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Lactate-driven type I collagen deposition facilitates cancer stem cell-like phenotype of head and neck squamous cell carcinoma.

ABSTRACT: Lactate is known to play a crucial role in the progression of malignancies. However, its mechanism in regulating the malignant phenotype of head and neck squamous cell carcinoma (HNSCC) remains unclear. This study found that lactate increases cancer stem cell (CSC) characteristics of HNSCC by influencing the deposition of type I collagen (Col I). Lactate promotes Col I deposition through two distinct pathways. One is to convert lactate to pyruvate, a substrate for Col I hydroxylation. The other is the activation of HIF1-α and P4HA1, the latter being a rate-limiting enzyme for Col I synthesis. Inhibition of these two pathways effectively counteracts lactate-induced enhanced cell stemness. Further studies revealed that Col I affects CSC properties by regulating cell cycle dynamics. In conclusion, our research proposes that lactate-driven Col I deposition is essential for the acquisition of CSC properties, and lactate-centric Col I deposition may be an effective target for CSCs.

SUBMITTER: Sun Y

PROVIDER: S-EPMC10945209 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Lactate-driven type I collagen deposition facilitates cancer stem cell-like phenotype of head and neck squamous cell carcinoma.

Sun Yunqing Y Chen Yang Y Zhao Hui H Wang Jingjing J Liu Yuantong Y Bai Junqiang J Hu Chuanyu C Shang Zhengjun Z

iScience 20240228 4

Lactate is known to play a crucial role in the progression of malignancies. However, its mechanism in regulating the malignant phenotype of head and neck squamous cell carcinoma (HNSCC) remains unclear. This study found that lactate increases cancer stem cell (CSC) characteristics of HNSCC by influencing the deposition of type I collagen (Col I). Lactate promotes Col I deposition through two distinct pathways. One is to convert lactate to pyruvate, a substrate for Col I hydroxylation. The other ...[more]

PMID: 38500829

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Project description:Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and incidence rates are continuing to rise globally. HNSCC patient prognosis is closely related to the occurrence of tumor metastases, and collagen within the tumor microenvironment (TME) plays a key role in this process. Lysyl hydroxylase 2 (LH2), encoded by the Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 2 (PLOD2) gene, catalyzes hydroxylation of telopeptidyl lysine (Lys) residues of fibrillar collagens which then undergo subsequent modifications to form stable intermolecular cross-links that change the biomechanical properties (i.e. quality) of the TME. While LH2-catalyzed collagen modification has been implicated in driving tumor progression and metastasis in diverse cancers, little is known about its role in HNSCC progression. Thus, using gain- and loss-of-function studies, we examined the effects of LH2 expression levels on collagen cross-linking and cell behavior in vitro and in vivo using a tractable bioluminescent imaging-based orthotopic xenograft model. We found that LH2 overexpression dramatically increases HNSCC cell migratory and invasive abilities in vitro and that LH2-driven changes in collagen cross-linking robustly induces metastasis in vivo. Specifically, the amount of LH2-mediated collagen cross-links increased significantly with PLOD2 overexpression, without affecting the total quantity of collagen cross-links. Conversely, LH2 knockdown significantly blunted HNSCC cells invasive capacity in vitro and metastatic potential in vivo. Thus, regardless of the total "quantity" of collagen crosslinks, it is the "quality" of these cross-links that is the key driver of HNSCC tumor metastatic dissemination. These data implicate LH2 as a key regulator of HNSCC tumor invasion and metastasis by modulating collagen cross-link quality and suggest that therapeutic strategies targeting LH2-mediated collagen cross-linking in the TME may be effective in controlling tumor progression and improving disease outcomes.

Dataset Information

Lactate-driven type I collagen deposition facilitates cancer stem cell-like phenotype of head and neck squamous cell carcinoma.

Publications

Lactate-driven type I collagen deposition facilitates cancer stem cell-like phenotype of head and neck squamous cell carcinoma.

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