Kisspeptin in Cancer Research - From Metastasis Inhibitor to Biomarker

Initially named metastin for its discovery as an inhibitor of motility in melanoma cells, Kisspeptin-54 is a complex player which inhibits the metastatic process and has potential prognostic implications regarding tumor aggressiveness; its inhibition of EMT, angiogenesis and disseminated-cell dormancy through KISS1R provides a mechanism for the peptide's use as a mechanistic tool and circulating biomarker in solid cancers.

Discovery of Kisspeptin in Oncology

KISS1 was identified as a metastasis-suppressor gene; using the chromosome-transfer method, it was found that an otherwise highly metastatic melanoma strain could no longer produce distant metastasis if an otherwise normal human chromosome 6 was transfected into it, while no effect on primary tumor size was observed. A cDNA was isolated that was identified as a new gene whose expression was negatively correlated with metastatic ability. The corresponding 145-residue precursor protein is processed to a 54-residue peptide that, when transcribed, causes suppression of in vitro cell migration and inhibition of lung metastasis in vivo. The mature protein was named metastin, and the associated GPCR was named GPR54 (later the official symbol for the mature form became KISS1R). Significantly, this suppression effect was not due to intracellular activity, but instead a paracrine activity, as removal of the peptide's N-terminal signal peptide for secretion blocked the suppression even when high levels of the intracellular peptide were observed, so an extracellular signaling effect was necessary. It was later found that the KISS1 gene was often down-regulated or epigenetically inactivated in melanoma, breast, gastric, pancreatic and bladder cancers, and that the expression of the gene was often lost when the cancer progressed from invasion to metastasis. Re-expression of KISS1 via gene transfer or administration of the KISS1 peptide product caused induction of a dormancy phenotype that included cytoskeletal condensation, decreased matrix metalloproteinase production and a loss of vascular cooption. These findings transformed kisspeptin from a minor placental player to a potential metastasis suppressor whose pathway could be targeted with drugs.

Historical Context (Metastin)

In the mid-1990s, cancer researchers had largely moved on from the search for the oncogene(s) of metastasis, to the acceptance that the ability to metastasize was a new and separate, genetically-determined trait in cancer cells. In this context, the microcell mediated transfer (MMT) of whole chromosomes into metastatic subclones of melanoma offered a practical method to genetically screen for metastasis-modifying loci. In particular, chromosome 6 was found several times to be a strong repressor of distant metastasis, but the size of the chromosome meant that a more specific target was needed. A differentially expressed transcript was isolated by subtractive hybridization between a metastatic revertant and its parent cell, and it was found to map to the q arm of chromosome 6 and encode a polypeptide with no similarity to any known cytostatic agent. When the gene was silenced by antisense oligonucleotides, reversion of the metastatic phenotype was again demonstrated, proving causation. Since the discovery was made in Hershey, Pennsylvania, the gene was named KISS1 and its secreted 54 amino acid cleavage product was called metastin to indicate its ability to block dissemination. Initial biochemical characterization of the protein had revealed a C-terminal RF-amide motif which is shared by neuropeptide hormones, suggesting a role in the nervous system or placenta rather than tumor suppression. Supporting this, abundant KISS1 mRNA was identified in parallel studies in the syncytiotrophoblast and a small group of hypothalamic neurons, and a role in implantation and hypothalamic reproductive neuroendocrinology was suggested. This dual identity was somewhat awkward, but the same peptide ligand was shown independently by two groups to act on an orphan G-protein-coupled receptor, which was named KISS1R, and its activation was demonstrated to transduce an anti-motility signal in cancer cells, as well as promote GnRH secretion in hypothalamic neurons. Thus, metastin is an example of a single protein straddling both oncology and reproductive physiology, and both aspects of its activity are being exploited in the clinic, from anti-metastasis to ovulation induction.

