Tumor innervation is triggered by endoplasmic reticulum stress

Jiang, Chen Chen; Marsland, Mark; Dowdell, Amiee; Eden, Edward; Gao, Fangfang; Faulkner, Sam; Jobling, Phillip; Li, Xiang; Liu, Lihua; He, Zhangyu; Hondermarck, Hubert

doi:10.1038/s41388-021-02108-6

Cited by 11 publications

(11 citation statements)

References 44 publications

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“…Second, the molecular mechanisms underlying the effect of doxorubicin on NGF expression in tumor cells were not investigated in the current study. A recent study found that induction of endoplasmic reticulum stress in cancer cells could promote neurite growth in PC12 cells through the precursor for BDNF ( 35 ). This suggests a plausible mechanism, because doxorubicin can induce endoplasmic reticulum stress in the heart ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Beta-blockade enhances anthracycline control of metastasis in triple-negative breast cancer

et al. 2023

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Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated β 2 -adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or β 2 -adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting β 2 -adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive β 2 -adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.

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Section: Discussionmentioning

confidence: 99%

Beta-blockade enhances anthracycline control of metastasis in triple-negative breast cancer

et al. 2023

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“…Interestingly, we observed how cancer cells in coculture could show even a higher effect in neuronal precursor differentiation compared to the NGF stimulation alone ( Figure 5 F). We are currently investigating the exact mechanism leading to the NMUMG-M-dependent neuronal differentiation, and previous reports have already demonstrated how cancer cells can promote neuronal precursor differentiation through various routes [ 12 , 13 , 15 , 17 , 19 , 25 , 26 , 27 ]. We can speculate that the NMuMG-M cells’ expression of several specific axon guidance molecules triggers a strong response in PC12 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Seminal studies have implicated the role of Semaphorins in cancer-induced neurogenesis and aggressivity [ 12 , 15 , 24 ], and in our previous study, we identified the TGFβ pathway as a mediator of cancer innervation, promoting the expression of the Semaphorin-4F in breast cancer cells and leading to increased cancer innervation associated with enhanced metastasis [ 19 ]. ER-stress has also been recently identified to promote the production of proBDNF in human prostate, colon, and pancreatic cancer and is linked to cancer innervation [ 25 ]. Additional studies demonstrated how other axon guidance molecules are involved in cancer innervation, such as Plexin B3 produced by breast cancer cells [ 26 ] or EphrinB1 secreted by head and neck squamous cell carcinoma through exosomes [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…In vivo methods for studying neuronal density within tumors typically involve pathology scoring, with intratumoral neuronal density assessed by immunohistochemistry (IHC) combined with stereology techniques [ 11 , 15 , 20 ]. In contrast, in vitro studies usually rely on measuring changes in neuronal morphology, including neurite length, branches, or number [ 13 , 19 , 25 , 28 ]. While effective, these approaches are time-consuming and do not easily provide a comprehensive picture of neuronal differentiation or the intermediate state of differentiation that may occur in the context of cancer.…”

Section: Introductionmentioning

confidence: 99%

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A CRISPR/Cas9-Based Assay for High-Throughput Studies of Cancer-Induced Innervation

Galappaththi

Katz

Howze

et al. 2023

Cancers

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The aggressive nature of certain cancers and their adverse effects on patient outcomes have been linked to cancer innervation, where neurons infiltrate and differentiate within the cancer stroma. Recently we demonstrated how cancer plasticity and TGFβ signaling could promote breast cancer innervation that is associated with increased cancer aggressivity. Despite the promising potential of cancer innervation as a target for anti-cancer therapies, there is currently a significant lack of effective methods to study cancer-induced neuronal differentiation, hindering the development of high-throughput approaches for identifying new targets or pharmacological inhibitors against cancer innervation. To overcome this challenge, we used CRISPR-based endogenous labeling of the neuronal marker β3-tubulin in neuronal precursors to investigate cancer-induced neuronal differentiation in nerve-cancer cocultures and provide a tool that allows for better standardization and reproducibility of studies about cancer-induced innervation. Our approach demonstrated that β3-tubulin gene editing did not affect neuronal behavior and enabled accurate reporting of cancer-induced neuronal differentiation dynamics in high-throughput settings, which makes this approach suitable for screening large cohorts of cells or testing various biological contexts. In a more context-based approach, by combining this method with a cell model of breast cancer epithelial-mesenchymal transition, we revealed the role of cancer cell plasticity in promoting neuronal differentiation, suggesting that cancer innervation represents an underexplored path for epithelial-mesenchymal transition-mediated cancer aggressivity.

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“…Cell growth assays were carried out using Cell Titer-Blue ® (Promega, Hawthorne, VIC, Australia) according to the manufacturer's instructions and as previously reported [24]. Cells were treated with AF38469 (400 nM, catalogue number HY-12802, MedChemExpress, Monmouth Junction, NJ, USA), TMZ (50 µM, catalogue number S1237, Selleck Chem, Sapphire Bioscience, NSW, Australia), or AF38469 + TMZ for 72 h. Vehicle control was DMSO at the same concentration.…”

Section: Measurement Of Cell Growth and Invasionsmentioning

confidence: 99%

The Membrane Protein Sortilin Is a Potential Biomarker and Target for Glioblastoma

Marsland

Dowdell

Faulkner

et al. 2023

Cancers

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Glioblastoma (GBM) is a devastating brain cancer with no effective treatment, and there is an urgent need for developing innovative biomarkers as well as therapeutic targets for better management of the disease. The membrane protein sortilin has recently been shown to participate in tumor cell invasiveness in several cancers, but its involvement and clinical relevance in GBM is unclear. In the present study, we explored the expression of sortilin and its potential as a clinical biomarker and therapeutic target for GBM. Sortilin expression was investigated by immunohistochemistry and digital quantification in a series of 71 clinical cases of invasive GBM vs. 20 non-invasive gliomas. Sortilin was overexpressed in GBM and, importantly, higher expression levels were associated with worse patient survival, pointing to sortilin tissue expression as a potential prognostic biomarker for GBM. Sortilin was also detectable in the plasma of GBM patients by enzyme-linked immunosorbent assay (ELISA), but no differences were observed between sortilin levels in the blood of GBM vs. glioma patients. In vitro, sortilin was detected in 11 brain-cancer-patient-derived cell lines at the anticipated molecular weight of 100 kDa. Interestingly, targeting sortilin with the orally bioavailable small molecule inhibitor AF38469 resulted in decreased GBM invasiveness, but cancer cell proliferation was not affected, showing that sortilin is targetable in GBM. Together, these data suggest the clinical relevance for sortilin in GBM and support further investigation of GBM as a clinical biomarker and therapeutic target.

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Tumor innervation is triggered by endoplasmic reticulum stress

Cited by 11 publications

References 44 publications

Beta-blockade enhances anthracycline control of metastasis in triple-negative breast cancer

Beta-blockade enhances anthracycline control of metastasis in triple-negative breast cancer

A CRISPR/Cas9-Based Assay for High-Throughput Studies of Cancer-Induced Innervation

The Membrane Protein Sortilin Is a Potential Biomarker and Target for Glioblastoma

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