Biology subjects

Powers, J. T.

Publications and source records attributed to Powers, J. T..

4 recordsLinked to original sources

bioRxiv2025

Divergent Effects of Ultra-High Dose Arachidonic Acid versus Docosahexaenoic Acid on MYCN-Driven Neuroblastoma Progression in a Syngeneic Mouse Model

Neuroblastoma (NB) represents the most common extracranial solid tumor in children, where high-risk cases have particularly poor prognosis. We used a syngeneic mouse model to investigate the effects of ultra-high dose highly unsaturated fatty acids (HUFA) on NB progression. Following tumor establishment, mice were randomized to receive daily oral gavage with omega-6 ({omega}6) arachidonic acid (ARA) at 4.7 g/d human equivalent (hEq), or omega-3 ({omega}3) docosahexaenoic acid (DHA) at 24 g/d hEq, and controls did not receive gavage. We observed strikingly divergent effects: ARA significantly promoted tumor growth, resulting in 100% tumor survival and 4-fold larger tumors compared to controls, with enhanced vascularization and invasive morphology. In contrast, DHA administration reduced tumor survival (40% versus 92% in controls) and significantly suppressed the progression of remaining tumors, with remaining DHA-treated tumors approximately 4.5-fold smaller than controls and 18-fold smaller than ARA-treated tumors. In a separate lipid mediator analysis, ARA supplementation significantly increased pro-inflammatory/pro-tumorigenic mediators including PGE2, TXB2, and epoxyeicosatrienoic acids in liver, spleen, brain and skeletal muscle. DHA supplementation increased anti-inflammatory/anti-tumor mediators, particularly EPA-derived 17,18-EpETE, 18-HEPE, and DHA-derived 14-HDHA in these same tissues. No significant differences in body weight were observed among treatment groups, indicating the treatments were well-tolerated. These findings build upon our previous research demonstrating that ultra-high dose {omega}3 supplementation can completely block tumor formation in MYCN-driven NB. The profound tumor-suppressive effects of DHA suggest that dietary modulation of {omega}3 and {omega}6 HUFA intake may offer a complementary, low-toxicity approach to high-risk NB standard of care (SoC). Our findings suggest that dietary intervention may be an effective primary or adjunctive strategy in pediatric oncology, enabling reduced SoC dosing while improving outcomes and survivorship.

cancer biology↗

bioRxiv2024

Novel sex-biased outcomes in neuroblastoma are associated with distinct gene expression and chromosomal loss patterns.

The worst patient outcomes in neuroblastoma are driven by high-risk disease1,2, which is divided into similarly sized MYCN amplified and MYCN non-amplified patient subgroups3. Male patients have been reported to have slightly worse outcomes than females in all-patient analyses of multiple studies3,4. However, we show here that in MYCN non- amplified high-risk and stage 4s low-risk disease, female patients have significantly worse overall survival than males. Female MYCN non-amplified high-risk patients highly express H19 and DLK1, both of which drive cell growth in vitro and are associated with worse outcomes in females but not males. Further, chromosome-specific expression analysis of these patients reveals broad sex disparities in chromosomal patterning, including female-specific retention of chromosome 11q, a pattern typically reserved for MYCN-amplified disease5,6. Finally, we show that H19, a known let-7 microRNA target7, sequesters let-7 in females, providing a rationale for worse female survival and reconciling retention of chromosome 11q. We propose that this novel sex-based outcome disparity is driven by let-7 inhibition, expanding on a model of neuroblastoma development where let-7 mitigation is central to disease pathology8.

cancer biology↗

bioRxiv2024

High dose ω3 eicosapentaenoic acid and docosahexaenoic acid block, whereas ω6 arachidonic acid accelerates, MYCN-driven tumorigenesis in vivo

