuals with PFP (SMD 1.01; 95% CI 0.33-1.70) were also identified. No alterations in trunk kinematics of individuals with TKA were identified. Evidence gap maps outlined the lack of investigations for individuals with PT or ACLD, as well as for trunk kinetics across knee disorders. CONCLUSION: Individuals with knee OA, PFP, or ACLR present with altered trunk kinematics in the sagittal and frontal planes. The findings of this review support the assessment of trunk biomechanics in these individuals in order to identify possible targets for rehabilitation and avoidance strategies. TRIAL REGISTRATION: PROSPERO registration number: CRD42019129257.

Evaluating the validity and reliability of inertial measurement units for determining knee and trunk kinematics during athletic landing and cutting movements.

Inertial Measurement Units (IMUs) are promising alternatives to laboratory-based motion capture methods in biomechanical assessment of athletic movements. The aim of this study was to investigate the validity of an IMU system for determining knee and trunk kinematics during landing and cutting tasks for clinical and research applications in sporting populations. Twenty-seven participants performed five cutting and landing tasks while being recorded using a gold-standard optoelectronic motion capture system and an IMU system. Intra-class coefficients, Pearson's r, root-mean-square error (RMSE), bias, and Bland-Altman limits of agreements between the motion capture and IMU systems were quantified for knee and trunk sagittal- and frontal-plane range-of-motion (ROM) and peak angles. Our results indicate that IMU validity was task-, joint-, and plane-dependent. Based on good-to-excellent (ICC) correlation, reasonable accuracy (RMSE < 5°), bias within 2°, and limits of agreements within 10°, we recommend the use of this IMU system for knee sagittal-plane ROM estimations during cutting, trunk sagittal-plane peak angle estimation during the double-leg landing task, trunk sagittal-plane ROM estimation for almost all tasks, and trunk frontal-plane peak angle estimation for the right single-leg landing task. Due to poor comparisons with the optoelectronic system, we do not recommend this IMU system for knee frontal-plane kinematic estimations.

When puberty strikes: Longitudinal changes in cutting kinematics in 172 high-school female athletes.

OBJECTIVES: Young female athletes involved in high-speed cutting and change-of-direction sports are particularly susceptible to anterior cruciate ligament (ACL) injuries. Little is known if maturational changes in cutting technique contribute to the increased injury risk. Our objective was to examine longitudinal changes in cutting kinematics in female athletes as they matured through puberty. DESIGN: Longitudinal cohort study METHODS: High school female athletes (n=172) performed an unanticipated 45° cutting task in the biomechanics laboratory across two or more pubertal stages. Pubertal stages were classified using a modified Pubertal Maturational Observational Scale (pre-, mid-, or post-pubertal stages). Generalized linear mixed models were used to compare kinematics across pubertal stages. RESULTS: As girls matured through puberty, they displayed a decrease in sagittal-plane hip (1.8-2.6°, p<0.03) and knee range-of-motion (ROM) (2.7-2.9°, p≤0.01), and decreased peak hip (2.9-3.2°, p≤0.02) and knee flexion angles (2.7-2.9°, p≤0.01), which is indicative of greater quadriceps dominance. Peak knee abduction angles also increased as girls progressed through puberty (0.9-1.4°, p≤0.02), suggesting greater ligament dominance. In terms of trunk dominance, there were mixed findings with a decrease in trunk frontal- (2.5-5.7°, p≤0.03) and sagittal-plane ROM (2.0°, p≤0.01), but an increase in trunk transverse-plane ROM (2.8-3.6°, p≤0.02) observed as girls mature. Other significant changes in cutting technique were decreased peak trunk flexion (3.8-7.8°, p≤0.01), and decreased hip flexion (2.9-3.3°, p≤0.02) and knee flexion angles (2.0-3.0°, p≤0.03) at initial contact, suggesting a more upright and stiffer cutting posture. CONCLUSIONS: As girls mature through puberty, there is a change in cutting strategy characterized by greater quadriceps and ligament dominance.