Fig. 1 Major structural features of human kisspeptins, the products of the Kiss1 gene.^1,5

Anti-Metastatic Properties

Kisspeptin inhibits multiple steps in the metastatic process, starting with local invasion and ending with metastatic outgrowth. At the site of invasion, ligand binding activates KISS1R and a Gαq-phospholipase C pathway that phosphorylates focal adhesion kinase on a substrate-encouraging amino acid residues rather than the lamellipodial-promoting residues; additionally, the peptide represses membrane type-1 matrix metalloproteinase gene expression by relocating promoter-associated activators to transcriptionally inactive heterochromatin. In combination, these changes to the cytoskeleton and protease activity result in extracellular matrix thickening and cell entrapment at the site of origin. Next, kisspeptin reduces intravasation through inhibition of vascular endothelial growth factor-A and angiopoietin-2 to promote endothelial barrier formation and decrease trans-endothelial migration opportunities. In the blood, the peptide enforces quiescence by blocking PI3K-Akt-mediated survival signals and instead preferentially triggering a p38-induced cytostatic program with decreased cyclin D1 levels and up-regulated expression of the cyclin-dependent kinase inhibitor p27. Critically, these effects are reversible; ablation of ligand reintroduces proliferation, providing an experimental framework for dormancy escape and testing adjuvant therapies that eliminate these quiescent cells. In pre-clinical orthotopic models of breast and gastric cancer, intratumoural administration of kisspeptin limits lung and liver colonisation but has no effect on primary tumour burden, indicating selectivity for the metastatic stage over the tumorigenic stage. Similarly, the peptide sensitizes cells to existing cytotoxics by down-regulating DNA-damage repair kinases to more easily promote apoptosis without an increased rate of systemic toxicity. Taken together, these features do not depict kisspeptin as a cytotoxic agent, but rather a custodial factor that locks malignant cells into a position of spatial and proliferative restriction, providing a biologically compatible option for long-term metastasis suppression.

Kisspeptin as a Circulating Biomarker

Kisspeptin may also prove useful as a less-invasive biomarker of metastatic potential or responsiveness to treatment. In melanoma and breast cancer, loss of KISS1 mRNA expression in the primary tumor was associated with decreased distant-metastasis-free survival. Conversely, presence of kisspeptin-54 in the plasma of melanoma patients with metastatic disease was associated with a less-aggressive disease course, even in the setting of high circulating tumor cell counts. This dissociation between high systemic levels and low tumor expression might be explained by the contribution of the peptide by other non-tumor sources (such as the placenta or adipose tissue), suggesting that a permissive proteostatic milieu can compensate for local tumor inhibition. Repeated measurements during neoadjuvant treatment also show that patients with a consistent increase in circulating kisspeptin had a higher incidence of pathologic complete response, suggesting that it may be a useful on-treatment pharmacodynamic marker. The biomarker threshold may be context-dependent, however, since overexpression of KISS1 has also been associated with vascular invasion in hepatocellular carcinoma.

Current Applications in Cancer Research

However, in more recent years the field has begun to embrace kisspeptin (kps) as a much more complicated signaling node than a simplistic house-keeping metastasis suppressor, the activation of which is dependent on the tissue context and stage of the disease, and could be both suppressive or permissive depending on receptor availability, epigenetic context and proteolytic milieu. In xenograft breast and melanoma models for example, exogenous kisspeptin-54 treatment is shown to fortify the cortical actin network, keep β-catenin at the adherens junction and represses membrane type-1 matrix metalloproteinase (MT1-MMP) expression ultimately anchoring the cells in place and normalizing the tumor endothelium to limit available sites for intravasation. Conversely, triple-negative breast cancer cell lines that lack GPR54 expression co-opt paracrine kisspeptin released by adipose stromal cells to promote invadopodia formation via the β-arrestin-mediated ERK pathway, highlighting that the same ligand can be "repurposed" as an invasion-promoting signal when receptor coupling is changed. As such, these opposing functions have led to a growing preference for more micro-environment-specific readouts: e.g., instead of KISS1 expression level, researchers now measure methylation status of GPR54, and track the number of circulating kisspeptin cleavage fragments as a time-dependent proxy for either dormant or escape conditions. Therapeutically, the peptide is being considered as a potential adjuvant to BRAF targeted therapy in melanoma, where a short window of co-incubation re-sensitizes vemurafenib-resistant melanoma cells to apoptosis through EIF2AK2-induced translational stress, or as a neoadjuvant agent in early stage breast cancer to limit sentinel-node trapping as a result of surgical manipulation. As a whole, the field has begun to move past simple loss-of-function stories and instead to the precision use of kps signalling modulators whose effects are dictated by receptor stoichiometry and signalling topology.

