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Melanoma central nervous system metastases: An update to approaches, challenges, and opportunities

Karz, Alcida; Dimitrova, Maya; Kleffman, Kevin; Alvarez-Breckenridge, Christopher; Atkins, Michael B; Boire, Adrienne; Bosenberg, Marcus; Brastianos, Priscilla; Cahill, Daniel P; Chen, Qing; Ferguson, Sherise; Forsyth, Peter; Glitza Oliva, Isabella C; Goldberg, Sarah B; Holmen, Sheri L; Knisely, Jonathan P S; Merlino, Glenn; Nguyen, Don X; Pacold, Michael E; Perez-Guijarro, Eva; Smalley, Keiran S M; Tawbi, Hussein A; Wen, Patrick Y; Davies, Michael A; Kluger, Harriet M; Mehnert, Janice M; Hernando, Eva
Brain metastases are the most common brain malignancy. This review discusses the studies presented at the third annual meeting of the Melanoma Research Foundation in the context of other recent reports on the biology and treatment of melanoma brain metastases (MBM). Although symptomatic MBM patients were historically excluded from immunotherapy trials, efforts from clinicians and patient advocates have resulted in more inclusive and even dedicated clinical trials for MBM patients. The results of checkpoint inhibitor trials were discussed in conversation with current standards of care for MBM patients, including steroids, radiotherapy and targeted therapy. Advances in the basic scientific understanding of melanoma brain metastases, including the role of astrocytes and metabolic adaptations to the brain microenvironment are exposing new vulnerabilities which could be exploited for therapeutic purposes. Technical advances including single cell omics and multiplex imaging are expanding our understanding of the MBM ecosystem and its response to therapy. This unprecedented level of spatial and temporal resolution is expected to dramatically advance the field in coming years and render novel treatment approaches that might improve the MBM patient outcomes.
PMID: 35912544
ISSN: 1755-148x
CID: 5287832

Dissecting the treatment-naive ecosystem of human melanoma brain metastasis

Biermann, Jana; Melms, Johannes C; Amin, Amit Dipak; Wang, Yiping; Caprio, Lindsay A; Karz, Alcida; Tagore, Somnath; Barrera, Irving; Ibarra-Arellano, Miguel A; Andreatta, Massimo; Fullerton, Benjamin T; Gretarsson, Kristjan H; Sahu, Varun; Mangipudy, Vaibhav S; Nguyen, Trang T T; Nair, Ajay; Rogava, Meri; Ho, Patricia; Koch, Peter D; Banu, Matei; Humala, Nelson; Mahajan, Aayushi; Walsh, Zachary H; Shah, Shivem B; Vaccaro, Daniel H; Caldwell, Blake; Mu, Michael; Wünnemann, Florian; Chazotte, Margot; Berhe, Simon; Luoma, Adrienne M; Driver, Joseph; Ingham, Matthew; Khan, Shaheer A; Rapisuwon, Suthee; Slingluff, Craig L; Eigentler, Thomas; Röcken, Martin; Carvajal, Richard; Atkins, Michael B; Davies, Michael A; Agustinus, Albert; Bakhoum, Samuel F; Azizi, Elham; Siegelin, Markus; Lu, Chao; Carmona, Santiago J; Hibshoosh, Hanina; Ribas, Antoni; Canoll, Peter; Bruce, Jeffrey N; Bi, Wenya Linda; Agrawal, Praveen; Schapiro, Denis; Hernando, Eva; Macosko, Evan Z; Chen, Fei; Schwartz, Gary K; Izar, Benjamin
Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.
PMID: 35803246
ISSN: 1097-4172
CID: 5278412

Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Kleffman, Kevin; Levinson, Grace; Rose, Indigo V L; Blumenberg, Lili M; Shadaloey, Sorin A A; Dhabaria, Avantika; Wong, Eitan; Galan-Echevarria, Francisco; Karz, Alcida; Argibay, Diana; Von Itter, Richard; Floristan, Alfredo; Baptiste, Gillian; Eskow, Nicole M; Tranos, James A; Chen, Jenny; Vega Y Saenz de Miera, Eleazar C; Call, Melissa; Rogers, Robert; Jour, George; Wadghiri, Youssef Zaim; Osman, Iman; Li, Yue-Ming; Mathews, Paul; DeMattos, Ronald; Ueberheide, Beatrix; Ruggles, Kelly V; Liddelow, Shane A; Schneider, Robert J; Hernando, Eva
Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. Our unbiased proteomics analysis of melanoma short-term cultures revealed that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. We showed that melanoma cells require amyloid beta (AB) for growth and survival in the brain parenchyma. Melanoma-secreted AB activates surrounding astrocytes to a pro-metastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacological inhibition of AB decreases brain metastatic burden.
PMID: 35262173
ISSN: 2159-8290
CID: 5183542

