Combined MEK and JAK/STAT3 pathway inhibition effectively decreases SHH medulloblastoma tumor progression

Zagozewski, Jamie; Borlase, Stephanie; Guppy, Brent J.; Coudière-Morrison, Ludivine; Shahriary, Ghazaleh M.; Gordon, Victor; Liang, Lisa; Cheng, Stephen Z. D.; Porter, Christopher J.; Kelley, Rhonda; Hawkins, Cynthia; Chan, Jennifer A.; Liang, Yan; Gong, Junsong; Nör, Carolina; Saulnier, Olivier; Wechsler‐Reya, Robert J.; Ramaswamy, Vijay

doi:10.1038/s42003-022-03654-9

Cited by 16 publications

(9 citation statements)

References 74 publications

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“…6C, D ). Similar to our previous findings following selumetinib treatment in vivo [ 40 ], the hallmark JAK/STAT3 and TNFα/NFκB signaling pathway gene sets each have a significant positive NES (1.53 and 2.43, respectively) and are thus enriched for genes that are upregulated in trametinib treated xenografts (Fig. 6E, F ).…”

Section: Resultssupporting

confidence: 87%

“…Trametinib was then administered, via oral gavage, on a 5-day on, 2-day off schedule until endpoint was reached. This drug holiday on weekends is associated with highly favorable toxicity profiles [ 40 ], and as anticipated, weights steadily increased overtime following trametinib treatment (Fig. 5D–F ).…”

Section: Resultsmentioning

confidence: 53%

“…We recently identified molecular pathways that could be compensating for selumetinib treatment, thus contributing to molecular adaptation and drug resistance in vivo [ 40 ]. JAK/STAT3 pathway activation is upregulated in SHH MB tumor cells following treatment with selumetinib.…”

Section: Discussionmentioning

confidence: 99%

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Cross-species analysis of SHH medulloblastoma models reveals significant inhibitory effects of trametinib on tumor progression

Borlase,

DeCarlo,

Coudière-Morrison

et al. 2023

Cell Death Discov.

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Sonic Hedgehog (SHH) medulloblastomas (MBs) exhibit an intermediate prognosis and extensive intertumoral heterogeneity. While SHH pathway antagonists are effective in post-pubertal patients, younger patients exhibit significant side effects, and tumors that harbor mutations in downstream SHH pathway genes will be drug resistant. Thus, novel targeted therapies are needed. Here, we performed preclinical testing of the potent MEK inhibitor (MEKi) trametinib on tumor properties across 2 human and 3 mouse SHH MB models in vitro and in 3 orthotopic MB xenograft models in vivo. Trametinib significantly reduces tumorsphere size, stem/progenitor cell proliferation, viability, and migration. RNA-sequencing on human and mouse trametinib treated cells corroborated these findings with decreased expression of cell cycle, stem cell pathways and SHH-pathway related genes concomitant with increases in genes associated with cell death and ciliopathies. Importantly, trametinib also decreases tumor growth and increases survival in vivo. Cell cycle related E2F target gene sets are significantly enriched for genes that are commonly downregulated in both trametinib treated tumorspheres and primary xenografts. However, IL6/JAK STAT3 and TNFα/NFκB signaling gene sets are specifically upregulated following trametinib treatment in vivo indicative of compensatory molecular changes following long-term MEK inhibition. Our study reveals a novel role for trametinib in effectively attenuating SHH MB tumor progression and warrants further investigation of this potent MEK1/2 inhibitor either alone or in combination with other targeted therapies for the treatment of SHH MB exhibiting elevated MAPK pathway activity.

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 53%

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Cross-species analysis of SHH medulloblastoma models reveals significant inhibitory effects of trametinib on tumor progression

Borlase,

DeCarlo,

Coudière-Morrison

et al. 2023

Cell Death Discov.

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“…Multiple different signaling pathways, including PI3K [21], FAK [22], NF-κB [23], JAK/STAT3 [24], HIF-1α/VEGF signaling pathway [25] had been reported to lymphangiogenesis in cancer metastasis. HIF-1α/VEGF signaling pathway is one of the most important pathways contributing to cell lymphangiogenesis and metastasis during tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

The novel oncogenic factor TET3 combined AHR to promote Thyroid cancer lymphangiogenesis via HIF-1α/VEGF signaling pathway

