In response to muscle injury, satellite cells activate the p38α/β MAPK pathway to exit quiescence, then proliferate, repair skeletal muscle, and self-renew, replenishing the quiescent satellite cell ...pool. Although satellite cells are capable of asymmetric division, the mechanisms regulating satellite cell self-renewal are not understood. We found that satellite cells, once activated, enter the cell cycle and a subset undergoes asymmetric division, renewing the satellite cell pool. Asymmetric localization of the Par complex activates p38α/β MAPK in only one daughter cell, inducing MyoD, which permits cell cycle entry and generates a proliferating myoblast. The absence of p38α/β MAPK signaling in the other daughter cell prevents MyoD induction, renewing the quiescent satellite cell. Thus, satellite cells employ a mechanism to generate distinct daughter cells, coupling the Par complex and p38α/β MAPK signaling to link the response to muscle injury with satellite cell self-renewal.
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► All satellite cells divide upon explant and a subset divide asymmetrically ► Asymmetric division generates quiescent satellite-SP cells ► Asymmetric activation/sequestration of p38α/β MAPK produces a myoblast daughter ► A PAR-3/PKCλ complex asymmetrically activates/sequesters p38α/β MAPK
Satellite cells activate p38α/β MAPK to divide asymmetrically in response to muscle injury. A Par-3/PKCλ complex localizes and sequesters p38α/β MAPK in one of the daughter cells, which becomes a myoblast, while the other daughter cell returns to quiescence.
Organoid technology has provided new translational research opportunities in oncology, in part by enabling the development of patient-representative living biobanks. Prostate cancer research ...historically has been constrained to a small number of in vitro models, limiting the ability to translate experimental conclusions for contemporary, heterogeneous patient populations. The facility of organoid culture methods to maintain luminal prostate epithelia, the common lineage of prostate cancers, has greatly expanded the phenotypic and genotypic diversity of available tractable models, including luminal stem/progenitor cells and progressive patient-derived cancers. Biobanks of patient prostate cancer organoids enable increased accuracy in predicting therapeutic efficacy and informative clinical trial designs. Here, we discuss how prostate organoid technology is currently being used, the promising areas of future therapeutic applications, and the current obstacles to be overcome.
Despite significant progress in breast cancer (BC) therapy, it is globally the most commonly diagnosed cancer and leads to the death of over 650,000 women annually. Androgen receptor (AR) is emerging ...as a potential new therapeutic target in BC. While the role of AR is well established in prostate cancer (PCa), its function in BC remains incompletely understood. Emerging data show that AR's role in BC is dependent on several factors including, but not limited to, disease subtype, tumour microenvironment, and levels of circulating oestrogens and androgens. While targeting AR in PCa is becoming increasingly effective, these advances have yet to make any significant impact on the care of BC patients. However, this approach is increasingly being evaluated in BC and it is clear that improvements in our understanding of AR's role in BC will increase the likelihood of success for AR-targeted therapies. This review summarizes our current understanding of the function of AR across BC subtypes. We highlight limitations in our current knowledge and demonstrate the importance of categorizing BC subtypes effectively, in relation to determining AR activity. Further, we describe the current state of the art regarding AR-targeted approaches for BC as monotherapy or in combination with radiotherapy.
Nerve growth factor (NGF) is increased in chronic pain conditions. This study examined analgesic efficacy and safety of fulranumab, a fully human monoclonal anti-NGF antibody, in adults with chronic ...osteoarthritis pain. Patients (n=466, intent-to-treat) were randomized to receive, in addition to their current pain therapy, subcutaneous injections in 1 of 6 parallel treatment groups: placebo (n=78), fulranumab 1 mg (n=77) or 3 mg (n=79) every 4 weeks (Q4wk), 3 mg (n=76), 6 mg (n=78), or 10 mg (n=78) every 8 weeks (Q8wk). Primary efficacy results showed that fulranumab significantly reduced the average pain intensity score (P < or = 0.030) from baseline to week 12 compared with placebo in the 3mgQ4wk, 6mgQ8wk, and 10mgQ8wk groups. Secondary efficacy outcomes indicated that significant improvement occurred compared with placebo at week 12 on the Western Ontario and McMaster Universities Osteoarthritis Index subscales of pain, stiffness, and physical function (P < 0.040) across all fulranumab groups except 1mgQ4wk, on the Brief Pain Inventory-Short Form subscales of pain intensity (P < or = 0.016) and pain interference (P < or = 0.030) in the 3mgQ4wk and 10mgQ8wk groups, and on the Patient Global Assessment score (P < or = 0.040) in the 3mgQ4wk, 6mgQ8wk, and 10mgQ8wk groups. The most common (> or = 5% of patients) treatment-emergent adverse events in overall fulranumab groups during the first 12weeks included paresthesia (7%), headache (5%), and nasopharyngitis (5%). Most neurologic-related treatment-emergent adverse events were mild or moderate and resolved at the end of week 12. Serious adverse events occurred in 3 patients, but they were not neurologically related and resolved before study completion. Fulranumab treatment resulted in statistically significant efficacy in pain measures and physical function versus placebo and was generally well tolerated.