A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis

Shadaloey, Arman Alberto Sorin; Karz, Alcida; Moubarak, Rana S; Agrawal, Praveen; Levinson, Grace; Kleffman, Kevin; Aristizabal, Orlando; Osman, Iman; Wadghiri, Youssef Z; Hernando, Eva
Metastasis is a complex process, requiring cells to overcome barriers that are only incompletely modeled by in vitro assays. A systematic workflow was established using robust, reproducible in vivo models and standardized methods to identify novel players in melanoma metastasis. This approach allows for data inference at specific experimental stages to precisely characterize a gene's role in metastasis. Models are established by introducing genetically modified melanoma cells via intracardiac, intradermal, or subcutaneous injections into mice, followed by monitoring with serial in vivo imaging. Once preestablished endpoints are reached, primary tumors and/or metastases-bearing organs are harvested and processed for various analyses. Tumor cells can be sorted and subjected to any of several 'omics' platforms, including single-cell RNA sequencing. Organs undergo imaging and immunohistopathological analyses to quantify the overall burden of metastases and map their specific anatomic location. This optimized pipeline, including standardized protocols for engraftment, monitoring, tissue harvesting, processing, and analysis, can be adopted for patient-derived, short-term cultures and established human and murine cell lines of various solid cancer types.
PMID: 35343960
ISSN: 1940-087x
CID: 5200892

The histone demethylase PHF8 regulates TGFβ signaling and promotes melanoma metastasis

Moubarak, Rana S; de Pablos-Aragoneses, Ana; Ortiz-Barahona, Vanessa; Gong, Yixiao; Gowen, Michael; Dolgalev, Igor; Shadaloey, Sorin A A; Argibay, Diana; Karz, Alcida; Von Itter, Richard; Vega-Sáenz de Miera, Eleazar Carmelo; Sokolova, Elena; Darvishian, Farbod; Tsirigos, Aristotelis; Osman, Iman; Hernando, Eva
The contribution of epigenetic dysregulation to metastasis remains understudied. Through a meta-analysis of gene expression datasets followed by a mini-screen, we identified Plant Homeodomain Finger protein 8 (PHF8), a histone demethylase of the Jumonji C protein family, as a previously unidentified prometastatic gene in melanoma. Loss- and gain-of-function approaches demonstrate that PHF8 promotes cell invasion without affecting proliferation in vitro and increases dissemination but not subcutaneous tumor growth in vivo, thus supporting its specific contribution to the acquisition of metastatic potential. PHF8 requires its histone demethylase activity to enhance melanoma cell invasion. Transcriptomic and epigenomic analyses revealed that PHF8 orchestrates a molecular program that directly controls the TGFβ signaling pathway and, as a consequence, melanoma invasion and metastasis. Our findings bring a mechanistic understanding of epigenetic regulation of metastatic fitness in cancer, which may pave the way for improved therapeutic interventions.
PMID: 35179962
ISSN: 2375-2548
CID: 5163652

In Vivo miRNA Decoy Screen Reveals miR-124a as a Suppressor of Melanoma Metastasis

