Proteomic analysis of CSF from patients with leptomeningeal melanoma metastases identifies signatures associated with disease progression and therapeutic resistance.

Publication date: Jan 10, 2020

The development of leptomeningeal melanoma metastases (LMM) is a rare and devastating complication of the late-stage disease, for which no effective treatments exist. Here, we performed a multi-omics analysis of the CSF from LMM patients to determine how the leptomeningeal microenvironment shapes the biology and therapeutic responses of melanoma cells.

A total of 45 serial CSF samples were collected from 16 patients, 8 of these with confirmed LMM. Of those with LMM, 7 had poor survival (35 months). CSF samples were analyzed by mass spectrometry and incubated with melanoma cells, that were subjected to RNA-Seq analysis. Functional assays were performed to validate the pathways identified.

Mass spectrometry analyses showed the CSF of most LMM patients to be enriched for pathways involved in innate immunity, protease-mediated damage, and IGF-related signaling. All of these were anti-correlated in the extraordinary responder. RNA-Seq analysis showed CSF to induce PI3K/AKT, integrin, B-cell activation, S-phase entry, TNFR2, TGF-band oxidative stress responses in the melanoma cells. ELISA assays confirmed that TGF-bexpression increased in the CSF of patients progressing with LMM. CSF from poorly responding patients conferred tolerance to BRAF inhibitor therapy in apoptosis assays.

These analyses identified proteomic/transcriptional signatures in the CSF of patients who succumbed to LMM. We further showed that the CSF from LMM patients has the potential to modulate BRAF inhibitor responses and may contribute to drug resistance.

, Smalley, , Law, Wyatt, C., Evernden, B., Fang, B., Koomen, J.M., Welsh, E.A., Macaulay, R.J.B., Forsyth, P.A., and Smalley, K.S.M. Proteomic analysis of CSF from patients with leptomeningeal melanoma metastases identifies signatures associated with disease progression and therapeutic resistance. 25435. 2020 Clin Cancer Res.

Concepts Keywords
AKT Apoptosis
Apoptosis Metastasis
B Cell BRAF
BRAF Inhibitor RTT
Drug Resistance Melanoma
ELISA Health
Innate Immunity Oncology
Integrin Cancer
Leptomeningeal Medicine
Mass Spectrometry Therapeutic melanoma
Melanoma Stage disease
Metastases Melanoma
Microenvironment
Omics
Oxidative Stress
PI3K
Protease
Proteomic
RNA
S Phase

Semantics

Type Source Name
disease MESH melanoma
pathway KEGG Melanoma
disease MESH metastases
disease MESH disease progression
disease MESH development
disease MESH multi
drug DRUGBANK Albendazole
disease MESH oxidative stress
pathway KEGG Apoptosis

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