Trunk endurance, posterior chain flexibility, and previous history of musculoskeletal pain predict overuse low back and lower extremity injury: a prospective cohort study of 545 Navy Cadets.

OBJECTIVE: To investigate predictors of low back and lower extremity musculoskeletal injury in a cohort of Naval cadets. DESIGN: Prospective Cohort Study METHODS: 545 Naval cadets (Males, n = 394, 72%) were followed-up over eight months. Nine variables were investigated as predictors: history of musculoskeletal symptoms in the last 12 months, ankle dorsiflexion range of motion, sit and reach test, isometric hip abduction and external rotation strength, alignment during the single leg squat test, single leg hop test for distance, prone plank and side plank tests. All injuries that required medical attention were registered. Predictive associations were examined using univariable and multivariable logistic regression analyses. RESULTS: The incidence of all injuries was 7%. Cadets who failed the 60-second plank test (OR = 3.3; 95% CI, 1.2-8.8, P = 0.04), had ≤18 cm in the sit and reach test (OR = 4.0; 95% CI, 1.4-11.2, P = 0.01), or reported pain in the last 12 months in two or more body regions (OR = 2.7; 95% CI, 1.02-7.3, P = 0.04), had greater odds of sustaining an overuse injury. No predictors were identified for acute injuries. CONCLUSION: Decreased trunk endurance on the prone plank test, reduced posterior chain flexibility on the sit and reach test, and a history of pain reported in two or more sites in the last 12 months were predictors of overuse injuries in Naval cadets. Assessment and intervention of these modifiable risk factors may be clinically relevant in injury screening and prevention.

Limited Support for Trunk and Hip Deficits as Risk Factors for Athletic Knee Injuries: A Systematic Review With Meta-analysis and Best-Evidence Synthesis.

OBJECTIVE: To determine whether neuromuscular deficits in trunk and hip-related function are risk factors for athletic knee injuries. DESIGN: Etiology systematic review with meta-analysis. LITERATURE SEARCH: Six online databases (MEDLINE, Web of Science, Embase, CINAHL, Scopus, and SPORTDiscus) were searched up to April 2019. STUDY SELECTION CRITERIA: Studies assessing trunk and hip neuromuscular function as risk factors for knee injuries in healthy athletic populations were included. DATA SYNTHESIS: Outcomes were synthesized quantitatively using meta-analysis of odds ratios, and qualitatively using best-evidence synthesis. RESULTS: Twenty-one studies met the inclusion criteria. There was very low-certainty evidence that greater hip external rotation strength protected against knee injuries (odds ratio = 0.78; 95% confidence interval: 0.70, 0.87; P<.05). There was limited evidence that deficits in trunk proprioception and neuromuscular control, and the combination of excessive knee valgus and ipsilateral trunk angle when landing unilaterally from a jump, may be risk factors for knee injuries. CONCLUSION: Most variables of trunk and hip function were not risk factors for injuries. Further research is required to confirm whether hip external rotation strength, trunk proprioception and neuromuscular control, and the combination of knee valgus angle and ipsilateral trunk control are risk factors for future knee injuries. J Orthop Sports Phys Ther 2020;50(9):476-489. Epub 1 Aug 2020. doi:10.2519/jospt.2020.9705.

Genetic Engineering of Primary Mouse Intestinal Organoids Using Magnetic Nanoparticle Transduction Viral Vectors for Frozen Sectioning.