Moubarak, Rana S; Koetz-Ploch, Lisa; Mullokandov, Gavriel; Gaziel, Avital; de Pablos-Aragoneses, Ana; Argibay, Diana; Kleffman, Kevin; Sokolova, Elena; Berwick, Marianne; Thomas, Nancy E; Osman, Iman; Brown, Brian D; Hernando, Eva
Melanoma is a highly prevalent cancer with an increasing incidence worldwide and high metastatic potential. Brain metastasis is a major complication of the disease, as more than 50% of metastatic melanoma patients eventually develop intracranial disease. MicroRNAs (miRNAs) have been found to play an important role in the tumorigenicity of different cancers and have potential as markers of disease outcome. Identification of relevant miRNAs has generally stemmed from miRNA profiling studies of cells or tissues, but these approaches may have missed miRNAs with relevant functions that are expressed in subfractions of cancer cells. We performed an unbiased in vivo screen to identify miRNAs with potential functions as metastasis suppressors using a lentiviral library of miRNA decoys. Notably, we found that a significant fraction of melanomas that metastasized to the brain carried a decoy for miR-124a, a miRNA that is highly expressed in the brain/neurons. Additional loss- and gain-of-function in vivo validation studies confirmed miR-124a as a suppressor of melanoma metastasis and particularly of brain metastasis. miR-124a overexpression did not inhibit tumor growth in vivo, underscoring that miR-124a specifically controls processes required for melanoma metastatic growth, such as seeding and growth post-extravasation. Finally, we provide proof of principle of this miRNA as a promising therapeutic agent by showing its ability to impair metastatic growth of melanoma cells seeded in distal organs. Our efforts shed light on miR-124a as an antimetastatic agent, which could be leveraged therapeutically to impair metastatic growth and improve patient survival.
PMCID:9036958
PMID: 35480113
ISSN: 2234-943x
CID: 5217562

HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness

Ho, Jessica Sy; Di Tullio, Federico; Schwarz, Megan; Low, Diana; Incarnato, Danny; Gay, Florence; Tabaglio, Tommaso; Zhang, JingXian; Wollmann, Heike; Chen, Leilei; An, Omer; Chan, Tim Hon Man; Hall Hickman, Alexander; Zheng, Simin; Roudko, Vladimir; Chen, Sujun; Karz, Alcida; Ahmed, Musaddeque; He, Housheng Hansen; Greenbaum, Benjamin D; Oliviero, Salvatore; Serresi, Michela; Gargiulo, Gaetano; Mann, Karen M; Hernando, Eva; Mulholland, David; Marazzi, Ivan; Wee, Dave Keng Boon; Guccione, Ernesto
High spliceosome activity is a dependency for cancer cells, making them more vulnerable to perturbation of the splicing machinery compared to normal cells. To identify splicing factors important for prostate cancer (PCa) fitness, we performed pooled shRNA screens in vitro and in vivo. Our screens identified HNRNPM as a regulator of PCa cell growth. RNA- and eCLIP-sequencing identified HNRNPM binding to transcripts of key homeostatic genes. HNRNPM binding to its targets prevents aberrant exon inclusion and back-splicing events. In both linear and circular mis-spliced transcripts, HNRNPM preferentially binds to GU-rich elements in long flanking proximal introns. Mimicry of HNRNPM dependent linear splicing events using splice-switching-antisense-oligonucleotides (SSOs) was sufficient to inhibit PCa cell growth. This suggests that PCa dependence on HNRNPM is likely a result of mis-splicing of key homeostatic coding and non-coding genes. Our results have further been confirmed in other solid tumors. Taken together, our data reveal a role for HNRNPM in supporting cancer cell fitness. Inhibition of HNRNPM activity is therefore a potential therapeutic strategy in suppressing growth of PCa and other solid tumors.
PMID: 34075878
ISSN: 2050-084x
CID: 4933892

The State of Melanoma: Emergent Challenges and Opportunities

Atkins, Michael B; Curiel-Lewandrowski, Clara; Fisher, David E; Swetter, Susan M; Tsao, Hensin; Aguirre-Ghiso, Julio A; Soengas, Maria S; Weeraratna, Ashani T; Flaherty, Keith T; Herlyn, Meenhard; Sosman, Jeffrey A; Tawbi, Hussein A; Pavlick, Anna C; Cassidy, Pamela B; Chandra, Sunandana; Chapman, Paul B; Daud, Adil; Eroglu, Zeynep; Ferris, Laura K; Fox, Bernard A; Gerhsenwald, Jeffrey E; Gibney, Geoffrey T; Grossman, Douglas; Hanks, Brent A; Hanniford, Douglas; Hernando, Eva; Jeter, Joanne M; Johnson, Douglas B; Khleif, Samir N; Kirkwood, John M; Leachman, Sancy A; Mays, Darren; Nelson, Kelly C; Sondak, Vernon K; Sullivan, Ryan J; Merlino, Glenn
Five years ago, the Melanoma Research Foundation (MRF) conducted an assessment of the challenges and opportunities facing the melanoma research community and patients with melanoma. Since then, remarkable progress has been made on both the basic and clinical research fronts. However, the incidence, recurrence and death rates for melanoma remain unacceptably high and significant challenges remain. Hence, the MRF Scientific Advisory Council and Breakthrough Consortium, a group that includes clinicians and scientists, reconvened to facilitate intensive discussions on thematic areas essential to melanoma researchers and patients alike - prevention, detection, diagnosis, metastatic dormancy and progression, response and resistance to targeted and immune-based therapy, and the clinical consequences of COVID-19 for melanoma patients and providers. These extensive discussions helped to crystalize our understanding of the challenges and opportunities facing the broader melanoma community today. In this report, we discuss the progress made since the last MRF assessment, comment on what remains to be overcome and offer recommendations for the best path forward.
PMID: 33414132
ISSN: 1557-3265
CID: 4739332

