FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4386525293> ?p ?o ?g. }

• W4386525293 endingPage "e006766" @default.
• W4386525293 startingPage "e006766" @default.
• W4386525293 abstract "Background Phenotypic heterogeneity of melanoma cells contributes to drug tolerance, increased metastasis, and immune evasion in patients with progressive disease. Diverse mechanisms have been individually reported to shape extensive intra-tumor and inter-tumor phenotypic heterogeneity, such as IFNγ signaling and proliferative to invasive transition, but how their crosstalk impacts tumor progression remains largely elusive. Methods Here, we integrate dynamical systems modeling with transcriptomic data analysis at bulk and single-cell levels to investigate underlying mechanisms behind phenotypic heterogeneity in melanoma and its impact on adaptation to targeted therapy and immune checkpoint inhibitors. We construct a minimal core regulatory network involving transcription factors implicated in this process and identify the multiple ‘attractors’ in the phenotypic landscape enabled by this network. Our model predictions about synergistic control of PD-L1 by IFNγ signaling and proliferative to invasive transition were validated experimentally in three melanoma cell lines—MALME3, SK-MEL-5 and A375. Results We demonstrate that the emergent dynamics of our regulatory network comprising MITF, SOX10, SOX9, JUN and ZEB1 can recapitulate experimental observations about the co-existence of diverse phenotypes (proliferative, neural crest-like, invasive) and reversible cell-state transitions among them, including in response to targeted therapy and immune checkpoint inhibitors. These phenotypes have varied levels of PD-L1, driving heterogeneity in immunosuppression. This heterogeneity in PD-L1 can be aggravated by combinatorial dynamics of these regulators with IFNγ signaling. Our model predictions about changes in proliferative to invasive transition and PD-L1 levels as melanoma cells evade targeted therapy and immune checkpoint inhibitors were validated in multiple RNA-seq data sets from in vitro and in vivo experiments. Conclusion Our calibrated dynamical model offers a platform to test combinatorial therapies and provide rational avenues for the treatment of metastatic melanoma. This improved understanding of crosstalk among PD-L1 expression, proliferative to invasive transition and IFNγ signaling can be leveraged to improve the clinical management of therapy-resistant and metastatic melanoma." @default.
• W4386525293 created "2023-09-08" @default.
• W4386525293 creator A5003277563 @default.
• W4386525293 creator A5009353114 @default.
• W4386525293 creator A5060463554 @default.
• W4386525293 creator A5062437642 @default.
• W4386525293 creator A5068276877 @default.
• W4386525293 date "2023-09-01" @default.
• W4386525293 modified "2023-10-04" @default.
• W4386525293 title "Dynamical modeling of proliferative-invasive plasticity and IFNγ signaling in melanoma reveals mechanisms of PD-L1 expression heterogeneity" @default.
• W4386525293 cites W1573937008 @default.
• W4386525293 cites W1972648258 @default.
• W4386525293 cites W1989121777 @default.
• W4386525293 cites W2000609012 @default.
• W4386525293 cites W2008118174 @default.
• W4386525293 cites W2008322756 @default.
• W4386525293 cites W2010457001 @default.
• W4386525293 cites W2018433132 @default.
• W4386525293 cites W2022465587 @default.
• W4386525293 cites W2043645272 @default.
• W4386525293 cites W2045565229 @default.
• W4386525293 cites W2052814985 @default.
• W4386525293 cites W2058932070 @default.
• W4386525293 cites W2078370873 @default.
• W4386525293 cites W2086509569 @default.
• W4386525293 cites W2089158037 @default.
• W4386525293 cites W2089415996 @default.
• W4386525293 cites W2096027620 @default.
• W4386525293 cites W2106543129 @default.
• W4386525293 cites W2112182696 @default.
• W4386525293 cites W2127956110 @default.
• W4386525293 cites W2128542677 @default.
• W4386525293 cites W2131488340 @default.
• W4386525293 cites W2134471382 @default.
• W4386525293 cites W2136657690 @default.
• W4386525293 cites W2136731993 @default.
• W4386525293 cites W2163184426 @default.
• W4386525293 cites W2164927488 @default.
• W4386525293 cites W2186855780 @default.
• W4386525293 cites W2253000935 @default.
• W4386525293 cites W2272397535 @default.
• W4386525293 cites W2490924980 @default.
• W4386525293 cites W2586357858 @default.
• W4386525293 cites W2591850802 @default.
• W4386525293 cites W2595182131 @default.
• W4386525293 cites W2600259521 @default.
• W4386525293 cites W2612431515 @default.
• W4386525293 cites W2616922646 @default.
• W4386525293 cites W2617191812 @default.
• W4386525293 cites W2621895366 @default.
• W4386525293 cites W2745109354 @default.
• W4386525293 cites W2767183168 @default.
• W4386525293 cites W2795763614 @default.
• W4386525293 cites W2797906965 @default.
• W4386525293 cites W2805619986 @default.
• W4386525293 cites W2884607428 @default.
• W4386525293 cites W2885507494 @default.
• W4386525293 cites W2898830231 @default.
• W4386525293 cites W2912456393 @default.
• W4386525293 cites W2914009212 @default.
• W4386525293 cites W2944727022 @default.
• W4386525293 cites W2952746001 @default.
• W4386525293 cites W2955029074 @default.
• W4386525293 cites W2964315448 @default.
• W4386525293 cites W2974615129 @default.
• W4386525293 cites W2990997382 @default.
• W4386525293 cites W3014374354 @default.
• W4386525293 cites W3028556187 @default.
• W4386525293 cites W3046906716 @default.
• W4386525293 cites W3080090248 @default.
• W4386525293 cites W3085427829 @default.
• W4386525293 cites W3091934903 @default.
• W4386525293 cites W3104142482 @default.
• W4386525293 cites W3107264782 @default.
• W4386525293 cites W3118950316 @default.
• W4386525293 cites W3130860691 @default.
• W4386525293 cites W3130937819 @default.
• W4386525293 cites W3152113472 @default.
• W4386525293 cites W3158287089 @default.
• W4386525293 cites W3194142756 @default.
• W4386525293 cites W3195032526 @default.
• W4386525293 cites W3200475404 @default.
• W4386525293 cites W3204197816 @default.
• W4386525293 cites W3209494262 @default.
• W4386525293 cites W4214510985 @default.
• W4386525293 cites W4220795887 @default.
• W4386525293 cites W4221099628 @default.
• W4386525293 cites W4296701485 @default.
• W4386525293 cites W4297541642 @default.
• W4386525293 cites W4308300380 @default.
• W4386525293 cites W4309944312 @default.
• W4386525293 cites W4382502030 @default.
• W4386525293 doi "https://doi.org/10.1136/jitc-2023-006766" @default.
• W4386525293 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37678920" @default.
• W4386525293 hasPublicationYear "2023" @default.
• W4386525293 type Work @default.
• W4386525293 citedByCount "1" @default.
• W4386525293 crossrefType "journal-article" @default.

• next