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

Abstract Background Lactate, the culprit of the acidic tumor microenvironment, is crucial for the therapeutic resistance and metastasis of malignancies. However, the mechanism by which lactate regulates the malignant phenotype of head and neck squamous cell carcinoma (HNSCC) has not been fully clarified. Results In this study, we found HNSCC cells had increased type I collagen (Col I) deposition along with stronger cancer stem cells (CSC) characteristics when treated with exogenous lactate. The lactate-driven Col I was essential for the acquisition of CSC properties, knocking down COL1A1 suppressed the self-renewal abilities of cancer cells. Further study revealed that lactate promoted Col I deposition through two different pathways. On the one hand, lactate converted to pyruvate, which was a substrate of Col I hydroxylation. On the other hand, lactate activated HIF1-α and promoted the transcription of P4HA1, which was a rate-limiting enzyme for Col I synthesis. Blocking of these two pathways inhibited the enhanced cell stemness caused by lactate, while the addition of exogenous Col I rescued the CSC phenotype. The transcriptome sequencing results suggested that Col I enhanced CSC properties by affecting cell cycle dynamics. Conlusions: Our research proposes that lactate-driven Col I deposition is essential for the acquisition of the CSC phenotype, and lactate-centric Col I deposition may be an effective target for HNSCC.