Road to Metastasis: The TWEAK Pathway as a Discriminant between Metastasizing and Non-Metastasizing Thick Melanomas

Abstract

Cutaneous melanoma (CM) is the most aggressive form of skin cancer, and its worldwide incidence is rapidly increasing. Early stages can be successfully treated by surgery, but once metastasis has occurred, the prognosis is poor. However, some 5–10% of thick (≥2 mm) melanomas do not follow this scenario and run an unpredictable course. Little is known about the factors that contribute to metastasis in some patient with thick melanomas and the lack thereof in thick melanoma patients who never develop metastatic disease. We were therefore interested to study differential gene expression and pathway analysis and compare non-metastatic and metastatic thick melanomas. We found that the TNF-like weak inducer of apoptosis (TWEAK) pathway was upregulated in thick non-metastasizing melanomas. MAP3K14 (NIK1), BIRC2 (cIAP1), RIPK1, CASP7, CASP8, and TNF play an important role in inhibiting proliferation and invasion of tumor cells via the activation of the non-canonical NF-κB signaling pathway. In particular, this pathway sensitizes melanoma cells to TNF-alpha and activates the apoptosis module of the TWEAK pathway in thick non-metastasizing melanomas. Hence, our study suggests a potential role of the TWEAK pathway in inhibiting thick melanoma from metastasis. Exploitation of these genes and the pathway they control may open future therapeutic avenues.

The Effect of Body Mass Index on Melanoma Biology, Immunotherapy Efficacy, and Clinical Outcomes: A Narrative Review

“…This notion is supported by the documented disparities in melanoma incidence rates across genders, underscoring the possible impact of hormonal dynamics [ 1 , 51 , 52 ]. Further research is necessary to study these mechanisms and assess the potential of targeting sex hormone pathways in the management of melanoma [ 15 , 29 ].…”

“…Arrow: common in obese individuals and have been linked to tumor growth and metastasis [12][13][14]. Additionally, our prior observations emphasize the role of augmented estrogen receptor (ER) pathways in non-metastasizing thick CM among the elderly, attributed to the possible contribution of adipose tissue to estrogen production post-menopause, further influencing immune responses [15,16]. BMI, a ratio of weight to height, stands as the predominant metric for assessing obesity, endorsed by the World Health Organization with defined thresholds: obesity refers to BMI ≥ 30 kg/m 2 , overweight to BMI 25-29.9 kg/m 2 , normal weight to BMI 18.5-24.9 kg/m 2 , and underweight to BMI < 18.5 kg/m 2 .…”

“…Elevated levels of inflammatory common in obese individuals and have been 14]. Additionally, our prior observations em ceptor (ER) pathways in non-metastasizing t possible contribution of adipose tissue to es influencing immune responses [15,16]. , and underweight to BMI < 18.5 kg/m level estimate of body composition, it is not tors, such as muscle mass, bone density, and surrogate marker for adiposity, associated w cluding cardiovascular diseases and gastroi cers, remains undisputed [7,12,17,18].…”

“…Elevated levels of inflammatory cytokines such as IL-6, TNF-α, and CRP are common in obese individuals and have been linked to tumor growth and metastasis [ 12 , 13 , 14 ]. Additionally, our prior observations emphasize the role of augmented estrogen receptor (ER) pathways in non-metastasizing thick CM among the elderly, attributed to the possible contribution of adipose tissue to estrogen production post-menopause, further influencing immune responses [ 15 , 16 ].…”

A Narrative Review of the Role of Estrogen (Receptors) in Melanoma

“…This upregulation was specifically identified in key members of the cytochrome P450 family, including CYP1A1, CYP1A2, and CYP1B1, along with an increased expression of estrogen receptor alpha (ERα). Moreover, the estrogen receptor pathway emerged as a significant finding and occupied a leading position in the list of identified pathways [ 4 ]. In line with this, other researchers discovered a better therapy response and a higher survival rate in women, who have higher estrogen levels than men.…”