Transactivation of Met signaling by oncogenic Gnaq drives the evolution of melanoma in Hgf-Cdk4 mice.

Recent pan-cancer genomic analyses have identified numerous oncogenic driver mutations that occur in a cell-type and tissue-specific distribution. For example, oncogenic mutations in Braf and Nras genes arise predominantly in melanocytic neoplasms of the epidermis, while oncogenic mutations in Gnaq/11 genes arise mostly in melanocytic lesions of the dermis or the uvea. The mechanisms promoting cell-type and tissue-specific oncogenic events currently remain poorly understood. Here, we report that Gnaq/11 hotspot mutations occur as early oncogenic drivers during the evolution of primary melanomas in Hgf-Cdk4 mice. Additional single base substitutions in the Trp53 gene and structural chromosomal aberrations favoring amplifications of the chromosomal region containing the Met receptor gene accumulate during serial tumor transplantation and in cell lines established in vitro. Mechanistically, we found that the GnaqQ209L mutation transactivates the Met receptor. Overexpression of oncogenic GnaqQ209L in the immortalized melanocyte cell line promoted in vivo growth that was enhanced by transgenic Hgf expression in the tumor microenvironment. This cross-signaling mechanism explains the selection of oncogenic Gnaq/11 in primary Hgf-Cdk4 melanomas and provides an example of how oncogenic driver mutations, intracellular signaling cascades, and microenvironmental cues cooperate to drive cancer development in a tissue-specific fashion.

Subcutaneous Fat Abundance and Density Are Associated with an Enhanced Response to Immunotherapy in Metastatic Melanoma: A Retrospective Cohort Study.

RATIONALE AND OBJECTIVES: Despite the impressive efficacy of immune checkpoint inhibitors (ICIs) in the treatment of metastatic melanoma, not all patients respond to therapy. In addition, ICI harbors the risk for serious adverse events (AEs), highlighting the need for novel biomarkers predicting treatment response and occurrence of AEs. Recently, the identification of enhanced response to ICI in obese patients has indicated that body composition might influence treatment efficacy. The aim of the current study is to assess radiologic measurements of body composition as biomarkers for treatment response and AEs to ICI in melanoma. MATERIALS AND METHODS: In the current work, we analyze adipose tissue abundance and density, as well as muscle mass via computed tomography scans in a retrospective cohort of 100 patients with non-resectable stage III/IV melanoma receiving first-line treatment with ICI in our department. From these, we investigate the impact of the subcutaneous adipose tissue gauge index (SATGI) and other parameters of body composition on treatment efficacy and occurrence of AEs. RESULTS: Low SATGI was associated with prolonged progression-free survival (PFS) in univariate and multivariate analyses (hazard ratio 2.56 [95% CI 1.18-5.55], P = .02), as well as an enhanced objective response rate (50.0% vs 27.1%; P = .02). Further analysis with a random forest survival model highlighted a nonlinear relationship between SATGI and PFS with a clear separation into high- and low-risk cohorts separated by the median. Finally, a significant enrichment of cases with vitiligo, but no other AEs, was observed in the SATGI-low cohort (11.5% vs 0%; P = .03). CONCLUSION: We identify SATGI as a biomarker predicting treatment response to ICI without increased risk for severe AEs in melanoma.

CD4+ T cell-induced inflammatory cell death controls immune-evasive tumours.

Most clinically applied cancer immunotherapies rely on the ability of CD8+ cytolytic T cells to directly recognize and kill tumour cells1-3. These strategies are limited by the emergence of major histocompatibility complex (MHC)-deficient tumour cells and the formation of an immunosuppressive tumour microenvironment4-6. The ability of CD4+ effector cells to contribute to antitumour immunity independently of CD8+ T cells is increasingly recognized, but strategies to unleash their full potential remain to be identified7-10. Here, we describe a mechanism whereby a small number of CD4+ T cells is sufficient to eradicate MHC-deficient tumours that escape direct CD8+ T cell targeting. The CD4+ effector T cells preferentially cluster at tumour invasive margins where they interact with MHC-II+CD11c+ antigen-presenting cells. We show that T helper type 1 cell-directed CD4+ T cells and innate immune stimulation reprogramme the tumour-associated myeloid cell network towards interferon-activated antigen-presenting and iNOS-expressing tumouricidal effector phenotypes. Together, CD4+ T cells and tumouricidal myeloid cells orchestrate the induction of remote inflammatory cell death that indirectly eradicates interferon-unresponsive and MHC-deficient tumours. These results warrant the clinical exploitation of this ability of CD4+ T cells and innate immune stimulators in a strategy to complement the direct cytolytic activity of CD8+ T cells and natural killer cells and advance cancer immunotherapies.

