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Yes-Associated Protein May Hold Prognostic Value in Cutaneous Melanoma

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A retrospective study analyzing tissue assays from patients with cutaneous melanoma demonstrated the promise of yes-associated protein (YAP) as a predictive biomarker for melanoma prognosis.

Yes-associated protein (YAP) may be a valuable biomarker in the prognosis of cutaneous melanoma, and interventions that target YAP inhibition could provide benefits for affected patients, according to a recent study published in Laboratory Investigation.

Yes-associated protein (YAP) may be a valuable biomarker in the prognosis of cutaneous melanoma and interventions that target YAP inhibition could provide benefits for affected patients, according to a recent study published in Laboratory Investigation.   Cutaneous melanoma is not as common as other forms of skin cancer; however, it constitutes one of the more fatal skin cancer diagnoses. Patient outcomes in this disease can be influenced by a myriad of factors such as the thickness of the tumor, lymphatic invasion, microscopic satellites, regression, and more. Due to the plethora and variety of features affecting patient prognosis, finding ways to predict disease behavior that can inform therapeutic approaches constitute an urgent clinical need in cutaneous melanoma.   “With an improved understanding of the biology and pathogenesis of melanoma in recent years, it has become evident that there is no single evolutionary pattern describing how neoplastic lesions progress into fully evolved, aggressive melanomas. Each melanoma subtype may have various precursor lesions, different gene alterations, and different stages of transformation,” Ryu et al wrote as they stressed the importance of identifying melanoma-specific biomarkers.   Therefore, the researchers conducted a study to investigate the capacity for YAP—which has been indicated in various cancerous malignancies—to predict the behavior of tumors, evaluate the role it plays in cutaneous melanoma, as well as assess the impact of therapeutic interventions aimed to inhibit YAP in melanoma cells.   A total of 140 patients with cutaneous melanoma from the Severance Hospital, Yonsei University College of Medicine were retrospectively recruited between 2005 and 2013. Immunohistochemical (IHC) staining was performed for YAP on the cancerous tissue of each participant and the cohort was subsequently divided into two groups: melanoma with cytoplasmic YAP expression (only detected in cytoplasm, n = 77 [55%]) and melanoma with nuclear YAP expression (detected in nucleus, n = 63 [45%]).   The researchers observed that nuclear YAP expression was more prevalent in men than women but noted that this was not significant. Patients with nuclear YAP expression demonstrated a significantly higher likelihood of experiencing metastasis to their regional lymph nodes (LN) and distant organs compared with those with cytoplasmic YAP expression (P = .0004 and P < .001). In their additional metastatic analysis, the authors also found that LN metastasis was linked to deeper tumor invasion (HR, 1.279; 95% CI, 1.076-1.520; P = .05), as was metastasis to distant organs (HR, 1.197; 95% CI, 1.016-1.409; P = .031). Furthermore, the recurrence of tumors was more prevalent in individuals with nuclear YAP expression compared with those with cytoplasmic YAP expression (37/63, 58.7% vs 19/77, 24.7%; P < .001). Metastasis of tumors to distant organs was also more frequent in cases of nuclear YAP expression compared to cytoplasmic (HR, 3.206; 95% CI, 1.032-9.961; P = .044).   Disease-free survival (DFS) and overall survival (OS) outcomes were reportedly worse in individuals with nuclear compared to cytoplasmic YAP expression (P < .001). Nuclear YAP expression was also found to be an independent risk factor for poorer DFS (HR, 2.493; 95% CI, 1.254-4.953; P = .009).   The authors noted that just over 60% (n = 85) cases of cutaneous melanoma were acral lentiginous melanoma, just under 19% (n = 30) were superficial spreading melanoma, and just over 15% (n = 25) were nodular melanoma. Nuclear location of YAP was significantly more prevalent in acral lentiginous and nodular subtypes compared to cases of superficial spreading melanoma (P = .007).   Mitotic activity was then calculated to compare the proliferative melanoma activity in the two forms of YAP expression and found a higher amount of activity on average in cases of nuclear YAP expression compared with cytoplasmic (3.293 vs 1.809; P = .016). In terms of melanoma cell invasiveness, nuclear YAP expression was also linked to longer migration distance in mutated cells, demonstrating how the cellular location of YAP was a regulator of melanoma cell invasion.   Verteporfin administration was additionally tested on melanoma tissue because it is a known YAP inhibitor. The inhibition of cellular proliferation with this treatment was significantly more impactful than solvent in B16F1 and B16F10 cells (P = .003 and P < .001), suggesting the efficacy for verteporfin to target melanoma cells that express YAP.   The researchers’ findings demonstrate the how the cellular location of YAP can be a predictive biomarker for tumor behavior in cutaneous melanoma. With this information, they conclude by stating how their preclinical data adds to the pathophysiological understanding of melanoma progression and guides treatment approaches by demonstrating the benefits of YAP inhibitor therapies for affected patients.   Reference  Ryu HJ, Kim C, Jang H, et al. Nuclear localization of YAP is associated with tumor progression in cutaneous melanoma. Lab Invest. Published online March 13, 2024. doi:10.1016/j.labinv.2024.102048

