Remote neuronal activity drives glioma progression through SEMA4F

Huang-Hobbs, Emmet; Cheng, Yi-Ting; Ko, Yeunjung; Luna-Figueroa, Estefania; Lozzi, Brittney; Taylor, Kathryn R.; McDonald, Malcolm; He, Peihao; Chen, Hsiao‐Chi; Yang, Yuhui; Maleki, Ehson; Lee, Zhung-Fu; Murali, Sanjana; Choi, Dong‐Joo; Curry, Rachel; Bayley, James C.; Woo, Junsung; Jalali, Ali; Monje, Michelle; Noebels, Jeffrey L.; Harmancı, Akdes Serin; Rao, Ganesh; Deneen, Benjamin

doi:10.1038/s41586-023-06267-2

Cited by 48 publications

(42 citation statements)

References 47 publications

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“…Another mechanism how our nervous system can control cancer initiation and progression is via paracrine factors that are frequently regulated by neuronal activity [1 ▪ ]. A current study finds that neuronal activity in remote contralateral brain regions stimulates the invasion of tumor cells enriched for axon guidance genes over the corpus callosum, with SEMA4F as the driving paracrine factor, promoting bidirectional brain-tumor signaling by remodeling tumor-adjacent neuronal synapses [21 ▪▪ ]. Similar neuronal-activity dependent mechanism of tumor progression have now also been reported for SCLC, both for brain metastases and for the primary site in the lung [22].…”

Section: Paracrine Neuro-cancer Interactionssupporting

confidence: 66%

Neuroscience and oncology: state-of-the-art and new perspectives

Winkler

2023

Current Opinion in Neurology

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Purpose of review Emerging discoveries suggest that both the central (CNS) and peripheral (PNS) nervous system are an important driver of cancer initiation, promotion, dissemination, and therapy resistance, not only in the brain but also in multiple cancer types throughout the body. This article highlights the most recent developments in this emerging field of research over the last year and provides a roadmap for the future, emphasizing its translational potential. Recent findings Excitatory synapses between neurons and cancer cells that drive growth and invasion have been detected and characterized. In addition, a plethora of paracrine, mostly tumor-promoting neuro-cancer interactions are reported, and a neuro-immuno-cancer axis emerges. Cancer cell-intrinsic neural properties, and cancer (therapy) effects on the nervous system that cause morbidity in patients and can establish harmful feedback loops receive increasing attention. Despite the relative novelty of these findings, ther apies that inhibit key mechanisms of this neuro-cancer crosstalk are developed, and already tested in clinical trials, largely by repurposing of approved drugs. Summary Neuro-cancer interactions are manyfold, have multiple clinical implications, and can lead to novel neuroscience-instructed cancer therapies and improved therapies of neurological dysfunctions and cancer pain. The development of biomarkers and identification of most promising therapeutic targets is crucial.

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Section: Paracrine Neuro-cancer Interactionssupporting

confidence: 66%

Neuroscience and oncology: state-of-the-art and new perspectives

Winkler

2023

Current Opinion in Neurology

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“…It will also be interesting to examine whether expression and genetic alteration of other axon guidance and neuronal development genes would have an impact on the immune cell infiltrates and have a similar dual role in human PDAs. Furthermore, a recent study found neurons in locations remote to tumors can promote malignant progression of cancer, which also remains to be explored in PDA 51 . Therefore, we do not think that a single axon guidance molecule itself, but a combination of multiple axon guidance family members together would impact the overall prognosis.…”

Section: Discussionmentioning

confidence: 99%

Tumor- and Nerve-Derived Axon Guidance Molecule Promotes Pancreatic Ductal Adenocarcinoma Progression and Metastasis through Macrophage Reprogramming

Thielman,

Funes,

Davuluri

et al. 2023

Preprint

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Axon guidance molecules were found to be the gene family most frequently altered in pancreatic ductal adenocarcinoma (PDA) through mutations and copy number changes. However, the exact molecular mechanism regarding PDA development remained unclear. Using genetically engineered mouse models to examine one of the axon guidance molecules, semaphorin 3D (SEMA3D), we found a dual role for tumor-derived SEMA3D in malignant transformation of pancreatic epithelial cells and a role for nerve-derived SEMA3D in PDA development. This was demonstrated by the pancreatic-specific knockout of the SEMA3D gene from the KRASG12D and TP53R172H mutation knock-in, PDX1-Cre (KPC) mouse model which demonstrated a delayed tumor initiation and growth comparing to the original KPC mouse model. Our results showed that SEMA3D knockout skews the macrophages in the pancreas away from M2 polarization, providing a potential mechanistic role of tumor-derived SEMA3D in PDA development. The KPC mice with the SEMA3D knockout remained metastasis-free, however, died from primary tumor growth. We then tested the hypothesis that a potential compensation mechanism could result from SEMA3D which is naturally expressed by the intratumoral nerves. Our study further revealed that nerve-derived SEMA3D does not reprogram macrophages directly, but reprograms macrophages indirectly through ARF6 signaling and lactate production in PDA tumor cells. SEMA3D increases tumor-secreted lactate which is sensed by GPCR132 on macrophages and subsequently stimulates pro-tumorigenic M2 polarization in vivo. Tumor intrinsic- and extrinsic-SEMA3D induced ARF6 signaling through its receptor Plexin D1 in a mutant KRAS-dependent manner. Consistently, RNA sequencing database analysis revealed an association of higher KRASMUT expression with an increase in SEMA3D and ARF6 expression in human PDAs. Moreover, multiplex immunohistochemistry analysis showed an increased number of M2-polarized macrophages proximal to nerves in human PDA tissue expressing SEMA3D. Thus, this study suggests altered expression of SEMA3D in tumor cells lead to acquisition of cancer-promoting functions and the axon guidance signaling originating from nerves is hijacked by tumor cells to support their growth. Other axon guidance and neuronal development molecules may play a similar dual role which is worth further investigation.

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“…Within the emerging field of cancer neuroscience, new findings by Curry and colleagues 2 add to a growing consensus of a reciprocity between dysregulated peritumoral neural activity and tumor growth. [3][4][5] Their data demonstrate a positive feedback loop that generates and reinforces the associated pathologies of GRE, in which gliomas alter the local microenvironment to skew peritumoral neural activity toward hyperexcitability, and subsequent neural hyperactivity further promotes tumor growth. The work reports a novel pathway by which gliomas may promote hyperexcitability through the upregulated expression of the membrane protein immunoglobulin superfamily 3 (IGSF3), modulating the capacity of its binding partner, the glial-specific inwardly rectifying potassium channel Kir4.1, to buffer potassium ions in peritumoral tissue.…”

Section: Commentarymentioning

confidence: 90%