Real-world outcomes using PD-1 antibodies and BRAF + MEK inhibitors for adjuvant melanoma treatment from 39 skin cancer centers in Germany, Austria and Switzerland.

BACKGROUND: Programmed death-1 (PD-1) antibodies and BRAF + MEK inhibitors are widely used for adjuvant therapy of fully resected high-risk melanoma. Little is known about treatment efficacy outside of phase III trials. This real-world study reports on clinical outcomes of modern adjuvant melanoma treatment in specialized skin cancer centers in Germany, Austria and Switzerland. METHODS: Multicenter, retrospective study investigating stage III-IV melanoma patients receiving adjuvant nivolumab (NIV), pembrolizumab (PEM) or dabrafenib + trametinib (D + T) between 1/2017 and 10/2021. The primary endpoint was 12-month recurrence-free survival (RFS). Further analyses included descriptive and correlative statistics, and a multivariate linear-regression machine learning model to assess the risk of early melanoma recurrence. RESULTS: In total, 1198 patients from 39 skin cancer centers from Germany, Austria and Switzerland were analysed. The vast majority received anti PD-1 therapies (n = 1003). Twelve-month RFS for anti PD-1 and BRAF + MEK inhibitor-treated patients were 78.1% and 86.5%, respectively (hazard ratio [HR] 1.998 [95% CI 1.335-2.991]; p = 0.001). There was no statistically significant difference in overall survival (OS) in anti PD-1 (95.8%) and BRAF + MEK inhibitor (96.9%) treated patients (p > 0.05) during the median follow-up of 17 months. Data indicates that anti PD-1 treated patients who develop immune-related adverse events (irAEs) have lower recurrence rates compared to patients with no irAEs (HR 0.578 [95% CI 0.443-0.754], p = 0.001). BRAF mutation status did not affect overall efficacy of anti PD-1 treatment (p > 0.05). In both, anti PD-1 and BRAF + MEK inhibitor treated cohorts, data did not show any difference in 12-month RFS and 12-month OS comparing patients receiving total lymph node dissection (TLND) versus sentinel lymph node biopsy only (p > 0.05). The recurrence prediction model reached high specificity but only low sensitivity with an AUC = 0.65. No new safety signals were detected. Overall, recorded numbers and severity of adverse events were lower than reported in pivotal phase III trials. CONCLUSIONS: Despite recent advances in adjuvant melanoma treatment, early recurrence remains a significant clinical challenge. This study shows that TLND does not reduce the risk of early melanoma recurrence and should only be considered in selected patients. Data further highlight that variables collected during clinical routine are unlikely to allow for a clinically relevant prediction of individual recurrence risk.

[Immunological mechanisms of cognitive dysfunction under systemic therapy in metastatic melanoma]. / Kognitive Funktionsstörungen unter Systemtherapie bei metastasiertem Melanom.

Neurocognitive impairments of memory, speech, and attention can occur in cancer patients as a direct result of the cancer but also in the context of therapy. With the development of modern immunotherapies and their use in combination with surgery and radiation therapy, the number of long-term survivors has significantly increased. As a result, detrimental effects on brain function and structure in cancer patients not only during treatment but also after completion of therapy have become a key issue in clinical oncology. Early diagnosis and treatment of neurocognitive disorders is of great importance for quality of life, therapy adherence, and overall survival of the affected patients. In this review, we discuss the underlying mechanisms with a special focus on metastatic melanoma. Furthermore, practice-relevant diagnostics, prophylaxis, and intervention options are discussed.

COL10A1 allows stratification of invasiveness of colon cancer and associates to extracellular matrix and immune cell enrichment in the tumor parenchyma.

Background: Treatment options for metastatic colorectal cancer (CRC) are mostly ineffective. We present new evidence that tumor tissue collagen type X alpha 1 (COL10A1) is a relevant candidate biomarker to improve this dilemma. Methods: Several public databases had been screened to observe COL10A1 expression in transcriptome levels with cell lines and tissues. Protein interactions and alignment to changes in clinical parameters and immune cell invasion were performed, too. We also used algorithms to build a novel COL10A1-related immunomodulator signature. Various wet-lab experiments were conducted to quantify COL10A1 protein and transcript expression levels in disease and control cell models. Results: COL10A1 mRNA levels in tumor material is clinical and molecular prognostic, featuring upregulation compared to non-cancer tissue, increase with histomorphological malignancy grading of the tumor, elevation in tumors that invade perineural areas, or lymph node invasion. Transcriptomic alignment noted a strong positive correlation of COL10A1 with transcriptomic signature of cancer-associated fibroblasts (CAFs) and populations of the immune compartment, namely, B cells and macrophages. We verified those findings in functional assays showing that COL10A1 are decreased in CRC cells compared to fibroblasts, with strongest signal in the cell supernatant of the cells. Conclusion: COL10A1 abundance in CRC tissue predicts metastatic and immunogenic properties of the disease. COL10A1 transcription may mediate tumor cell interaction with its stromal microenvironment.