Prostate cancer translational research has been hampered by the lack of comprehensive and tractable models that represent the genomic landscape of clinical disease. Metastatic castrate-resistant ...prostate cancer (mCRPC) patient-derived xenografts (PDXs) recapitulate the genetic and phenotypic diversity of the disease. We sought to establish a representative, preclinical platform of PDX-derived organoids that is experimentally facile for high-throughput and mechanistic analysis.
Using 20 models from the LuCaP mCRPC PDX cohort, including adenocarcinoma and neuroendocrine lineages, we systematically tested >20 modifications to prostate organoid conditions. Organoids were evaluated for genomic and phenotypic stability and continued reliance on the AR signaling pathway. The utility of the platform as a genotype-dependent model of drug sensitivity was tested with olaparib and carboplatin.
All PDX models proliferated as organoids in culture. Greater than 50% could be continuously cultured long-term in modified conditions; however, none of the PDXs could be established long-term as organoids under previously reported conditions. In addition, the modified conditions improved the establishment of patient biopsies over current methods. The genomic heterogeneity of the PDXs was conserved in organoids. Lineage markers and transcriptomes were maintained between PDXs and organoids. Dependence on AR signaling was preserved in adenocarcinoma organoids, replicating a dominant characteristic of CRPC. Finally, we observed maximum cytotoxicity to the PARP inhibitor olaparib in
organoids, similar to responses observed in patients.
The LuCaP PDX/organoid models provide an expansive, genetically characterized platform to investigate the mechanisms of pathogenesis as well as therapeutic responses and their molecular correlates in mCRPC.
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Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer. Treatment-refractory prostate cancers are increasingly associated with loss of luminal prostate ...markers, and in many cases induction of developmental programs, stem cell-like phenotypes, and neuroendocrine/neuronal features. Clinically, lineage plasticity may manifest as low PSA progression, resistance to androgen receptor (AR) pathway inhibitors, and sometimes small cell/neuroendocrine pathologic features observed on metastatic biopsy. This mechanism is not restricted to prostate cancer as other malignancies also demonstrate lineage plasticity during resistance to targeted therapies. At present, there is no established therapeutic approach for patients with advanced prostate cancer developing lineage plasticity or small cell neuroendocrine prostate cancer (NEPC) due to knowledge gaps in the underlying biology. Few clinical trials address questions in this space, and the outlook for patients remains poor. To move forward, urgently needed are: (i) a fundamental understanding of how lineage plasticity occurs and how it can best be defined; (ii) the temporal contribution and cooperation of emerging drivers; (iii) preclinical models that recapitulate biology of the disease and the recognized phenotypes; (iv) identification of therapeutic targets; and (v) novel trial designs dedicated to the entity as it is defined. This Perspective represents a consensus arising from the NCI Workshop on Lineage Plasticity and Androgen Receptor-Independent Prostate Cancer. We focus on the critical questions underlying lineage plasticity and AR-independent prostate cancer, outline knowledge and resource gaps, and identify strategies to facilitate future collaborative clinical translational and basic studies in this space.
Neural stem and precursor cell (NSPC) proliferation in the rodent adult hippocampus is essential to maintain stem cell populations and produce new neurons. Retinoic acid (RA) signaling is implicated ...in regulation of adult hippocampal neurogenesis, but its exact role in control of NSPC behavior has not been examined. We show RA signaling in all hippocampal NSPC subtypes and that inhibition of RA synthesis or signaling significantly decreases NSPC proliferation via abrogation of cell-cycle kinetics and cell-cycle regulators. RA signaling controls NSPC proliferation through hypoxia inducible factor-1α (HIF1α), where stabilization of HIF1α concurrent with disruption of RA signaling can prevent NSPC defects. These studies demonstrate a cell-autonomous role for RA signaling in hippocampal NSPCs that substantially broadens RA's function beyond its well-described role in neuronal differentiation.