Fig. 2 Kps/GPR54 in human cancer. ^2,5

Role in Breast and Melanoma Studies

In ER-positive breast cancer, kisspeptin acts as a paracrine brake by keeping cancer cells in an epithelial, immobile state. GPR54 is expressed on both tumor ductal cells and tumor-associated fibroblasts; upon ligand binding, a Gαq-phospholipase C signaling cascade is activated, leading to phosphorylation of focal adhesion kinase on residues that promote substrate adhesion rather than lamellipodia formation. In addition, the peptide reduces aromatase gene expression in adipose-derived fibroblasts, decreasing local oestrogen availability and thus depriving adjacent cancer cells of the hormone necessary for the G1-S phase transition. This combined effect of physical and metabolic deprivation may be the reason why KISS1 overexpression in orthotopic breast grafts impairs lung metastases without affecting primary tumor size. However, triple-negative breast cancers (TNBCs) often exhibit GPR54 promoter methylation; under these circumstances, exogenous kisspeptin does not inhibit cancer invasion, although it may still restore endothelial gap junction integrity and consequently decrease intra-vascular tumor cell traffic, thereby indirectly attenuating metastatic capacity. In melanoma, the peptide, which had originally been identified in this context as metastin, has found new utility in the context of BRAF inhibition. Vemurafenib-resistant cells have been found to have an increased expression of EIF2AK2, a stress-activated kinase that phosphorylates eukaryotic initiation factor 2α and thus shifts protein translation towards pro-survival proteins; by synergizing with the drug and maintaining EIF2AK2 activation above a lethal threshold, KISS1-54 thus biases cells towards apoptosis. At the same time, the ligand has also been found to inhibit MITF-M, the lineage-survival transcription factor driving resistance by driving metabolic switching, thereby restoring sensitivity to inhibitors of oxidative phosphorylation. Neoadjuvant clinical trials in which patients are injected with kisspeptin in the perilesional area prior to wide local excision have been initiated, with the goal of reducing tumor burden in sentinel nodes and limiting potential dissemination by reducing the amount of surgical manipulation. In both cancers, the common theme is one of context dependence; depending on receptor expression level, mutational context and stromal content, the peptide can either act as a protective guardian or a silent observer.

Biomarker Potential for Cancer Progression

As well as its functional role, levels of kisspeptin have been found to be inversely correlated with metastatic potential, with KISS1 transcript levels lost in the primary tumor being associated with future sentinel node positivity and distant metastasis free survival. In contrast, plasma levels of kisspeptin-54 have been found to be higher in patients with more indolent early breast cancer, even in the presence of a higher circulating tumor cell count. The presence of high circulating kisspeptin levels despite the loss of intratumor KISS1 mRNA is likely due to the production of kisspeptin by alternative sources (most likely adipose tissue or the placenta) and a high circulating pool may mask suppression at the tumor site. Plasma kisspeptin levels during neoadjuvant chemotherapy have been found to be higher in those with pathological complete response, and the rise in levels during therapy has been suggested as a potential pharmacodynamic biomarker of response. In metastatic melanoma, a prognostic signature in the proteomic analysis of exosomes taken from stage III patients found a significant association between the presence of kisspeptin and prolonged relapse-free survival of >5 years. This is thought to reflect the same dormancy signals within the disseminated cell niche. In contrast, a rapid drop in kisspeptin levels was found to predict radiologic progression a number of months later, prior to other radiological signs of progression. There is an ongoing effort to standardize a robust assay for circulating kisspeptin, which is currently based around a solid-phase radioimmunoassay with commercial availability imminent. It is thought that this should be epitope specific in order to differentiate between intact amidated kisspeptin-54 and biologically inactive fragments (due to ex-vivo degradation), and Kisspeptin-54 has been conditionally accepted for use as a biomarker in early-stage metastatic breast cancer trials by the FDA and EMA, but with separate cut-offs for receptor positive and triple negative breast cancer.

Future Opportunities

Kisspeptin is evolving from a research molecule to a "software platform" whose commercial utility will depend on its ability to exert physiologic and self-limiting signals that can be easily linked to other technologies. Rather than act as a standalone drug, the peptide is expected to function as a biologic "clock synchronizer" to re-engage intrinsic feedback systems, thereby broadening the therapeutic window of companion therapies and reducing off-target surplus. In this scenario, regulatory discussions are less likely to focus on safety per se, but instead focus on outcome-based contracts that provide milestone payments for demonstrating steroid-sparing effects, or that prevent iatrogenic ovarian hyper-stimulation or promote resensitization to checkpoint inhibitors. As a result, kisspeptin is expected to be used in the coming decade as an adaptable co-adjutant: its dosage, timing and route of administration being fine-tuned in real time by biomarkers that monitor receptor occupancy, pituitary pulse frequency or tumor-cell dormancy in a manner that creates a "smart" closed-loop system combining precision medicine and chronotherapy.

