| 1. |
- Wu, Jing, et al.
(författare)
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Interleukin-33 is a Novel Immunosuppressor that Protects Cancer Cells from TIL Killing by a Macrophage-Mediated Shedding Mechanism
- 2021
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Ingår i: Advanced Science. - : Wiley. - 2198-3844. ; 8:21
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Tidskriftsartikel (refereegranskat)abstract
- Recognition of specific antigens expressed in cancer cells is the initial process of cytolytic T cell-mediated cancer killing. However, this process can be affected by other non-cancerous cellular components in the tumor microenvironment. Here, it is shown that interleukin-33 (IL-33)-activated macrophages protect melanoma cells from tumor-infiltrating lymphocyte-mediated killing. Mechanistically, IL-33 markedly upregulates metalloprotease 9 (MMP-9) expression in macrophages, which acts as a sheddase to trim NKG2D, an activating receptor expressed on the surface of natural killer (NK) cells, CD8+ T cells, subsets of CD4+ T cells, iNKT cells, and gamma delta T cells. Further, MMP-9 also cleaves the MHC class I molecule, cell surface antigen-presenting complex molecules, expressed in melanoma cells. Consequently, IL-33-induced macrophage MMP-9 robustly mitigates the tumor killing-effect by T cells. Genetic and pharmacological loss-of-function of MMP-9 sheddase restore T cell-mediated cancer killing. Together, these data provide compelling in vitro and in vivo evidence showing novel mechanisms underlying the IL-33-macrophage-MMP-9 axis-mediated immune tolerance against cancer cells. Targeting each of these signaling components, including IL-33 and MMP-9 provides a new therapeutic paradigm for improving anticancer efficacy by immune therapy.
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| 2. |
- Yang, Muyi, et al.
(författare)
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Novel loss-of-function variant in DENND5A impedes melanosomal cargo transport and predisposes to familial cutaneous melanoma
- 2022
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Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600 .- 1530-0366. ; 24:1, s. 157-169
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: More than half of the familial cutaneous melanomas have unknown genetic predisposition. This study aims at characterizing a novel melanoma susceptibility gene. Methods: We performed exome and targeted sequencing in melanoma-prone families without any known melanoma susceptibility genes. We analyzed the expression of candidate gene DENND5A in melanoma samples in relation to pigmentation and UV signature. Functional studies were carried out using microscopic approaches and zebrafish model. Results: We identified a novel DENND5A truncating variant that segregated with melanoma in a Swedish family and 2 additional rare DENND5A variants, 1 of which segregated with the disease in an American family. We found that DENND5A is significantly enriched in pigmented melanoma tissue. Our functional studies show that loss of DENND5A function leads to decrease in melanin content in vitro and pigmentation defects in vivo. Mechanistically, harboring the truncating variant or being suppressed leads to DENND5A losing its interaction with SNX1 and its ability to transport the SNX1-associated vesicles from melanosomes. Consequently, untethered SNX1-premelanosome protein and redundant tyrosinase are redirected to lysosomal degradation by default, causing decrease in melanin content. Conclusion: Our findings provide evidence of a physiological role of DENND5A in the skin context and link its variants to melanoma susceptibility.
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| 3. |
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| 4. |
- Tuominen, Rainer, et al.
(författare)
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The Role of Germline Alterations in the DNA Damage Response Genes BRIP1 and BRCA2 in Melanoma Susceptibility
- 2016
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley-Blackwell. - 1045-2257 .- 1098-2264. ; 55:7, s. 601-611
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Tidskriftsartikel (refereegranskat)abstract
- We applied a targeted sequencing approach to identify germline mutations conferring a moderately to highly increased risk of cutaneous and uveal melanoma. Ninety-two high-risk melanoma patients were screened for inherited variation in 120 melanoma candidate genes. Observed gene variants were filtered based on frequency in reference populations, cosegregation with melanoma in families and predicted functional effect. Several novel or rare genetic variants in genes involved in DNA damage response, cell-cycle regulation and transcriptional control were identified in melanoma patients. Among identified genetic alterations was an extremely rare variant (minor allele frequency of 0.00008) in the BRIP1 gene that was found to cosegregate with the melanoma phenotype. We also found a rare nonsense variant in the BRCA2 gene (rs11571833), previously associated with cancer susceptibility but not with melanoma, which showed weak association with melanoma susceptibility in the Swedish population. Our results add to the growing knowledge about genetic factors associated with melanoma susceptibility and also emphasize the role of DNA damage response as an important factor in melanoma etiology.