Generalized Nodules and Sclerosis of the Skin: A Quiz.

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The aryl hydrocarbon receptor promotes inflammation-induced dedifferentiation and systemic metastatic spread of melanoma cells.

The aryl hydrocarbon receptor (AHR) is a ligand binding-transcription factor of the basic helix-loop-helix family regulating multiple cellular functions such as differentiation, cell cycle, apoptosis, and inflammatory reactions. In neoplastic diseases, the AHR has been described to modulate proliferation and differentiation in dichotomous ways, either inhibiting or augmenting the growth of tumors. The precise role of AHR in melanoma is mostly unknown. Here, we report a functional effect of AHR activation on inflammation-induced melanoma cell dedifferentiation and the development of lung metastases in a mouse model. Via in silico analyses of "The Cancer Genome Atlas" human melanoma cohort, we detected a correlation between AHR expression levels and a dedifferentiated melanoma cell phenotype with an invasive gene signature, which we were able to functionally recapitulate in a panel of human melanoma cell lines. Both human and mouse melanoma cell lines upregulated AHR expression after inflammatory stimulation with tumor necrosis factor-α (TNF-α). Activation of AHR in human and mouse melanoma cell lines with the endogenous ligand formylindolo(3,2-b)carbazole (FICZ) promoted inflammation-induced dedifferentiation in vitro. Importantly, mouse melanoma cells with CRISPR/Cas9-mediated disruption of the AHR gene showed impaired in vivo tumor growth after transplantation in the skin as well as decreased numbers of spontaneous lung metastases. Taken together, our results demonstrate a functional role for AHR expression in melanoma development and metastatic progression. This provides a scientific basis for future experiments that further dissect the underlying molecular mechanisms and assess the potential for AHR inhibition as part of multimodal melanoma treatment strategies.

Cutaneous manifestations of internal malignancy.

Skin lesions associated with internal malignancy may present as cutaneous metastases or as typical lesions occurring in the context of certain cancer-associated genetic syndromes. Paraneoplastic syndromes, on the other hand, are only indirectly associated with an underlying malignancy and are not malignant per se. Historically, a distinction has been made between "obligate" and "facultative" paraneoplastic disorders, depending on the likelihood with which they are potentially associated with malignancy. In addition, there are nonspecific cutaneous manifestations that are only rarely associated with an underlying malignancy. Another possible classification is based on the pathophysiological mechanisms underlying the cutaneous lesions. In everyday practice, it is essential that dermatologists recognize potentially cancer-associated dermatoses, as this will frequently contribute to the initial diagnosis of an underlying neoplasm.

Activated Hgf-Met Signaling Cooperates with Oncogenic BRAF to Drive Primary Cutaneous Melanomas and Angiotropic Lung Metastases in Mice.

Oncogenic mutations in the BRAF kinase gene represent the most frequent genomic driver in acquired melanocytic nevi and in cutaneous melanomas. It is currently thought that oncogene-induced senescence and cell cycle arrest limit the ability of oncogenic BRAF to promote melanocyte proliferation in benign nevi. The molecular and cellular mechanisms that allow an oncogenic BRAF mutation to fully transform melanocytes into invasively growing melanoma cells that are able to metastasize systemically are only partially understood. In this study, we show in a genetic mouse model that constitutively enhanced Hgf-Met signaling cooperates with oncogenic BRAF to drive tumor development and metastatic spread. Activation of oncogenic BRAF in mice with transgenic Hgf overexpression and an oncogenic CDK4 germline mutation accelerated and increased the development of primary cutaneous melanomas. Primary melanomas showed considerable phenotypic heterogeneity with frequent signs of dedifferentiation. BRAF activation in Hgf-CDK4 mice also increased the number of lung metastases. Melanoma cells showed a pronounced angiotropic growth pattern both at the invasive front in primary tumors and in metastatic lesions of the lung. Taken together, our work supports the notion that activated Hgf-Met signaling and oncogenic BRAF can cooperate in melanoma pathogenesis.