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197


Targeting EZH2 in acral lentiginous melanoma (ALM) [Meeting Abstract]

Izsak, A; Giles, K M; Lui, K P; Weiss, S A; Moran, U; De, Miera E V -S; Stein, J; Lee, A Y; Darvishian, F; Shapiro, R L; Berman, R S; Pavlick, A C; Wilson, M; Osman, I
Background: Efforts to identify targeted therapies that can improve treatment outcome in metastatic ALM have been unsuccessful. In a previous genomic screening, we identified copy number amplification of the histone methyltransferase EZH2 in 47% of ALM cases, a higher frequency than previously reported in cutaneous melanomas (CM) (5%). Here, we tested the hypothesis that increased EZH2 expression contributes to ALM progression and may confer selective sensitivity to EZH2 inhibition. Methods: EZH2 expression was examined by immunohistochemistry (IHC) in 51 primary (21 stage I, 13 Stage II and 17 Stage III) and 23 metastatic (11 in transit, 8 nodal and 4 visceral) ALM cases with extensive clinicopathological data and protocol-driven follow up. Colony formation and cell proliferation was assessed following treatment of ALM and CM cell lines with three EZH2 inhibitors, including GSK126, currently in clinical trials. The effect of GSK126 on H3K27me3 and downstream EZH2 targets was analyzed by western blotting. Results: EZH2 is commonly overexpressed in both primary (30/51; 65%) and metastatic (20/23; 87%) ALM cases, with a significant increase in mean IHC score between primary and metastatic tumors (1.9 vs. 2.7, respectively, p = 0.047). EZH2 expression increased in 6/10 metastatic ALM tumors compared to their matched primary tumors. ALM tumors with EZH2 gene amplification showed increased EZH2 protein expression; however more cases showed overexpression with no amplification suggesting a potential epigenetic component of EZH2 regulation. GSK126 significantly suppressed ALM colony formation at lower doses compared to CM (1 muM vs. 5 muM, respectively). EZH2 inhibition also increased expression of the downstream tumor suppressor E-cadherin in ALM but not in CM cell lines. Finally, ALM cell lines had significantly lower basal H3K27me3 levels than CM cell lines, suggesting an additional, histone methyltransferase-independent function of EZH2 in ALM. Conclusions: Our data demonstrate thatEZH2 upregulation is common in ALM, and suggest that it may play a role in ALM's metastatic progression that requires further investigation. Selective sensitivity of ALM cell lines to EZH2 inhibitors supports the therapeutic potential of EZH2-targeted therapy in ALM
EMBASE:617436089
ISSN: 0732-183x
CID: 2650982

A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis

Agrawal, Praveen; Fontanals-Cirera, Barbara; Sokolova, Elena; Jacob, Samson; Vaiana, Christopher A; Argibay, Diana; Davalos, Veronica; McDermott, Meagan; Nayak, Shruti; Darvishian, Farbod; Castillo, Mireia; Ueberheide, Beatrix; Osman, Iman; Fenyo, David; Mahal, Lara K; Hernando, Eva
Association of aberrant glycosylation with melanoma progression is based mainly on analyses of cell lines. Here we present a systems-based study of glycomic changes and corresponding enzymes associated with melanoma metastasis in patient samples. Upregulation of core fucosylation (FUT8) and downregulation of alpha-1,2 fucosylation (FUT1, FUT2) were identified as features of metastatic melanoma. Using both in vitro and in vivo studies, we demonstrate FUT8 is a driver of melanoma metastasis which, when silenced, suppresses invasion and tumor dissemination. Glycoprotein targets of FUT8 were enriched in cell migration proteins including the adhesion molecule L1CAM. Core fucosylation impacted L1CAM cleavage and the ability of L1CAM to support melanoma invasion. FUT8 and its targets represent therapeutic targets in melanoma metastasis.
PMCID:5649440
PMID: 28609658
ISSN: 1878-3686
CID: 2593662

Multifocal Invasive Ductal Cancer: Distinguishing Independent Tumor Foci From Multiple Satellites