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| 5. |
- Yang, Muyi
(författare)
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Molecular biomarkers in melanoma susceptibility and therapy response
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Melanoma accounts for the majority of the mortality from all types of skin cancers. Five to ten percent of the cases are familial melanoma, yet more than 50% of the melanoma families cannot be explained by established susceptibility genes. By understanding the genetics behind unexplained families may shed lights on melanoma etiology and in turn provide these susceptible individuals with opportunities of more precise medical care. Over the last decade, treatment options for melanoma patients have expanded with the introduction of targeted therapies and immunotherapies. For the melanoma patients with advanced disease whose tumors harbor BRAF mutations, targeted therapy (TT) of BRAF-inhibitors (BRAFi) in combination with MEK-inhibitors have shown promising results with improved clinical outcome. However, acquired resistance is common among these patients. Immunotherapy with immune checkpoint inhibitors (ICIs) have also been proven successful in melanoma. Yet a subset of patients shows intrinsic or acquired resistance and benefits little from ICIs. There is an urgent need of predictive biomarkers to identify patients who will benefit from a durable response to TT or ICIs. In this thesis, we first describe a targeted sequencing project in which we performed massive parallel sequencing of a selected 120 genes in the germline DNA of 92 melanoma patients with family history or multiple primary melanomas. We reported a rare nonsense variant in BRCA2 and showed moderately increased risk for melanoma according to our case-control analysis. Moreover, we identified another rare variant in the BRIP1gene that segregated with the disease in one family, but the variant did not seem to alter the expression or subcellular location of BRIP protein. In paper II, we genotyped the MC1R gene for 103 melanoma patients receiving ICIs and compared the characteristics and prognosis of those carrying ≥1 R alleles and those not. Our data showed that patients with ≥1 R alleles had more favorable progression free survival (PFS) after ICIs, but no significant difference in overall survival (OS). Multivariate analyses suggested that the superior PFS in “≥1 R alleles” group was attributed to more than the previously anticipated R allele-associated pigmentation phenotype. This study was the first to assess the impact of germline MC1R variants on the efficacy of ICIs in melanoma. In paper III, we performed whole-exome sequencing on multiple cases from a melanoma-prone family and identified a germline, heterozygous, frameshift variant in DENND5A gene. We were able to report two additional rare variants in two separate melanoma-prone families segregating with the disease. Our follow-up functional study discovered that DENND5A was enriched in pigmented tissue. Impaired DENND5A function led to mis-trafficking of melanosomal cargo protein and thereafter reduction of melanin content in vitro and in zebrafish. Altogether, paper III uncovered a novel biological function of DENND5A in melanoma and linked its loss-of-function variant to melanoma susceptibility. In paper IV, we revisited our previously published quantitative proteome profiling on vemurafenib-induced BRAFi-resistant subline A375VR4 and its parental A375 cell line, and identified the down-regulation of RAB7B in A375VR4. We showed that silencing of RAB7B in A375 cells led to reduced sensitivity towards BRAFi in 3D spheroids and to enhanced cell motility in vitro and in zebrafish. We performed RAB7B-immunoprecipitated mass spectrometry (IP-MS) and identified tyrosine kinase SRC as a novel effector of RAB7B. Silencing RAB7B in A375 spheroids led to up-regulated kinase activity reflected by increase of phospho-SRC (Tyr416), which might have contributed to the BRAFi resistance and enhanced cell motility.
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