Biomarker DNA Graphic | image credit: iQoncept - stock.adobe.com

Cutaneous melanoma is not as common as other forms of skin cancer; however, it constitutes one of the more fatal skin cancer diagnoses. Patient outcomes in this disease can be influenced by a myriad of factors such as the thickness of the tumor, lymphatic invasion, microscopic satellites, regression, and more. Due to the plethora and variety of features affecting patient prognosis, finding ways to predict disease behavior that can inform therapeutic approaches constitute an urgent clinical need in cutaneous melanoma.

“With an improved understanding of the biology and pathogenesis of melanoma in recent years, it has become evident that there is no single evolutionary pattern describing how neoplastic lesions progress into fully evolved, aggressive melanomas. Each melanoma subtype may have various precursor lesions, different gene alterations, and different stages of transformation,” authors Ryu et al wrote as they stressed the importance of identifying melanoma-specific biomarkers.

Therefore, the researchers conducted a study to investigate the capacity for YAP—which has been indicated in various cancerous malignancies—to predict the behavior of tumors, evaluate the role it plays in cutaneous melanoma, as well as assess the impact of therapeutic interventions aimed to inhibit YAP in melanoma cells.

A total of 140 patients with cutaneous melanoma from the Severance Hospital, Yonsei University College of Medicine between 2005 and 2013 were retrospectively recruited. Immunohistochemical (IHC) staining was performed for YAP on the cancerous tissue of each participant and the cohort was subsequently divided into two groups: melanoma with cytoplasmic YAP expression (only detected in cytoplasm, n = 77 [55%]) and melanoma with nuclear YAP expression (detected in nucleus, n = 63 [45%]).

The researchers observed that nuclear YAP expression was more prevalent in men than women but noted that this was not significant. Patients with nuclear YAP expression demonstrated a significantly higher likelihood of experiencing metastasis to their regional lymph nodes (LN) and distant organs compared with those with cytoplasmic YAP expression (P = .0004 and P < .001).

In their additional metastatic analysis, the authors also found that LN metastasis was linked to deeper tumor invasion (HR, 1.279; 95% CI, 1.076-1.520; P = .05), as was metastasis to distant organs (HR, 1.197; 95% CI, 1.016-1.409; P = .031). Furthermore, the recurrence of tumors was more prevalent in individuals with nuclear YAP expression compared with those with cytoplasmic YAP expression (37/63, 58.7% vs 19/77, 24.7%; P < .001). Metastasis of tumors to distant organs was also more frequent in cases of nuclear YAP expression compared to cytoplasmic (HR, 3.206; 95% CI, 1.032-9.961; P = .044).

Disease-free survival (DFS) and overall survival (OS) outcomes were reportedly worse in individuals with nuclear compared to cytoplasmic YAP expression (P < .001). Nuclear YAP expression was also found to be an independent risk factor for poorer DFS (HR, 2.493; 95% CI, 1.254-4.953; P = .009).

The authors noted that just over 60% (n = 85) cases of cutaneous melanoma were acral lentiginous melanoma, just under 19% (n = 30) were superficial spreading melanoma, and just over 15% (n = 25) were nodular melanoma. Nuclear location of YAP was significantly more prevalent in acral lentiginous and nodular subtypes compared to cases of superficial spreading melanoma (P = .007).

Mitotic activity was then calculated to compare the proliferative melanoma activity in the two forms of YAP expression and found a higher amount of activity on average in cases of nuclear YAP expression compared with cytoplasmic (3.293 vs 1.809; P = .016). In terms of melanoma cell invasiveness, nuclear YAP expression was also linked to longer migration distance in mutated cells, demonstrating how the cellular location of YAP was a regulator of melanoma cell invasion.

Verteporfin administration was additionally tested on melanoma tissue because it is a known YAP inhibitor. The inhibition of cellular proliferation with this treatment was significantly more impactful than solvent in B16F1 and B16F10 cells (P = .003 and P < .001), suggesting the efficacy for verteporfin to target melanoma cells that express YAP.

The researchers’ findings demonstrate how the cellular location of YAP can be a predictive biomarker for tumor behavior in cutaneous melanoma. With this information, they concluded by stating how their preclinical data adds to the pathophysiological understanding of melanoma progression and guides treatment approaches by demonstrating the benefits of YAP inhibitor therapies for affected patients.

Reference

Ryu HJ, Kim C, Jang H, et al. Nuclear localization of YAP is associated with tumor progression in cutaneous melanoma. Lab Invest. Published online March 13, 2024. doi:10.1016/j.labinv.2024.102048

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