Noval insights and therapeutic strategies for tumor-induced kidney pathologies (2024)

Recent progress in elucidating the role of specific antidiuretic hormones in Drosophila models has provided valuable insights into the mechanisms underlying tumor-induced renal dysfunction. Xu et al. identified the mammalian neurokinin 3 receptor (TACR3), a homolog of the G protein-coupled receptor TkR99D in fruit flies, as a potential therapeutic target for alleviating renal tubular dysfunction in mice with malignant neoplasms. Here, we commented on these findings by emphasizing the structural and evolutionary significance of TACR3 and provided an in-depth analysis of cell type specific expression of TACR3 in response to renal injury and expressional dynamics during renal carcinoma progression. The implications of these findings for transforming the therapeutic approaches to renal complications associated with oncological disorders were highlighted. We also acknowledged the limitations of current experimental models in this study and emphasized the necessary clinical validation in the future. These insights could contribute to the advancement of diagnostic and therapeutic strategies for treating tumor-related renal pathologies.

Graphical Abstract

Recently, the neurokinin 3 receptor (TACR3) has emerged as a crucial factor of renal dysfunction among cancer patients, suggesting its potential as a target for innovative therapeutic intervention.

Our analysis delves into the evolutionary insights of TACR3 from multiple studies on both Drosophila and mammals.

We elucidate the role of TACR3 in renal pathologies by integrating multi-omics datasets and conducting a thorough phylogenetic and structural analyses.

Renal damage has emerged as a notable complication of cancer patients. The pathogenesis is multifactorial, involving direct mechanical effects on the kidney, such as tissue compression or invasion, systemic metabolic alterations, and indirect impacts via bioactive mediators such as cytokines and hormones [2]. Renal damage is also often precipitated by standard treatments such as chemotherapy and radiotherapy, known for their nephrotoxic potential [3, 4]. These complex interactions pose a significant challenge for oncological management, necessitating treatment strategies that effectively balance tumor suppression and renal preservation.

Identification of novel antidiuretic hormone and receptor

In this groundbreaking study, Xu et al. identified ITPF (see Glossary), a novel antidiuretic hormone in Drosophila, as a key regulator of cancer-associated renal dysfunction [1]. They revealed that tumor-derived ITPF impaired renal function, manifesting in abdominal bloating and fluid accumulation. This dysfunction was mediated by targeting G protein-coupled receptors (GPCRs) in renal stellate cells, specifically in the Malpighian tubules, that led to the activation of cGMP cascade and subsequent inhibition of fluid excretion. Significantly, the study has drawn a parallel illustration with mammals by identifying the neurokinin 3 receptor (TACR3) as the mammalian counterpart of the Drosophila receptor, which highlighted TACR3 as a potential therapeutic target for treating cancer-related renal dysfunction in human patients.

The agonists of TACR3 include natural peptide Neurokinin B (NKB) and Substance P, as well as the synthetic senktide. Recent study using cryogenic electron microscopy has provided a fine conformational insights on how TACR3 is activated by these peptides [5]. Those results revealed non-canonical activation and specific interaction within extracellular regions of TACR3. Upon activation, TACR3 triggers downstream signaling cascades mediated by G proteins and lead to various intracellular responses, that includes Gonadotropin-Releasing Hormone (GnRH) regulation [6], neurotransmitter release [7], and alterations in intracellular calcium concentrations [8]. Consequently, TACR3 is primarily recognized for its vital role in controlling the reproductive axis [9, 10], mood [11, 12], pain response [13], and body temperature [14].

Evolutionary perspective of TACR3

From a systemic evolutionary perspective, the TACR3 gene exhibits a notable evolutionary trajectory, evidenced by its presence across a diverse array of species, including both invertebrates and mammals (Fig.1). Comparative sequence alignment demonstrates substantial homology of TACR3 protein, particularly in pivotal regions for maintaining pharmacological and physiological functions. Particularly the conserved transmembrane domains that are integral for ligand binding and signal transduction, play a crucial role for the proper interaction of TACR3 with neurokinin B, and ensure the intracellular signaling cascades [15]. Furthermore, the sequence similarity extends to the conserved function across various species. In teleost, TACR3-like receptors imply potential participation in reproduction processes analogous to those observed in mammals [16]. The cross-species functional conservation underscores the evolutionary significance of TACR3 in maintaining vital biological functions.

