Melanoma-Induced Reprogramming of Schwann Cell Signaling Aids Tumor Growth

Shurin, Michael R.; Kruglov, Oleg; Ding, Fei; Lin, Ya; Hao, Xinchang; Keskinov, Anton A.; You, Zhaoyang; Lokshin, Anna; LaFramboise, William A.; Falo, Louis D.; Bunimovich, Yuri L.

doi:10.1158/0008-5472.can-18-3872

Cited by 52 publications

(65 citation statements)

References 45 publications

(75 reference statements)

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“…For the second gene expression dataset, RNA-sequencing data of formalin fixed primary human melanoma tissue sections were retrieved from GEO (GSE126076), as un-normalized data. Each single tumor was microdissected into samples containing tumor center, tumor border, or tissue adjacent to the tumor (Shurin et al, 2019). Differential expression analysis was performed using the edgeR package (Robinson et al, 2010), applying the TMM normalization method and the glmQLFTest function.…”

Section: Public Gene Expression Analysismentioning

confidence: 99%

Knockdown of PTGS2 by CRISPR/CAS9 System Designates a New Potential Gene Target for Melanoma Treatment

et al. 2019

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CRISPR/Cas9 has become a powerful method to engineer genomes and to activate or to repress genes expression. As such, in cancer research CRISPR/Cas9 technology represents an efficient tool to dissect mechanisms of tumorigenesis and to discover novel targets for drug development. Here, we employed the CRISPR/Cas9 technology for studying the role of prostaglandin-endoperoxide synthase 2 (PTGS2) in melanoma development and progression. Melanoma is the most aggressive form of skin cancer with a median survival of less than 1 year. Although oncogene-targeted drugs and immune checkpoint inhibitors have demonstrated a significant success in improving overall survival in patients, related toxicity and emerging resistance are ongoing challenges. Gene therapy appears to be an appealing option to enhance the efficacy of currently available melanoma therapeutics leading to better patient prognosis. Several gene therapy targets have been identified and have proven to be effective against melanoma cells. Particularly, PTGS2 is frequently expressed in malignant melanomas and its expression significantly correlates with poor survival in patients. In this study we investigated on the effect of ptgs2 knockdown in B16F10 murine melanoma cells. Our results show that reduced expression of ptgs2 in melanoma cells: i) inhibits cell proliferation, migration, and invasiveness; ii) modulates immune response by impairing myeloid derived suppressor cell differentiation; iii) reduces tumor development and metastasis in vivo. Collectively, these findings indicate that ptgs2 could represent an ideal gene to be targeted to improve success rates in the development of new and highly selective drugs for melanoma treatment.

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Section: Public Gene Expression Analysismentioning

confidence: 99%

Knockdown of PTGS2 by CRISPR/CAS9 System Designates a New Potential Gene Target for Melanoma Treatment

et al. 2019

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“…We now have significant experimental evidence that activated SCs contribute to wound healing, [ ] neurofibromatosis, [ ] leprosy [ ] and melanoma growth and invasion. [ ] Taken together with the known functions of SCs, these studies have highlighted a previous unappreciated role of SCs in cutaneous biology and pathology. Namely, SCs possess significant immunologic and tissue homeostatic/reparative functions.…”

Section: Role Of Scs In Human Skin Physiology and Clinical Dermatologymentioning

confidence: 86%

“…These SCs then modulate the tumor immune environment and remodel the extracellular matrix. [ ] SCs are able to secrete multiple inflammatory mediators known to play a role in psoriasis and AD (TNF‐α, IL‐1, IL‐4, IL‐6), promote keratinocyte proliferation (NGF, NT3, AREG) and express receptors known to convey itch signalling (TRPA1, TRPV1, LPAR1), Figure B and Table . Therefore, SCs are equipped to perform a causal role in these diseases.…”

Section: Discussionmentioning

confidence: 99%

“…[ ] Yet, recent discoveries have revealed important roles for SCs in non‐neural biology: gut homeostasis, [ ] stem cell maintenance, [ ] immune modulation, [ ] cutaneous wound healing [ ] and cancer progression. [ ] Given their abundance and distribution under the dermal‐epidermal junction, the question has been raised regarding their role in cutaneous homeostasis and neoplastic and inflammatory dermatoses. [ ]…”

