Browsing by Subject "Melanoma"
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Item Advances in the treatment of metastatic melanoma(2012-10-12) Harker-Murray, AmyItem Biologic therapy of melanoma(1998-03-26) Levinson, Barry S.Item Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma(2016-06-23) Eskiocak, Banu; DeBerardinis, Ralph J.; White, Michael A.; Brekken, Rolf A.; Cobb, Melanie H.Genomic diversity and adaptive plasticity of melanoma tumors limit durable control with conventional and targeted therapies. Nevertheless, pathological activation of the ERK1/2 regulatory system is a linchpin tumorigenic mechanism associated with the majority of both primary and recurrent disease. To avoid common resistance mechanisms associated with perdurance of ERK1/2 signaling, we sought to identify therapeutic targets that are selectively required for tumorigenicity in the presence of pathological ERK1/2 signaling. Such targets could be leveraged in jiu jitsu fashion to breach selective pressure to engage any of the many BRAF-independent ERK1/2 pathway activation mechanisms. By integration of multi-genome chemical and genetic screens; recurrent architectural variants in melanoma tumor genomes; and patient outcome data; we identified 2 mechanistic subtypes of BRAF(V600) melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKE inhibitors. Importantly, subtype membership can be predicted using a robust quantitative 5-feature genetic biomarker. This biomarker, or the mechanistic relationships linked to it, can identify a cohort of best responders to clinical MEK inhibitors (detectable in 25% of melanoma patients) and identify a cohort of TBK1/IKBKE inhibitor-sensitive disease among non-responders to current targeted therapy (detectable in 9.9% of melanomas).Item Clinical Features and Outcomes of Black Patients with Melanoma: A Case Series Between 2006-2022(2024-01-30) Brown, Ariel B.; Wix, Sophia N.; Heberton, Meghan; Adamson, Adewole S.; Gill, Jennifer G.BACKGROUND: The incidence of melanoma in Black patients is rare, therefore most studies describing outcomes have been performed using population databases with limited patient-level information. OBJECTIVE: To describe specific anatomic sites, clinical features, histologic subtypes, risk factors, and outcomes of Black patients with melanoma. METHODS: Case series of Black patients with melanoma identified between January 2006 and October 2022 at University of Texas Southwestern Medical Center and Parkland Health in Dallas, TX. Participants included self-identified Black patients with a histopathologic diagnosis of melanoma. Data collection included demographics, clinical characteristics, personal and family medical history, immunosuppression history, comorbidities, histopathology reports, imaging reports, melanoma treatments and responses, time to progression, metastatic sites, and survival. Kaplan-Meier analysis captured melanoma-related survival by primary site. RESULTS: Of the 48 patients identified, the median age at diagnosis of melanoma was 61.5 (range: 23-86) with the majority being female (30/48). Seventy-five percent (30/40) of primary cutaneous melanomas were located on acral skin despite only one-third (10/30) being histologically classified as acral lentiginous melanomas. Compared to those with acral disease, patients with non-acral cutaneous melanomas were more likely to be immunocompromised (40% vs. 7%) or have a personal history of cancer (60% vs. 17%) with all (3/3) superficial spreading melanoma patients having a history of both. No patients had more than 1 confirmed primary melanoma. In total, 13 (27%) Black patients with melanoma developed stage IV disease, of which 12 ultimately died due to disease progression. Those diagnosed with advanced acral melanoma, mucosal/ocular melanoma, or unknown primary had the poorest melanoma outcomes. No patients with non- acral cutaneous melanomas developed distant metastases or died of their disease. CONCLUSION: Most cutaneous melanomas in Black patients occur on acral sites. Non-acral cutaneous melanomas had limited contribution to melanoma mortality in Black patients and were diagnosed primarily in immunocompromised patients or those with a history of other cancers. Improving melanoma mortality in Black patients will require focused therapeutic and early detection strategies for acral, mucosal/ocular, and melanoma of unknown primary.Item Hyperactive Rac1 Drives MAPK-Independent Proliferation in Melanoma by Assembly of a Mechanosensitive Dendritic Actin Network(2018-06-26) Mohan, Ashwathi; Brekken, Rolf A.; Danuser, Gaudenz; Cobb, Melanie H.; Alto, NealCancer cells use a variety of mechanisms to subvert growth regulation and overcome environmental challenges. Often, these same mechanisms enable cancer cells to develop resistance to targeted therapies. Here, we describe how a hyperactivating mutation of the Rac1 GTPase (Rac1P29S) harnesses Rac1's function as a regulator of actin polymer assembly to sustain cell cycle progression in growth limiting conditions. This proliferative advantage supports metastatic colonization of melanoma cells and confers insensitivity to inhibitors of the mitogen-activated protein kinase (MAPK) pathway, a frequent target for melanoma treatment. Rac1P29S bypasses the MAPK axis through a mechanism that necessitates cell-matrix attachment, however, does not depend on integrin-mediated focal adhesion assembly and focal adhesion kinase signaling. Even without involvement of canonical adhesion signaling, cells carrying the Rac1P29S mutation show elevated traction upon drug treatment and require mechanical resistance from their surrounding matrix to gain a proliferative advantage. We describe an alternative arm for cell mechanosensing, whereby actin polymerization against a matrix of minimal rigidity organizes biochemical cues to drive proliferative signals. Hyperactivation of Rac1 by the P29S mutation channels this pathway in melanoma through