Yang

Zhao

Qiao

et al. 2023

Preprint

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Background Lymphangiogenesis is an important factor in the invasion and metastasis of thyroid cancer (THCA). The relative researches of lymphangiogenesis have always been a hot topic in THCA, but its specific regulatory mechanism has not been totally clear. Methods Public databases including the Cancer Genome Atlas (TCGA), TIMER, GEPIA, and UALCAN database were employed to analyze and visualize the expression and prognosis of TET3 and AHR in THCA. GEPIA and TIMER were used to analyze the correlation between these molecules. Rt-PCR and Western Blot were used to detect the mRNA and protein expression of related proteins. Plate colony formation, cycle, apoptosis, angiogenesis and transwell assay were used to examine the ability of proliferation, lymphangiogenesis and invasion of THCA cells. Results TCGA database were showed that TET3 and AHR in tumor tissue compared to normal tissue in THCA. And there was a high correlation between TET3 and AHR. UALCAN and GEPIA database were exhibited that high expression of TET3 and AHR were corelated with THCA TNM stages and poor prognosis of THCA patients. Moreover, the TET3 activation accelerated THCA cells proliferation by inducing G2/M phase arrest and restraining apoptosis, and the AHR inactivation reduced THCA cells proliferation by decreasing G2/M phase arrest and inducing apoptosis in vitro of THCA cells. Notably, TET3 and AHR markedly promoted THCA cells lymphangiogenesis and invasion. In addition, TET3 activation and AHR inactivation regulated HIF-1α/VEGF signaling pathway. Conclusions TET3 combined AHR to promote THCA lymphangiogenesis via HIF-1α/VEGF signaling pathway and targeting TET3 and AHR might provide a potential treatment strategy for THCA.

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“…The PI3K/Akt pathway has crosstalk with multiple cells signaling pathways. Activation of STAT3 is thought to upregulate Shh gene expression ( Zagozewski et al, 2022 ), whereas PI3K/AKT inhibition promotes STAT3 activation. Recently, RARβ2, another promoter of Shh expression, was also found to be negatively regulated by PI3K/AKT ( Huang et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Parthenolide promotes expansion of Nestin+ progenitor cells via Shh modulation and contributes to post-injury cerebellar replenishment

et al. 2022

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Background: Regeneration of injuries occurring in the central nervous system is extremely difficult. Studies have shown that the developing cerebellum can be repopulated by a group of Nestin-expressing progenitors (NEPs) after irradiation injury, suggesting that modulating the mobilization of NEPs is beneficial to promoting nerve regeneration. To date, however, effect of exogenous pharmaceutical agonist on NEPs mobilization remains unknown. Parthenolide (PTL), a sesquiterpene lactone isolated from shoots of feverfew. Although it has been shown to possess several pharmacological activities and is considered to have potential therapeutic effects on the regeneration of peripheral nerve injury, its efficacy in promoting central nervous system (CNS) regeneration is unclear. In this study, we aimed to elucidate the role and possible mechanism of PTL on regeneration in injured CNS after irradiation using a developing cerebellum model.Methods: We investigated the radioprotective effects of PTL on the developing cerebellum by immunoblotting as well as immunofluorescence staining and ROS detection in vivo and in vitro experiments, and then determined the effects of PTL on NEPs in Nestin CFP and Nestin GFP fluorescent mice. Inducible lineage tracing analysis was used in Nestin-CreERT2×ROSA26-LSL YFP mice to label and track the fate of NEPs in the cerebellum after irradiation. Combined with cell biology and molecular biology techniques to determine changes in various cellular components in the cerebellum and possible mechanisms of PTL on NEPs mobilization in the injured developing cerebellum.Results: We found that PTL could attenuate radiation-induced acute injury of granule neuron progenitors (GNPs) in irradiated cerebellar external granule layer (EGL) by alleviating apoptosis through regulation of the cells’ redox state. Moreover, PTL increased cerebellar Shh production and secretion by inhibiting the PI3K/AKT pathway, thus promoting expansion of NEPs, which is the compensatory replenishment of granule neurons after radiation damage.Conclusion: Collectively, our results indicate that activation and expansion of NEPs are critical for regeneration of the injured cerebellum, and that PTL is a promising drug candidate to influence this process.

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Combined MEK and JAK/STAT3 pathway inhibition effectively decreases SHH medulloblastoma tumor progression

Cited by 16 publications

References 74 publications

Cross-species analysis of SHH medulloblastoma models reveals significant inhibitory effects of trametinib on tumor progression

Cross-species analysis of SHH medulloblastoma models reveals significant inhibitory effects of trametinib on tumor progression

The novel oncogenic factor TET3 combined AHR to promote Thyroid cancer lymphangiogenesis via HIF-1α/VEGF signaling pathway

Parthenolide promotes expansion of Nestin+ progenitor cells via Shh modulation and contributes to post-injury cerebellar replenishment

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