Section: Introductionmentioning

confidence: 99%

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Schwann cells as underestimated, major players in human skin physiology and pathology

Bray

Chéret

Yosipovitch

et al. 2019

Experimental Dermatology

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Schwann cells (SCs) have long been recognized for their ability to support repair and promote axon regeneration following injury to the peripheral nervous system. In response to nerve injury, they rapidly dedifferentiate into a precursor‐like state, secrete an array of inflammatory mediators and growth factors, proliferate, undergo epithelial‐to‐mesenchymal‐like transformation to facilitate migration, phagocytose cellular debris and remodel the extracellular environment to promote regeneration of axons through the site of injury. However, even though a cutaneous role for SCs is becoming increasingly recognized, we argue in this Viewpoint essay that the likely complex functions of SCs in skin physiology and pathology beyond skin sensation and nerve repair deserve more attention and systemic research than they have received so far. For example, SCs promote wound healing, disseminate infection in leprosy, support the growth of neurofibromas/schwannomas and facilitate/accelerate the growth and invasion of melanoma. Despite representing a major dermal cell population, comparatively little is still known about the role of SCs in other dermatoses. To quintessentially illustrate the opportunities that promise to arise from a new skin research focus on SCs, we focus on two dermatoses that are not traditionally associated with SCs, that is, psoriasis and atopic dermatitis (AD), since both show distinct SC changes along with continuous nerve fibre degeneration and regeneration, and an impact of denervation on skin lesions. Specifically, we critically discuss the hypothesis that repeated activation of the SC repair programme occurs in and contributes to psoriasis and AD and delineate experimental approaches how to probe this clinically relevant hypothesis.

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“…Schwann cells are recognized as an emerging player in cancers of the skin, colon, prostate, and pancreas 13 – 16 , 18 , 52 – 54 . Schwann cells become activated as evidenced by dedifferentiating, proliferating, and migrating in the cancer microenvironment.…”

Section: Discussionmentioning

confidence: 99%

TNFα promotes oral cancer growth, pain, and Schwann cell activation

Salvo

Scheff

et al. 2021

Sci Rep

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Oral cancer is very painful and impairs a patient’s ability to eat, talk, and drink. Mediators secreted from oral cancer can excite and sensitize sensory neurons inducing pain. Cancer mediators can also activate Schwann cells, the peripheral glia that regulates neuronal function and repair. The contribution of Schwann cells to oral cancer pain is unclear. We hypothesize that the oral cancer mediator TNFα activates Schwann cells, which further promotes cancer progression and pain. We demonstrate that TNFα is overexpressed in human oral cancer tissues and correlates with increased self-reported pain in patients. Antagonizing TNFα reduces oral cancer proliferation, cytokine production, and nociception in mice with oral cancer. Oral cancer or TNFα alone increases Schwann cell activation (measured by Schwann cell proliferation, migration, and activation markers), which can be inhibited by neutralizing TNFα. Cancer- or TNFα-activated Schwann cells release pro-nociceptive mediators such as TNFα and nerve growth factor (NGF). Activated Schwann cells induce nociceptive behaviors in mice, which is alleviated by blocking TNFα. Our study suggests that TNFα promotes cancer proliferation, progression, and nociception at least partially by activating Schwann cells. Inhibiting TNFα or Schwann cell activation might serve as therapeutic approaches for the treatment of oral cancer and associated pain.

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Melanoma-Induced Reprogramming of Schwann Cell Signaling Aids Tumor Growth

Cited by 52 publications

References 45 publications

Knockdown of PTGS2 by CRISPR/CAS9 System Designates a New Potential Gene Target for Melanoma Treatment

Knockdown of PTGS2 by CRISPR/CAS9 System Designates a New Potential Gene Target for Melanoma Treatment

Schwann cells as underestimated, major players in human skin physiology and pathology

TNFα promotes oral cancer growth, pain, and Schwann cell activation

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