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OXTR^High stroma fibroblasts control the invasion pattern of oral squamous cell carcinoma via ERK5 signaling.

ABSTRACT: The Pattern Of Invasion (POI) of tumor cells into adjacent normal tissues clinically predicts postoperative tumor metastasis/recurrence of early oral squamous cell carcinoma (OSCC), but the mechanisms underlying the development of these subtypes remain unclear. Focusing on the highest score of POIs (Worst POI, WPOI) present within each tumor, we observe a disease progression-driven shift of WPOI towards the high-risk type 4/5, associated with a mesenchymal phenotype in advanced OSCC. WPOI 4-5-derived cancer-associated fibroblasts (CAFs^WPOI4-5), characterized by high oxytocin receptor expression (OXTR^High), contribute to local-regional metastasis. OXTR^High CAFs induce a desmoplastic stroma and CCL26 is required for the invasive phenotype of CCR3⁺ tumors. Mechanistically, OXTR activates nuclear ERK5 transcription signaling via Gαq and CDC37 to maintain high levels of OXTR and CCL26. ERK5 ablation reprograms the pro-invasive phenotype of OXTR^High CAFs. Therefore, targeting ERK5 signaling in OXTR^High CAFs is a potential therapeutic strategy for OSCC patients with WPOI 4-5.

SUBMITTER: Ding L

PROVIDER: S-EPMC9433374 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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OXTR<sup>High</sup> stroma fibroblasts control the invasion pattern of oral squamous cell carcinoma via ERK5 signaling.

Ding Liang L Fu Yong Y Zhu Nisha N Zhao Mengxiang M Ding Zhuang Z Zhang Xiaoxin X Song Yuxian Y Jing Yue Y Zhang Qian Q Chen Sheng S Huang Xiaofeng X O'Reilly Lorraine A LA Silke John J Hu Qingang Q Ni Yanhong Y

Nature communications 20220831 1

The Pattern Of Invasion (POI) of tumor cells into adjacent normal tissues clinically predicts postoperative tumor metastasis/recurrence of early oral squamous cell carcinoma (OSCC), but the mechanisms underlying the development of these subtypes remain unclear. Focusing on the highest score of POIs (Worst POI, WPOI) present within each tumor, we observe a disease progression-driven shift of WPOI towards the high-risk type 4/5, associated with a mesenchymal phenotype in advanced OSCC. WPOI 4-5-de ...[more]

PMID: 36045118

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Project description:BackgroundThe molecular mechanisms involved in the invasion of bone by oral squamous cell carcinomas (OSCC) are poorly understood, and little is known about the role of cancer-associated fibroblasts (CAF), the presence of which confers a poor prognosis.MethodsClinicopathological data from 277 OSCC cases involving bone resections were reviewed, and 32 cases thoroughly analysed histologically. Immunohistochemistry was used to examine αSMA, RANKL and OPG. Western blotting and qPCR were used to assess myofibroblast (CAF-like) differentiation, RANKL and OPG expression in vitro, and RANKL secretion was analysed by ELISA. Osteoclastogenesis was examined using TRAP staining, multinucleation and pit forming assays.ResultsFibrous stroma intervened between tumour and bone in the majority of cases, with no direct contact between cancer cells and bone. RANKL and OPG, two proteins key to regulating bone resorption, were expressed in tumour cells as well as fibrous stroma adjacent to bone and αSMA-positive myofibroblastic CAF were consistently seen infiltrating into bone ahead of tumour cells. Human primary osteoblasts cultured with conditioned media from human OSCC-derived cells and human primary CAF showed a significant increase in RANKL and a decline in OPG mRNA expression. RANKL secretion was significantly increased in primary oral fibroblasts induced to differentiate into a CAF-like phenotype by transforming growth factor-β1 (TGF-β1) treatment and in primary CAF. Indirect co-culture of murine macrophages with conditioned media from CAF (experimentally derived and isolated from OSCCs) resulted in a marked increase in osteoclastogenesis (in excess of that provoked by cancer cells) determined by tartrate-resistant acid phosphatase activity, multinucleation and resorption pit formation.ConclusionsThis study is the first to describe a functional role for CAFs in bone invasion and turnover, identifying a novel potential therapeutic target and diagnostic indicator in this difficult to treat bone invasive malignancy.

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OXTR^High stroma fibroblasts control the invasion pattern of oral squamous cell carcinoma via ERK5 signaling.

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OXTR<sup>High</sup> stroma fibroblasts control the invasion pattern of oral squamous cell carcinoma via ERK5 signaling.

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OXTRHigh stroma fibroblasts control the invasion pattern of oral squamous cell carcinoma via ERK5 signaling.

Publications

OXTR<sup>High</sup> stroma fibroblasts control the invasion pattern of oral squamous cell carcinoma via ERK5 signaling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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OXTR^High stroma fibroblasts control the invasion pattern of oral squamous cell carcinoma via ERK5 signaling.