Therapeutic potential of TACR3 antagonists

TACR3 antagonists have shown potential therapeutic benefits across a variety of human disorders. Table1 provides a detailed comparison of current drug development pipelines targeting TACR3. The recent FDA approval of the first TACR3 antagonist for managing menopausal hot flushes represents a precedent and a significant advance of clinical therapy for targeting TACR3 [17]. Beyond the initial application, recent evidence proposes the targeting of TACR3 as a novel anti-angiogenic strategy for oncological interventions. In vitro studies with human umbilical vein endothelial cells (HUVECs) have demonstrated the antagonism of TACR3 in inhibiting cellular migration [18]. This finding is critical for elucidating the endogenous function of TACR3 for tumor angiogenesis and metastasis with a highlight of its clinical potential for treating multiple human diseases. Xu et al. assessed the therapeutic effects of Fezolinetant and Pavinetant on renal dysfunction across various tumor models, including those of gastric, lung, colon, and melanoma, as well as in patient-derived xenograft (PDX) models [1]. This study provides a foundation of TACR3 antagonism for transition into clinical treatment for renal impairments caused by tumors. However, we also noticed that they did not directly compare the efficacy of Fezolinetant and Pavinetant across these tumor types.

Clinical evidence of several TACR3 antagonists have emphasized the requirement for hepatic monitoring due to asymptomatic increases in hepatic transaminases, though bilirubin levels remain unaffected [19]. Additionally, recent studies indicated minor increase of blood glucose level resulted from TACR3 antagonism [20]. Fezolinetant showed common side effects in 2.3–4.3% of participants in a 52-week safety trial. These included abdominal pain, diarrhea, insomnia, back pain, hot flashes, and elevated hepatic transaminases, with incidences notably higher than those observed in the placebo group [20]. Although TACR3 antagonism show promise for cancer treatment, particularly in tumor-associated disorders, these adverse effects emphasize the importance of ongoing hepatic monitoring and further evaluation to ensure the safe application in conjunction with other means of cancer therapies.

Structural insights into TACR3 activation

GPCRs, including TACR3, have emerged as significant targets for cancer treatment due to their essential roles for regulating abnormal cell growth and facilitating tumor invasion and metastasis [21]. However, drug development pipeline targeting TACR3 faces challenges similar to those of other GPCRs, such as low specificity and high toxicity, which limit their clinical application [22]. Identifying the precise binding sites and conformational changes upon binding of antagonist is crucial for the structure-based drug design of TACR3 [23]. Despite the well-accepted importance, the correlation between the TACR3-antagonist complex and its inhibitory mechanism remains poorly understood. To bridge this gap, future research should aim to gain a deep conformational illustration of TACR3 complex with advanced structural techniques, such as Cryo-Electron Microscopy (Cryo-EM). Here, a molecular docking platform was employed to delineate the binding topography of TACR3 with its inhibitors, Fezolinetant and Pavinetant, as depicted in Fig.2A-B. The interactive locus of Fezolinetant is identified within the fourth ECL and fifth transmembrane helices of TACR3, while Pavinetant is postulated to predominantly interact within the first transmembrane helix. These findings suggest that these domains are integral to ligand selectivity and instrumental in modulating antagonistic signal transduction pathway of the receptor. Elucidation of these binding sites has enhanced our understanding of the pharmacological properties of TACR3 and will facilitate the rational design of targeted therapeutic molecules in the future.

Opportunities of drug development for TACR3

Furthermore, an interactive network analysis of TACR3 could reveal new biomarkers for early diagnosis and disease monitoring [24, 25]. A network diagram illustrating the known interactive protein partners of TACR3 is depicted in Fig.2C. Researchers could utilize new technologies, such as single-cell RNAseq to further identify notable regulators of TACR3 membrane expression and downstream signaling pathways, with a potential to facilitate the TACR3 targeted development of combined therapeutic approaches. To overcome the challenges associated with small molecule screening of TACR3, recruitment of a combination of advanced models and technologies in future studies is highly recommended. These novel approaches should commence with the artificial intelligence (AI) and virtual screening platforms for the primary identification of potential molecular candidates. Subsequently, organoid tumor models could be employed for a comprehensive high-throughput in vitro assessment of drug efficacy. This strategy aims not only to discover small molecule inhibitors but also to develop peptide-based nanobodies and proteolysis-targeting chimeras (PROTAC) that could specifically target TACR3. The subsequent phase should utilize murine models to evaluate the in vivo safety and toxicity of the lead compounds. Such comprehensive approach integrates advanced computational and experimental methodologies to enhance the efficiency and efficacy of the drug development progress of TACR3 (Fig.2D).

In a preceding study, genetic analyses demonstrated that TACR3 inhibitors significantly decreased the likelihood of ischemic heart disease in the male population, proposing an innovative preventive measure against this condition [26]. Concurrently, the preliminary evidence showing a concurrent reduction in prostate cancer risk with TACR3 antagonism underscores the necessity for in-depth biological and clinical investigation to confirm these findings in the near future. In our extensive analysis of the roles of TACR3 across various cancer types, we expanded our examination beyond the primary model in the study by Xu et al., which included partial digestion tumors such as ApcMin/+ colon tumors, ipMFC mouse gastric tumors, ipHCT human colon tumors, PDX patient-derived gastric xenografts, and LLC mouse lung tumors. The previous focus restricted the application of these findings to a broad range of cancer types.