Background/ObjectivesNeuroblastoma is a genetically diverse, highly metastatic pediatric cancer accounting for 15% of childhood cancer deaths despite only having ~8% of childhood cancer incidence. The current standard of care for high-risk disease is highly genotoxic. This, combined with less than 50% survival in high-risk disease and an abysmal 5% survival in relapsed cases, makes discovering novel, effective, and less toxic treatments essential. MethodsA prophylactic syngeneic mouse model was used to test high-dose lipid-mediator highly unsaturated fatty acids on tumorigenesis. Wild-type mice were gavaged with 12.3-14.6 g/d (adult human equivalent) omega-3 EPA, DHA, or oxidation-resistant bis allylic deuterated DHA (D-DHA) and 4.6-6.0 g/d arachidonic acid (ARA). At seven days, MYCN-expressing murine neuro-2a cells syngeneic to the gavaged mice were injected subcutaneously. Oral gavage continued for 10-20 d post-injection when tumors and tissues were harvested. ResultsFifty percent of control (not gavaged) animals form tumors (4/8) at about 10 d. High-dose DHA, D-DHA, and EPA block tumor formation completely in n=8 or 10 animals. In contrast, {omega}6 arachidonic acid (4.6-6.0 g/d) enhances tumor formation (6/10 tumors) and reduces latency (5.5 to 10 days)compared to control. Co-delivery of ARA and EPA results in a reduced tumor burden analogous to the control group, suggesting that EPA directly opposes the mechanism of ARA-mediated tumor formation. DHA acts through a non-oxidative mechanism. ConclusionsSustained high dose {omega}3 (weeks/months) is safe and well tolerated in humans. These results suggest that {omega}3 DHA and EPA delivery at ultra-high doses may represent a viable low-toxicity therapy for neuroblastoma. Simple SummaryPediatric Neuroblastoma has an overall mortality rate above 50%, and the current standard of care consists of highly genotoxic compounds. The biological actions of omega-6 ({omega}6) and omega-3 ({omega}3) highly unsaturated fatty acids (HUFA) generally oppose one another with the {omega}6 HUFA signaling for inflammation and angiogenesis (new blood vessel formation). Prolonged use of ultrahigh dose (15-20 g/d) {omega}3 HUFA has shown efficacy in catastrophic human traumatic brain injury and is well tolerated. Tumors form in about 50% of mice in our pediatric neuro-blastoma model. We show that 12-14 g/d adult human equivalent doses of {omega}3 EPA or DHA, as well as an oxidation-resistant form of DHA (D-DHA), completely block tumor formation, whereas a dose of about 5 g/d of {omega}6 ARA enhances tumorigenesis. Our data suggest that ultra-high dose {omega}3 therapy should be carefully investigated as a low-toxicity approach to neuroblastoma intervention.

cancer biology↗

bioRxiv2023

Unsaturated fatty acid synthesis is associated with poor prognosis in pediatric neuroblastoma and is differentially regulated by MYCN and tumor suppressor microRNAs.

MYCN amplification and disruption of tumor suppressor microRNA (TSmiR) function are central drivers of poor outcomes in neuroblastoma (NB). MYC, MYCN, and TSmiRs regulate glucose metabolism; however, their role in unsaturated fatty acid synthesis (UFAS) remains poorly understood. Here we show that de novo and UFAS pathway genes FASN, ELOVL6, SCD, FADS2, and FADS1 are upregulated in high-risk NB and are associated with poor prognosis. RNA-Seq analysis of eight human NB cell lines revealed parallel UFAS gene expression patterns. Consistent with this, we found that NB-related TSmiRs were predicted to extensively target these genes. In addition, we observed that both MYC and MYCN upregulated UFAS pathway genes while suppressing TSmiR host gene expression, thereby creating a possible UFAS regulatory network between MYCN and TSmiRs in NB. Furthermore, NB cells are high in omega 9 ({omega}9) unsaturated fatty acids that can be synthesized de novo and low in both {omega}6 and {omega}3, providing a plausible means for NB to limit cell-autonomous immune stimulation and reactive oxygen species (ROS)-driven apoptosis from {omega}6 and {omega}3 unsaturated fatty acid derivatives, respectively. We propose a model in which the UFAS pathway, through novel regulation by MYCN and TSmiRs, plays a key role in neuroblastoma pathology with implications for other MYC-driven cancers.

cancer biology↗