Arp 2/3-dependent formation of a constrained actin brush network that results in the inactivation of tumor suppressor NF2/Merlin. These data suggest an alternative mechanism for mechanosensitive growth regulation that can be hijacked by cancer cells to circumvent the adverse conditions of foreign microenvironments or drug treatment.Item Immune Checkpoint Blockade Induces Gut Microbiota Translocation That Augments Extraintestinal Anti-Tumor Immunity(2023-05-01T05:00:00.000Z) Choi, Yongbin; Yan, Nan; Koh, Andrew Y.; Hooper, Lora V.; Winter, Sebastian E.Gut microbiota are critical for effective immune checkpoint blockade therapy (ICT) for cancer. The mechanisms by which gut microbiota augment extraintestinal anti-cancer immune responses, however, are largely unknown. Here, we find that ICT induces the translocation of specific endogenous gut microbiota into secondary lymphoid organs and subcutaneous melanoma tumors. Mechanistically, ICT induces lymph node remodeling and dendritic cell (DC) activation which facilitates the translocation of a selective subset of gut bacteria to extraintestinal tissues which promote optimal anti-tumor T-cell responses in both the tumor-draining lymph nodes (TDLN) and the primary tumor. Antibiotic treatment results in decreased gut microbiota translocation into MLN and TDLN, diminished DC and effector CD8+ T cell responses, and attenuated response to ICT. Our findings illuminate a key mechanism by which gut microbiota promote extraintestinal anti-cancer immunity.Item Immunotherapy: a new era in cancer treatment(2015-07-10) Nijhawan, DeepakItem Melanoma: what a difference a decade makes(2019-07-19) Homsi, JadeItem Metabolomic Investigation of Melanoma Metastasis in a Patient-Derived Xenograft Mouse Model(2017-07-19) Shi, Xiaolei; Zhu, Hao; DeBerardinis, Ralph J.; Wang, Richard; Morrison, Sean J.; Davies, MichaelMetabolic reprogramming is considered a major factor in cellular transformation and tumor initiation, but whether or how metabolism supports tumor metastasis remains an open question. This study seeks to identify metabolic predictors of metastasis, with the rationale that understanding metabolic changes accompanying metastasis may lead to new therapies to prevent metastatic cancer. We used a set of patient-derived xenograft mouse models of melanoma, in which the metastatic potential of individual tumor lines correlated strongly with the history of metastasis in the patient donors. Six tumor lines with low metastatic potential (L-met) and nine with high metastatic potential (H-met) were implanted into several mice individually, then several fragments were isolated from each tumor, yielding a total of 182 individual tumor fragments for metabolomics. A tandem mass spectrometry (MS/MS)-based analytical platform was used to characterize 133 metabolites extracted from each tumor specimen. We then used a suite of statistical tools to identify metabolites differentiating H-met from L-met tumors. We identified durable metabolomic signatures correlating with molecular and biological features of the tumors. BRAF-mutant tumors had metabolomic and metabolic flux features of enhanced glycolysis compared to BRAF-wild type tumors. Tumors that metastasized efficiently from their primary sites had elevated levels of metabolites related to protein methylation, including trimethyllysine (TML). TML levels correlated with histone H3 trimethylation at lysines 9 and 27, and methylation at these sites was also enhanced in efficiently metastasizing tumors. Erasing either of these marks by genetically or pharmacologically silencing the histone methyltransferases SETDB1 or EZH2 had no effect on primary tumor growth but reduced cellular invasiveness, circulating tumor cell count and metastatic spread. Thus, metabolite profiling can uncover targetable epigenetic requirements for the metastasis of human melanoma cells.Item [Southwestern News](1995-01-31) Lyons, MorganItem [Southwestern News](1998-04-07) Stieglitz, HeatherItem TRPML1 Promotes Protein Homeostasis in Melanoma Cells by Negatively Regulating MAPK and mTORC1 Signaling(2019-07-08) Kasitinon, Stacy Yuan; DeBerardinis, Ralph J.; Morrison, Sean J.; Mendell, Joshua T.; Vernino, StevenA major goal of studying melanoma is to identify therapeutic vulnerabilities that can be exploited to improve patient treatment. Melanoma cells are particularly sensitive to perturbations in ion homeostasis, especially when ion gradients are perturbed in combination with MAP kinase inhibition. I hypothesized that melanoma cells preferentially require certain ion channels and transporters for growth and survival. I thus screened ion channels and transporters throughout the genome to identify those required by human melanoma cells but not by normal human melanocytes. I discovered that Mucolipin-1 (MCOLN1), which encodes the lysosomal cation channel TRPML1, is preferentially required for the survival and proliferation of melanoma cells. Loss of MCOLN1/TRPML1 function impaired the growth of patient-derived melanomas in culture and in xenografts but did not affect the growth of human melanocytes. TRPML1 expression was elevated in melanoma cells relative to melanocytes and was required in melanoma cells to negatively regulate MAPK pathway and mTORC1 signaling. TRPML1-deficient melanoma cells exhibited decreased survival, proliferation, tumor growth, and macropinocytosis as well as serine depletion and proteotoxic stress. All of these phenotypes were partially or completely rescued by mTORC1 inhibition. Melanoma cells thus increase TRPML1 expression relative to melanocytes to attenuate MAPK and mTORC1 signaling. This helps melanoma cells prevent overactivation of these oncogenic signaling pathways, sustain macropinocytosis and avoid proteotoxic stress. Further investigation of the role of TRPML1 in melanoma may ultimately guide future patient therapies and contribute to our understanding of ion channels and transporters in cancer.