The adenylate cyclase (ADCY) superfamily is a group of glycoproteins regulating intracellular signaling. ADCYs act as key regulators in the cyclic adenosine monophosphate (cAMP) signaling pathway and are related to cell sensitivity to chemotherapy and ionizing radiation. Many members of the superfamily are detectable in most chemoresistance cases despite the complexity and unknownness of the specific mechanism underlying the role of ADCYs in the proliferation and invasion of cancer cells. The overactivation of ADCY, as well as its upstream and downstream regulators, is implicated as a major potential target of novel anticancer therapies and markers of exceptional responders to chemotherapy. The present review focuses on the oncogenic functions of the ADCY family and emphasizes the possibility of the mediating roles of deleterious nonsynonymous single nucleotide polymorphisms (nsSNPs) in ADCY as a prognostic therapeutic target in modulating resistance to chemotherapy and immunotherapy. It assesses the mediating roles of ADCY and its counterparts as stress regulators in reprogramming cancer cell metabolism and the tumor microenvironment. Additionally, the well-evaluated inhibitors of ADCY-related signaling, which are under clinical investigation, are highlighted. A better understanding of ADCY-induced signaling and deleterious nsSNPs (p.E1003K and p.R1116C) in ADCY6 provides new opportunities for developing novel therapeutic strategies in personalized oncology and new approaches to enhance chemoimmunotherapy efficacy in treating various cancers.

https://www.frontiersin.org/articles/10.3389/fonc.2022.829212/pdf

Targeting Adenylate Cyclase Family: New Concept of Targeted Cancer Therapy

Acral melanoma (AM) is a malignant cutaneous melanocytic tumour specifically located on the palms, soles, and nail apparatus, which are areas of glabrous (hairless) skin. Acral lentiginous melanoma, a subtype of AM, represents a histopathological subtype diagnosis of cutaneous melanoma with unique morphological and structural features. Despite clear definitions, the misuse of these terms and the inconsistency in reporting the histopathological features of AM cases have become a major obstacle to the study of the disease. In this review, we discuss the epidemiology, histopathological features, prognosis, and genetic profile of AM, highlighting the differences observed when histopathological subtypes are considered. The increasing global effort to characterise AM cases from ethnically diverse populations would benefit greatly from a more consistent classification of the disease.

More than just acral melanoma: the controversies of defining the disease.

Elevated cyclic AMP levels promote BRAFCA/Pten-/- mouse melanoma growth but pCREB is negatively correlated with human melanoma progression.

Recurrence rates of both lentigo maligna (LM) and lentigo maligna melanoma (LMM) following conventional surgery are usually relatively high. We aimed to assess the frequencies of melanocytes in tumour-free margins around LM/LMM using soluble adenylyl cyclase (sAC) immunohistochemistry, and to compare these with those of matched healthy contralateral skin. Using the primary mouse-anti-human sAC antibody R21, we evaluated pan-nuclear melanocytic R21 immunostaining, and found that it was significantly (P < 0.001) higher in peritumoural melanocytes (median 20%; range 0-100%) than in contralateral healthy skin (mean 0%; range 0-20%). Accordingly, there was no correlation between peritumoural and contralateral R21 immunoreactivity (r = 0.12; P = 0.18). In conclusion, melanocytic R21 immunoreactivity in melanocytes is higher in tumour-free margins around LM/LMM than in site-matched contralateral skin. This observation may indicate that the biology of 'healthy'-appearing melanocytes around LM/LMM might be different from that of truly benign melanocytes.

Melanocytic soluble adenylyl cyclase protein expression around lentigo maligna and in contralateral control skin.

cAMP signaling pathways are critical for both oncogenesis and tumor suppression. cAMP signaling is localized to multiple spatially distinct microdomains, but the role of cAMP microdomains in cancer cell biology is poorly understood. We developed a tunable genetic system that allows us to activate cAMP signaling in specific microdomains. We uncovered a previously unappreciated nuclear cAMP microdomain that functionally activates a tumor suppressive pathway in a broad range of cancers by inhibiting YAP, a key effector protein of the Hippo pathway, inside the nucleus. We show that nuclear cAMP induces a LATS-dependent pathway leading to phosphorylation of nuclear YAP solely at serine 397, export of YAP from the nucleus, without YAP protein degradation. Thus, nuclear cAMP inhibition of nuclear YAP is distinct from other known mechanisms of Hippo regulation. Pharmacologic targeting of specific cAMP microdomains remains an untapped therapeutic approach for cancer, and since Hippo pathway deregulation can lead to oncogenesis and chemotherapeutic resistance, drugs directed at the nuclear cAMP microdomain may provide new avenues for the treatment of cancer.

https://biorxiv.org/content/10.1101/2021.11.15.468656v1.full.pdf

A nuclear cAMP microdomain suppresses tumor growth by Hippo pathway inactivation

Soluble adenylyl cyclase (sAC) regulates melanocytic cells, and is a diagnostic marker for pigmented skin lesions. Because only a few studies on sAC expression in acral melanomas have been performed, we investigated the histopathological significance of sAC expression in 33 cases of acral melanoma, and assessed its diagnostic value in distinguishing melanoma in situ (MIS, n = 17) from acral invasive melanomas (n = 16) and melanocytic naevi (n = 11). Acral melanomas exhibited more marked nuclear immunopositivity compared with acral melanocytic naevi. sAC expression significantly correlated with the nuclear morphology of melanocytes and melanoma cells, namely, hyperchromatic nuclei and prominent nucleoli within vesicular nuclei. sAC expression was predominantly observed in the hyperchromatic nuclei of MIS and the prominent nucleoli invasive melanomas, respectively. In vitro culture models of melanocytes and melanoma cell lines exhibited sAC staining patterns similar to those of acral melanomas. Differentiation induction showed that nuclear and nucleolar expression varied depending on cell morphology. sAC immunostaining may be useful for the differential diagnosis of acral melanocytic lesions, and sAC expressed in the nucleus and nucleolus might be related to cytological and nuclear changes associated with invasion and progression of acral melanomas.

Expression of soluble adenylyl cyclase in acral melanomas

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Expression of soluble adenylyl cyclase in acral melanomas