Letter to the Editor: Autophagy related RHEB-CSF1R complex promotes tumor metastasis in pancreatic cancer: Mechanobiological perspective for RHEB-targeted cancer treatment

Abstract

We read with great interest the study by Deng et al published in the World Journal of Gastroenterology, which reported that Ras homolog enriched in brain (RHEB) overexpression is associated with reduced survival in patients with pancreatic cancer (PC). The researchers demonstrated that RHEB enhances cancer cell proliferation, migration, and invasion while suppressing autophagy concurrently. This occurs through the upregulation and interaction of colony stimulating factor 1 receptor, which leads to the phosphorylation of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT1), and mammalian target of rapamycin (TOR) signaling components. This cascade was proposed to drive the expression of epithelial-mesenchymal transition markers, thereby promoting metastatic potential. While these findings provide significant mechanistic insight into RHEB-driven tumor progression, an essential consideration remains unaddressed: The impact of PI3K/AKT1/mTOR phosphorylation on tumor cell mechanosensing and its interaction with the extracellular matrix (ECM). Given the central role of ECM remodeling and mechanical cues in PC aggressiveness, future studies should integrate the mechanobiological aspects of PI3K/AKT1/mTOR pathway activation to better elucidate how RHEB modulates tumor behavior within the physical microenvironment. This letter highlights the potential of interlinked molecular signaling, cellular mechanosensing, and tumor ECM properties to find a promising therapy for PC progression.

Key Words: Cancer; Epithelial-mesenchymal transition; Extracellular matrix; Mechanosensing; Metastasis; mTOR; Pancreatic cancer; RHEB; Solid tumors; Tumor progression

Core Tip: Ras homolog enriched in brain (RHEB)-driven pathways promote tumor aggressiveness by phosphorylating phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin, which influences tumor cell mechanosensing and interaction with the extracellular matrix. Advanced therapeutic strategies for treating solid tumors could target RHEB-mediated signaling.

TO THE EDITOR

We read with great interest the study by Deng et al[1] published in the World Journal of Gastroenterology, which found that Ras homolog enriched in brain (RHEB) lowered the survival rate of patients with pancreatic cancer (PC). The authors explained the mechanistic basis of this phenomenon, demonstrating that RHEB expression promotes PC cell proliferation, migration, and invasiveness. RHEB expression also inhibits autophagy by upregulating and interacting with the colony stimulating factor 1 receptor (CSF1R), which leads to the phosphorylation of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT1), and the mammalian target of rapamycin (mTOR). The authors hypothesize that this promoted the expression of epithelial-mesenchymal transition (EMT) markers, which in turn promoted PC metastasis[1]. We propose an additional dimension regarding the role of PI3K, AKT1, mTOR phosphorylation in regulation of the tumor cell mechanosensing and tumor progression via interaction with the extracellular matrix (ECM)[2]. The purpose of this letter was to discuss the mechanisms of ECM-axis regulations which could underlie advanced targeted therapy of solid tumors.

ECM-associated phosphorylation patterns

Tumor ECM (oncomatrix) differs from the normal by the stiffness, and altered chemical properties[2,3], therefore affecting the cellular mechanosensing. Focal adhesion kinase (FAK)/PI3K/AKT1 and mitogen-activated protein kinase cascades regulate cellular responses to mechanical cues and ECM components. These cascades influence cell migration, proliferation, and survival[4], including EMT[5,6]. The PI3K/AKT1/mTOR pathway influences tumor formation through eukaryotic initiation factors[7,8], and mediates the cytoskeletal remodeling and EMT[9]. It is not surprising that PI3K modulators have been identified as suitable targets for gastric tumors with dysregulated ECM[10], with advanced perspectives for reducing the toxicity of molecularly targeted therapy[11]. Targeting the ECM could also be applied to chimeric antigen receptor T-cell therapy for solid tumors and other diseases characterized by ECM-related therapeutic barriers[12,13].

The phosphorylation of PI3K, AKT1, and mTOR proteins is directly associated with decreased enzyme activity as epigenetic regulation, independent of changes in the transcription profile. Deng et al[1] showed that RHEB promotes phosphorylation by increasing CSF1R expression. This hinders autophagy and induces EMT, which is particularly significant for solid tumors because stimulation of EMT leads to metastasis[1], and also associated with cell-ECM interaction properties. The PI3K/AKT1/mTOR pathway serves as a primary transducer of physical stimuli into cell survival, growth, and cell cycle progression through its mechanosensing function, directly modulating ECM-mediated cellular regulation.

RHEB strongly interacts with mTOR to regulate cell growth, and CSF1R signals via CSF1/IL-34 to control macrophages[14]. Deng et al[1] investigated that the RHEB-CSF1R complex might promote PC metastasis by upregulating the EMT markers N-cadherin and vimentin and downregulating E-cadherin via autophagy inhibition. Interestingly, the mechanism of RHEB affecting PC metastasis was correlated with the upregulation of RHEB, CSF1R, PI3K, AKT1, and mTOR expression[1]. Recent investigations have shown that RHEB can form complexes with various binding partners in a GTP-dependent manner beyond CSF1R, including the Bcl-2 interacting protein 3, phospholipase D1, cAMP-specific 3’,5’-cyclic phosphodiesterase 4D[15], thereby contributing to tumor progression through the regulation of ECM properties. Therefore, due to their role in modification of the scope of ECM regulation, the RHEB complexes could be identified as potential targets for advanced therapeutics for solid tumors, or therapeutic adjuvants.

Conclusion

The emerging role of ECM in the progression and fate of human tumors identifies more acceptable targets and associated pathways. The study by Deng et al[1] examined how the RHEB-CSF1R complex regulates the PI3K, AKT1, and mTOR pathways, which lead to cancer progression. However, the wide range of RHEB complexes involved in tumor cell interactions with the ECM could be identified as potential targets for solid tumor treatments.