Intestinal organoid cultures provide a unique opportunity to investigate intestinal stem cell and crypt biology in vitro, although efficient approaches to manipulate gene expression in organoids have made limited progress in this arena. While CRISPR/Cas9 technology allows for precise genome editing of cells for organoid generation, this strategy requires extensive selection and screening by sequence analysis, which is both time-consuming and costly. Here, we provide a detailed protocol for efficient viral transduction of intestinal organoids. This approach is rapid and highly efficient, thus decreasing the time and expense inherent in CRISPR/Cas9 technology. We also present a protocol to generate frozen sections from intact organoid cultures for further analysis with immunohistochemical or immunofluorescent staining, which can be used to confirm gene expression or silencing. After successful transduction of viral vectors for gene expression or silencing is achieved, intestinal stem cell and crypt function can be rapidly assessed. Although most organoid studies employ in vitro assays, organoids can also be delivered to mice for in vivo functional analyses. Moreover, our approaches are advantageous for predicting therapeutic responses to drugs because currently available therapies generally function by modulating gene expression or protein function rather than altering the genome.

Functional Loss of ATRX and TERC Activates Alternative Lengthening of Telomeres (ALT) in LAPC4 Prostate Cancer Cells.

A key hallmark of cancer, unlimited replication, requires cancer cells to evade both replicative senescence and potentially lethal chromosomal instability induced by telomere dysfunction. The majority of cancers overcome these critical barriers by upregulating telomerase, a telomere-specific reverse transcriptase. However, a subset of cancers maintains telomere lengths by the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway. The presence of ALT is strongly associated with recurrent cancer-specific somatic inactivating mutations in the ATRX-DAXX chromatin-remodeling complex. Here, we generate an ALT-positive adenocarcinoma cell line following functional inactivation of ATRX and telomerase in a telomerase-positive adenocarcinoma cell line. Inactivating mutations in ATRX were introduced using CRISPR-cas9 nickase into two prostate cancer cell lines, LAPC-4 (derived from a lymph node metastasis) and CWR22Rv1 (sourced from a xenograft established from a primary prostate cancer). In LAPC-4, but not CWR22Rv1, abolishing ATRX was sufficient to induce multiple ALT-associated hallmarks, including the presence of ALT-associated promyelocytic leukemia bodies (APB), extrachromosomal telomere C-circles, and dramatic telomere length heterogeneity. However, telomerase activity was still present in these ATRXKO cells. Telomerase activity was subsequently crippled in these LAPC-4 ATRXKO cells by introducing mutations in the TERC locus, the essential RNA component of telomerase. These LAPC-4 ATRXKO TERCmut cells continued to proliferate long-term and retained ALT-associated hallmarks, thereby demonstrating their reliance on the ALT mechanism for telomere maintenance. IMPLICATIONS: These prostate cancer cell line models provide a unique system to explore the distinct molecular alterations that occur upon induction of ALT, and may be useful tools to screen for ALT-specific therapies.

Lessons from the Crypt: HMGA1-Amping up Wnt for Stem Cells and Tumor Progression.

High mobility group A1 (HMGA1) chromatin remodeling proteins are enriched in aggressive cancers and stem cells, although their common function in these settings has remained elusive until now. Recent work in murine intestinal stem cells (ISC) revealed a novel role for Hmga1 in enhancing self-renewal by amplifying Wnt signaling, both by inducing genes expressing Wnt agonist receptors and Wnt effectors. Surprisingly, Hmga1 also "builds" a stem cell niche by upregulating Sox9, a factor required for differentiation to Paneth cells; these cells constitute an epithelial niche by secreting Wnt and other factors to support ISCs. HMGA1 is also highly upregulated in colon cancer compared with nonmalignant epithelium and SOX9 becomes overexpressed during colon carcinogenesis. Intriguingly, HMGA1 is overexpressed in diverse cancers with poor outcomes, where it regulates developmental genes. Similarly, HMGA1 induces genes responsible for pluripotency and self-renewal in embryonic stem cells. These findings demonstrate that HMGA1 maintains Wnt and other developmental transcriptional networks and suggest that HMGA1 overexpression fosters carcinogenesis and tumor progression through dysregulation of these pathways. Studies are now needed to determine more precisely how HMGA1 modulates chromatin structure to amplify developmental genes and how to disrupt this process in cancer therapy. Cancer Res; 78(8); 1890-7. ©2018 AACR.