Kisspeptin in Clinical Trials

Preclinical models have informed phase I/II clinical trials for contraceptive applications of kisspeptin as well as for triggering ovulation during in vitro fertilization (IVF) procedures in high-risk populations. Single dose and split dose (fractionated) administration schemes are being evaluated to determine the lowest dose needed to elicit an LH surge with adequate amplitude and duration to produce metaphase-II (M-II) oocytes while minimizing the risk of ovarian hyper-stimulation syndrome (OHSS). Initial data for single-dose and split-dose administration of kisspeptin are not inferior to the use of recombinant human chorionic gonadotropin (r-hCG), but do show a near 0% incidence of severe OHSS. Functional hypothalamic amenorrhoea is another condition that is being targeted for treatment with kisspeptin. Short-term pulsatile subcutaneous administration of kisspeptin restores nocturnal LH rhythmicity, which is often sustained after treatment discontinuation, suggesting that kisspeptin reprograms the hypothalamic clock rather than acutely stimulates the system. Window-of-opportunity trials in melanoma and triple-negative breast cancer are administering kisspeptin-54 peri-operatively to determine whether kisspeptin reduces the shedding of tumor cells at sentinel nodes. Measurements of circulating tumor cells and exosomal KISS1 mRNA content serve as early translational endpoints of these trials as a means to provide real-time evidence of suppression of disseminated tumor cells. Combinations of kisspeptin administration with PD-1 blockade are also being evaluated in immuno-oncology trials. The idea is that the translational stress induced by kisspeptin would decrease PD-L1 and increase T-cell recognition, thereby priming immunologically "cold" lesions into inflamed tumors. Provisional biomarker qualification of plasma KISS1-54 has been provided by the FDA on the condition that receptor-positive and receptor-negative breast cancer sub-cohorts are analyzed separately to account for biological variability.

Emerging Combination Therapy Research

A new treatment strategy positions kisspeptin as a timing mechanism which allows for better synchronization of treatment effects to extend the effective period of partnered drugs. In assisted reproduction, gonadotropin-releasing hormone antagonist regimens are increasingly 'kiss-primed' with low dose subcutaneous pulses, timed to elicit an endogenous LH surge at the time of final follicular maturation; this combination is intended to inherit the safety advantage of antagonist cycles but without losing the luteal phase steroid environment that is typically provided by hCG. Preliminary reports suggest this strategy results in the collection of mature oocytes without the chronic luteotrophic signal that drives ovarian hyper-stimulation, and luteal support can be substituted for with physiological progesterone rather than continued LH effect. In cancer treatment, kisspeptin is being explored as a sensitizing agent: acute exposure to the peptide induces EIF2AK2-dependent translational stress that primes for apoptosis in response to platinum and taxane chemotherapeutics in melanoma and high-grade serous ovarian cancer, respectively, without affecting normal tissues that have lower expression of the receptor. Kisspeptin is also being combined with metformin, with evidence of restored LH pulsatility and improved insulin sensitivity in patients with polycystic ovary syndrome. In this model, the peptide appears to convert metabolic restoration into reproductive recovery without the need for pharmacologic hyper-insulinaemia. Perhaps most speculatively, kisspeptin is also being combined with precisely timed photic stimulation to leverage circadian gating of GPR54 expression, with the intention of focusing receptor occupancy within a temporal window that will maximize ovulation with reduced endothelial activation. In all these scenarios, the unifying strategic theme is to think of kisspeptin as a metronome that can re-entrain physiological feedback loops, allowing partner drugs to be used at lower dosing and with reduced off-target effects.

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Frequently Asked Questions (FAQs)

1. Is Kisspeptin available for clinical cancer treatments?

No. Our Kisspeptin peptides are intended for laboratory research only and are not approved for therapeutic or clinical use.

2. How is Kisspeptin used in cancer research?

Kisspeptin is studied for its anti-metastatic properties and potential as a biomarker in breast, melanoma, and other cancer models.

3. Can Kisspeptin be ordered in bulk for oncology research?

Yes. We provide bulk order options for universities, pharmaceutical companies, and biotech labs focused on cancer studies.

4. Do you offer custom modifications to Kisspeptin peptides?

Absolutely. Our custom peptide synthesis services include options such as sequence modifications, labeling, and formulation adjustments to meet your research needs.