Comprehensive analysis of TACR3 expression

To obtain a more comprehensive understanding of TACR3 across various tumors, we integrated an extensive array of multi-omics datasets, including single-cell transcriptomics, spatial transcriptomics and TCGA(Fig.3). Our findings uncovered a dynamic Tacr3 expression pattern in mouse models of ischemia-reperfusion injury (IRI) at various time points, as evidenced by the t-SNE visualization and bubble chart of transcriptomic profiles from the IRI kidney. This expression varied significantly over time, that indicated a potential role of Tacr3 in renal injury and recovery processes. Moreover, spatial expressional distribution emphasized the roles of Tacr3 in specific kidney regions upon injury, that highlighted its localized function in renal repair mechanism. Furthermore, comparison of transcriptional levels of TACR3 in various renal cell types during acute kidney injury to normal conditions revealed a unique expression profile and implicated the participation of TACR3 in the pathology of kidney injury. Crucially, our analysis included human datasets and examined the expression levels of TACR3 across various stages of kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP). The violin plots showed significant differential TACR3 expression between different tumor stages and statistical analysis further confirmed the significance of this variance. Insights from our multi-omics analysis suggest a significant role of TACR3 not only in renal injury but also in the tumorigenesis and progression of renal carcinomas.

Concluding remarks

In summary, Xu et al. identifies a novel pathway involving antidiuretic hormone, and underscores its impact on cancer-induced renal dysfunction. However, the precise molecular mechanism of this pathway remain elusive. The expanding role of TACR3 antagonists, including Fezolinetant, is significant, ranging from managing menopausal symptoms to potential applications in hormone-related disorders and cancer therapy. Despite these promising findings, direct evidence from clinical trials or human studies is scarce, making the clinical relevance and therapeutic application speculative at this stage. Future research should concentrate on the conserved function and specificity of TACR3, Fezolinetant’s binding sites, and the heterogeneity of TACR3 expression across various tumor types and cell models (see Outstanding questions). This should be complemented by clinical trials to validate the safety and efficacy of these findings in human patients, thereby assessing their feasibility as potential therapeutic options. Finally, the future development of TACR3 antagonists could be advanced through innovative drug design and screening strategies.

Outstanding questions

What is the precise molecular mechanism by which tumor-derived ITPF impairs renal function in cancer patients?

How does TACR3 interact with other receptors and affect downstream signaling pathways in the context of cancer-associated renal dysfunction?

Can TACR3 antagonists be safely and effectively integrated into current oncological treatment regimens to mitigate renal damage?

What kind of role does TACR3 play in the broader context of tumor angiogenesis and metastasis, and how can this be targeted therapeutically?

How does the expression of TACR3 vary across different stages and renal cancer types, and what implications does this have for medical intervention?

ITPF (Inhibitory Tumor Peptide Factor):

A novel antidiuretic hormone identified in Drosophila, shown to impair renal function in cancer-associated renal dysfunction.

G protein-coupled receptors (GPCRs):

A large family of seven-transmembrane cell surface receptors that respond to various external signals and activate intracellular signaling pathways through the interaction with G proteins.

TACR3 (Tachykinin Receptor 3):

Also known as neurokinin 3 receptor (NK3R), a receptor involved in various physiological processes, including reproductive hormone release, mood regulation, and pain response.

Cryo-electron microscopy (Cryo-EM):

A microscopy technique that allows the imaging of samples at cryogenic temperatures, providing detailed structural conformation of biological molecules.

GnRH (Gonadotropin-Releasing Hormone):

A hormone responsible for the release of follicle-stimulating hormone and luteinizing hormone from the anterior pituitary gland, with a crucial role in regulating reproduction.

HUVECs (Human Umbilical Vein Endothelial Cells):

Endothelial cells derived from the vein of the umbilical cord, commonly used in studies of vascular biology and angiogenesis.

KIRC (Kidney Renal Clear Cell Carcinoma):

A type of kidney cancer characterized by the presence of clear cells in the tumor, often associated with mutations in the VHL gene.

KIRP (Kidney Renal Papillary Cell Carcinoma):

A type of kidney cancer that forms in the lining of the kidney tubules and is characterized by a papillary growth pattern.

PROTAC (Proteolysis-Targeting Chimera):

A type of molecule designed to target specific proteins for degradation by the proteasome, used in targeted protein degradation therapies.

Single-cell sequencing:

A technique that allows the analysis of the genomic, transcriptomic, or epigenomic content of individual cells, providing insights into cellular heterogeneity and function.

Authors and Affiliations

1. Department of Endocrinology, Songjiang Research Institute, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China

   Meng Wang&Yong Han

2. Department of Orthopedics and Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China

   Chao Zhang

Contributions

Investigation and concept establishment: CZ and MW; Writing‒original draft preparation: MW; Writing‒review and editing: YH and CZ; Supervision: CZ; Funding acquisition: CZ.

Corresponding author

Correspondence to Chao Zhang.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no conflict of interest.

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