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•Retinoic acid (RA) signaling in mouse hippocampal neural stem and progenitors (NSPCs)•Systemic reduction in RA synthesis impairs NSPC proliferation and neurogenesis•HIF1α acts downstream of RA to regulate NSPC S-phase re-entry and cell-cycle genes•RA signaling is required cell autonomously in NSPCs for normal proliferation
In this article, Mishra and colleagues identify a critical role for retinoic acid (RA) signaling in adult hippocampal neural stem and progenitor cell (NSPC) proliferation via hypoxia inducible factor-1α. Using RA reporter mice and conditional disruption of RA signaling in adult NSPCs, the authors identify RA signaling in adult NSPCs and NSPC RA signaling is required for normal proliferative behavior.
Objective
To evaluate the long‐term safety and efficacy of fulranumab in patients with knee or hip pain caused by moderate‐to‐severe chronic osteoarthritis (OA).
Methods
In this phase II ...double‐blind, placebo‐controlled extension study, patients who were randomized in equal proportions to receive subcutaneous doses of either placebo or fulranumab (1 mg every 4 weeks, 3 mg every 8 weeks, 3 mg every 4 weeks, 6 mg every 8 weeks, or 10 mg every 8 weeks) in the 12‐week double‐blind efficacy phase and who completed this double‐blind efficacy phase were eligible to continue the dosage throughout a 92‐week double‐blind extension phase, followed by a 24‐week posttreatment follow‐up period. Safety assessments included evaluation of treatment‐emergent adverse events (TEAEs), pre‐identified AEs of interest, and joint replacements. Efficacy assessments included changes from baseline to the end of the double‐blind extension phase in scores on the patient's global assessment and the pain and physical function subscales of the Western Ontario and McMaster Universities Osteoarthritis Index.
Results
Overall, 401 of the 423 patients who completed the 12‐week double‐blind efficacy phase entered the extension study. Long‐term sustained improvements were observed in all efficacy parameters following fulranumab treatment (1 mg every 4 weeks, 3 mg every 4 weeks, and 10 mg every 8 weeks) as compared with placebo. Similar percentages of patients in both groups experienced TEAEs (88% taking placebo and 91% taking fulranumab; all phases). Across all fulranumab groups, arthralgia (21%) and OA (18%) (e.g., exacerbation of OA pain) were the most common TEAEs. The most common serious TEAEs were the requirement for knee (10%) and hip (7%) arthroplasty, with 80% occurring during the posttreatment follow‐up period. Neurologic‐related TEAEs (28%; all phases) were generally mild‐to‐moderate. Overall, 81 joint replacements were performed in 71 patients (8 11% receiving placebo and 63 89% receiving fulranumab); 15 patients (21%) had rapid progression of OA (RPOA). All cases of RPOA occurred in fulranumab‐treated patients who were concurrently receiving nonsteroidal antiinflammatory drugs and occurred in joints with preexisting OA.
Conclusion
Long‐term treatment with fulranumab was generally well‐tolerated and efficacious. RPOA was observed as a safety signal. Future studies are warranted to demonstrate whether the risk of RPOA can be reduced in patients taking fulranumab.
The NADPH-dependent oxidase NOX2 is an important effector of immune cell function, and its activity has been linked to oncogenic signaling. Here, we describe a role for NOX2 in leukemia-initiating ...stem cell populations (LSCs). In a murine model of leukemia, suppression of NOX2 impaired core metabolism, attenuated disease development, and depleted functionally defined LSCs. Transcriptional analysis of purified LSCs revealed that deficiency of NOX2 collapses the self-renewal program and activates inflammatory and myeloid-differentiation-associated programs. Downstream of NOX2, we identified the forkhead transcription factor FOXC1 as a mediator of the phenotype. Notably, suppression of NOX2 or FOXC1 led to marked differentiation of leukemic blasts. In xenotransplantation models of primary human myeloid leukemia, suppression of either NOX2 or FOXC1 significantly attenuated disease development. Collectively, these findings position NOX2 as a critical regulator of malignant hematopoiesis and highlight the clinical potential of inhibiting NOX2 as a means to target LSCs.
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•Depletion of NOX2 reduces basal ROS levels and impairs core metabolism•NOX2 regulates self-renewal- and differentiation-associated transcriptional programs•Downstream of NOX2, FOXC1 controls part of the differentiation program•Depletion of FOXC1 or NOX2 impairs leukemogenesis in murine models and xenografts
The NADPH-dependent oxidase NOX2 is important for normal myeloid cell function. Adane et al. show that NOX2 is expressed in leukemic stem cells, where it regulates the balance of myeloid differentiation and self-renewal. Deficiency of NOX2 altered core metabolism, exacerbated inflammatory signaling, and limited in vivo disease development.
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