Network models of primary melanoma microenvironments identify key melanoma regulators underlying prognosis

Song, Won-Min; Agrawal, Praveen; Von Itter, Richard; Fontanals-Cirera, Barbara; Wang, Minghui; Zhou, Xianxiao; Mahal, Lara K; Hernando, Eva; Zhang, Bin
Melanoma is the most lethal skin malignancy, driven by genetic and epigenetic alterations in the complex tumour microenvironment. While large-scale molecular profiling of melanoma has identified molecular signatures associated with melanoma progression, comprehensive systems-level modeling remains elusive. This study builds up predictive gene network models of molecular alterations in primary melanoma by integrating large-scale bulk-based multi-omic and single-cell transcriptomic data. Incorporating clinical, epigenetic, and proteomic data into these networks reveals key subnetworks, cell types, and regulators underlying melanoma progression. Tumors with high immune infiltrates are found to be associated with good prognosis, presumably due to induced CD8+ T-cell cytotoxicity, via MYO1F-mediated M1-polarization of macrophages. Seventeen key drivers of the gene subnetworks associated with poor prognosis, including the transcription factor ZNF180, are tested for their pro-tumorigenic effects in vitro. The anti-tumor effect of silencing ZNF180 is further validated using in vivo xenografts. Experimentally validated targets of ZNF180 are enriched in the ZNF180 centered network and the known pathways such as melanoma cell maintenance and immune cell infiltration. The transcriptional networks and their critical regulators provide insights into the molecular mechanisms of melanomagenesis and pave the way for developing therapeutic strategies for melanoma.
PMID: 33619278
ISSN: 2041-1723
CID: 4794382

Treatment with therapeutic anticoagulation is not associated with immunotherapy response in advanced cancer patients

Johannet, Paul; Sawyers, Amelia; Gulati, Nicholas; Donnelly, Douglas; Kozloff, Samuel; Qian, Yingzhi; Floristan, Alfredo; Hernando, Eva; Zhong, Judy; Osman, Iman
BACKGROUND:Recent preclinical data suggest that there may be therapeutic synergy between immune checkpoint blockade and inhibition of the coagulation cascade. Here, we investigate whether patients who received immune checkpoint inhibitors (ICI) and were on concomitant anticoagulation (AC) experienced better treatment outcomes than individuals not on AC.Affiliation: Kindly confirm if corresponding authors affiliation is identified correctly.The corresponding author's affiliation is correct. METHODS:We studied a cohort of 728 advanced cancer patients who received 948 lines of ICI at NYU (2010-2020). Patients were classified based on whether they did (n = 120) or did not (n = 828) receive therapeutic AC at any point during their treatment with ICI. We investigated the relationship between AC status and multiple clinical endpoints including best overall response (BOR), objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and the incidence of bleeding complications.Affiliations: Journal instruction requires a country for affiliations; however, this is missing in affiliations 1 to 5. Please verify if the provided country is correct and amend if necessary.The country is correct for all affiliations (1 - 5). RESULTS:Treatment with AC was not associated with significantly different BOR (P = 0.80), ORR (P =0.60), DCR (P =0.77), PFS (P = 0.59), or OS (P =0.64). Patients who received AC were significantly more likely to suffer a major or clinically relevant minor bleed (P = 0.05). CONCLUSION/CONCLUSIONS:AC does not appear to impact the activity or efficacy of ICI in advanced cancer patients. On the basis of our findings, we caution that there is insufficient evidence to support prospectively evaluating the combination of AC and immunotherapy.
PMCID:7847556
PMID: 33516263
ISSN: 1479-5876
CID: 4798912