Alexander, Melissa; Acosta Gonzalez, Gabriel; Malerba, Stefano; Hochman, Tsivia; Goldberg, Judith D; Darvishian, Farbod
Patients with multifocal breast cancers (MBCs) have a poorer prognosis than patients with unifocal breast cancers. Studies have attributed this to tumor size underestimation in MBC. An alternative hypothesis is that some MBCs behave in a fashion analogous to the "satellite" and "in-transit metastasis" observed in melanoma and, thereby, are more clinically aggressive. We identified 79 cases of MBC, which we classified into 2 groups: study cases defined as >/=2 morphologically similar tumor foci with >/=1 focus without in situ carcinoma (n = 21); and a control group defined as >/=2 morphologically similar or dissimilar foci with associated in situ carcinoma in all foci (n = 58). The odds of being a study case is 1.86 (95% confidence interval [CI] 1.26-2.74) times greater per unit increase in number of tumor foci (median of 4 tumor foci; P = .002). Study cases were 73.33 (95% CI = 8.91-603.16) times more likely to have lymphovascular invasion (LVI) and 14.72 (95% CI = 4.37-49.61) times more likely to have nodal metastases. Grade I/II tumors were 0.20 (95% CI = 0.07-0.59) times less likely to be study cases. There was a significant positive interaction (P < 0.001) indicated by the relationship of LVI status and nodal status with the study case and control group. We conclude that there is a subset of MBC that presents with more numerous tumor foci and a higher rate of nodal metastasis. The aggressive behavior of these cases may be attributed to their proclivity for LVI.
PMID: 27831532
ISSN: 1940-2465
CID: 2304462

Corrigendum to "Immunologic heterogeneity of tumor-infiltrating lymphocyte composition in primary melanoma" (Hum Pathol 2016;57:116-25) [Correction]

Weiss, Sarah A; Han, Sung Won; Lui, Kevin; Tchack, Jeremy; Shapiro, Richard; Berman, Russell; Zhong, Judy; Krogsgaard, Michelle; Osman, Iman; Darvishian, Farbod
PMID: 28449825
ISSN: 1532-8392
CID: 2544212

MicroRNA-125a promotes resistance to BRAF inhibitors through suppression of the intrinsic apoptotic pathway

Koetz-Ploch, Lisa; Hanniford, Douglas; Dolgalev, Igor; Sokolova, Elena; Zhong, Judy; Diaz-Martinez, Marta; Bernstein, Emily; Darvishian, Farbod; Flaherty, Keith T; Chapman, Paul B; Tawbi, Hussein; Hernando, Eva
Melanoma patients with BRAFV600E -mutant tumors display striking responses to BRAF inhibitors (BRAFi); however, almost all invariably relapse with drug-resistant disease. Here we report that microRNA-125a (miR-125a) expression is upregulated in human melanoma cells and patient tissues upon acquisition of BRAFi resistance. We show that miR-125a induction confers resistance to BRAFV600E melanoma cells to BRAFi by directly suppressing pro-apoptotic components of the intrinsic apoptosis pathway, including BAK1 and MLK3. Apoptotic suppression and prolonged survival favor reactivation of the MAPK and AKT pathways by drug-resistant melanoma cells. We demonstrate that miR-125a inhibition suppresses the emergence of resistance to BRAFi and, in a subset of resistant melanoma cell lines, leads to partial drug re-sensitization. Finally, we show that miR-125a upregulation is mediated by TGFbeta signaling. In conclusion, the identification of this novel role for miR-125a in BRAFi resistance exposes clinically relevant mechanisms of melanoma cell survival that can be exploited therapeutically
PMCID:5411293
PMID: 28140520
ISSN: 1755-148x
CID: 2425092

Whole Transcriptome Analysis Identifies Upregulated Genes and Pathways Differentially Expressed in Ductal Carcinoma In Situ Mimicking Usual Ductal Hyperplasia [Meeting Abstract]

Zeng, Jennifer; Serrano, Jonathan; Snuderl, Matija; Darvishian, Farbod
ISI:000393724400306
ISSN: 1530-0307
CID: 2506592

Live Digital Telepathology Enables Rapid Remote Frozen Section Diagnosis and Cytology Adequacy Assessment by Subspecialists [Meeting Abstract]

Kane, Yehonatan; Darvishian, Farbod; Deng, Fang-Ming; Moreira, Andre L; Simsir, Aylin; William, Christopher; Snuderl, Matija
ISI:000394467302170
ISSN: 1530-0285
CID: 2517622

Live Digital Telepathology Enables Rapid Remote Frozen Section Diagnosis and Cytology Adequacy Assessment by Subspecialists [Meeting Abstract]

Kane, Yehonatan; Darvishian, Farbod; Deng, Fang-Ming; Moreira, Andre L; Simsir, Aylin; William, Christopher; Snuderl, Matija
ISI:000393724402076
ISSN: 1530-0307
CID: 2506802

Biomarker Profile Before and After Neoadjuvant Chemotherapy [Meeting Abstract]

Zeng, Jennifer; Hernandez, Andrea; Darvishian, Farbod
ISI:000394467300307
ISSN: 1530-0285
CID: 2517422

Biomarker Profile Before and After Neoadjuvant Chemotherapy [Meeting Abstract]

Zeng, Jennifer; Hernandez, Andrea; Darvishian, Farbod
ISI:000393724400307
ISSN: 1530-0307
CID: 2506602