GPR81 nuclear transportation is critical for cancer growth: Interaction of lactate receptor signaling and cell-extracellular matrix mechanotransduction

Abstract

The interaction between the lactate receptor GPR81 (also known as hydroxycarboxylic acid receptor 1, or HCAR1) and Splicing Factor Proline- and Glutamine-Rich protein promotes the tumor cell malignancy. GPR81 nuclear translocation plays an important role in driving cancer progression and could serve as a potential therapeutic target. Yang et al concluded in their study that lactate and its receptor, GPR81, play crucial roles in cancer progression, and are key players in linking the lactate-rich tumor microenvironment to cancer cell behavior. The ability of nuclear GPR81 to directly regulate gene expression, combined with extracellular matrix -mediated mechanical signaling, creates a potentially robust system for the coordinated adaptation and survival of cancer cells. Understanding these interactions could lead to the discovery of new therapeutic targets and improved treatment strategies for cancer.

Key Words: Cancer; Extracellular matrix; GPR81; Lactate; Mechanotransduction; Tumor microenvironment; Warburg effect

Core Tip: The interaction between GPR81 nuclear transport and cell-extracellular matrix mechanotransduction is a novel axis in cancer biology that could greatly affect tumor growth and progression, and could be a target for future therapeutics.

TO THE EDITOR

We read with great interest the paper by Yang et al[1], which disclosed the role of GPR81 nuclear transport in the growth and progression of solid tumors. The authors concluded that GPR81 interacts with Splicing Factor Proline- and Glutamine-Rich (SFPQ) to promote the tumor cell malignancy, and that GPR81 nuclear translocation is critical for cancer progression. This process may be a potential therapeutic target for limiting cancer progression. Therefore, lactate and its receptor, GPR81, play crucial roles in cancer progression and are key players in linking the lactate-rich tumor microenvironment (TME) to cancer cell behavior. However, we believe the paper by Yang et al[1] lacked a key point: The interconnections between GPR81 signaling and the extracellular matrix properties.

GPR81 SIGNALING AND TUMOR MICROENVIRONMENT

The altered TME in solid tumors is profoundly affected by extracellular matrix (ECM) properties, which are characteristics of non-cellular tissue scaffolds[2]. GPR81 signaling is activated by lactate and regulates the expression of genes directly involved in modifying the ECM and cell adhesion[2,3]. GPR81 exerts its influence on genes such as the Notch ligand DLL4, which plays a pivotal role in cell-to-cell communication and tissue patterning. GPR81 contributes to the remodeling of the tumor's ECM by controlling these genes, which makes the ECM more conducive to the aggressiveness, migration, and invasion of cancer[4]. The discovery of nuclear GPR81 activity establishes a direct link between the lactate signal and the cell's genetic machinery. This bypasses traditional signaling cascades, allowing for more direct control over the phenotype of cancer cells[5]. Nuclear GPR81 transcriptionally up-regulates FN1, LOX, and MMP3, creating a self-reinforcing lactate–stiff ECM–invasion loop[6]. The stiffened ECM acts as a mechanobiological "switch" that moves GPR81 from the cell membrane to the nucleus[6,7]. Therefore, ECM-crosstalk genes lead to a positive feedback loop that gives tumors enhanced growth, invasion, metabolic reprogramming, and the ability to escape drugs, including advanced therapeutics such as CAR T-cell therapy for solid tumors[8].

Preclinical models of breast cancer have shown that blocking GPR81 can slow tumor growth and improve immune infiltration[9,10]. However, GPR81 is highly expressed in adipose tissue, muscle, the liver, the brain, and some immune cells, increasing the risk of systemic side effects. Additionally, lactate is present in millimolar concentrations under normal physiological conditions, which makes complete pathway blockade difficult without off-target metabolic effects. Thus, the primary effect of GPR81, which is associated with the inhibition of adenylyl cyclase and decreased intracellular cAMP, requires the specific intracellular transport of therapeutic agents. Recent advances in nanotheranostic designs suggest that GPR81-mediated signaling may regulate not only tumor metabolic disadaptation but also for modulating ECM remodeling through lactate-driven crosstalk, enhancing the effectiveness of nanoparticle-targeted delivery[11,12].

The molecular mechanisms underlying GPR81’s nuclear transportation remain unclear. However, recent studies have shown the proof of the GPR81 nuclear location bias phenomenon[1,5]. Some GPCRs have been found in the nucleus or endoplasmic reticulum[13-15]. The detailed mechanism of interaction between GPR81 and SFPQ has not yet been investigated, but it could be explained by primary and secondary molecular mechanisms. Primary signaling after lactate binds to GPR81 could lead to a reduction in intracellular cAMP levels. This decrease would attenuate the PKA/CREB signaling pathway, resulting in reduced phosphorylation of transcriptional coactivators and altered transcription factor recruitment. These two regulatory axes - cAMP, a key second messenger, and the PKA/CREB signaling pathway - can modulate cell-ECM interactions by influencing cell adhesion, stiffness, migration, and gene expression. Secondary signaling involves changes in the composition of nuclear SFPQ-containing complexes. These alterations can modulate the transcription and/or splicing of mechanosensing- and mechanotransduction-related genes, thereby amplifying or sustaining the effects initiated by GPR81 activation.

CONCLUSION

Therefore, the interaction between GPR81 nuclear transport and ECM properties represents a novel axis in cancer biology that may significantly impact tumor growth and progression. The ability of nuclear GPR81 to directly regulate gene expression, combined with ECM-mediated mechanical signaling, creates a potentially robust system for the coordinated adaptation and survival of cancer cells. Understanding these interactions could lead to the discovery of new therapeutic targets and improved treatment strategies for cancer.