Project description:Melanoma brain metastases (MBM) and leptomeningeal metastases (LMM) are two manifestations of melanoma CNS metastasis with vastly different survival outcomes. Using single cell RNA-Seq analysis we uncovered a unique, immune-suppressed T-cell landscape in the LMM microenvironment distinct from that of brain and skin metastases. An LMM patient with an unusually long survival demonstrated an immune repertoire that was distinct from those of poor survivors and more similar to CSF from non-LMM patients. Upon response to PD-1 therapy, this extreme responder showed increased levels of T-cells and dendritic cells in their CSF, whereas poor survivors showed little improvement in their T-cell responses. In MBM patients, systemic therapy was associated with increased immune infiltrate, with similar T-cell transcriptional diversity noted between skin metastases and MBM - suggestive of immune cell trafficking into the brain. A correlation analysis across the entire immune landscape identified the presence of a rare population of dendritic cells (DC3s) that correlated with increased overall survival and positively regulated the immune environment through modulation of activated T-cells and MHC expression. Our study provides the first atlas of two distinct sites of melanoma CNS metastases and identifies rare populations of cells that underlie the biology of this devastating disease.
Project description:Metastatic dissemination is the most frequent cause of death sporadic colorectal cancer (sCRC) patients. The genomic abnormalities which are potentially characteristic of such advanced stages of the disease are complex and so far, they have been poorly described and only partially understood. We evaluate the molecular heterogeneity of sCRC tumors based on simultaneous assessment of the overall GEP of both coding mRNA and non-coding RNA genes in primary sCRC tumor samples from 23 consecutive patients and their paired liver metastases. Liver metastases from the sCRC patients analyzed, systematically showed deregulated transcripts of those genes identified as also deregulated in their paired primary colorectal carcinomas. However, some transcripts were found to be specifically deregulated in liver metastases while expressed at normal levels in their primary tumors, suggesting an increased genomic instability of neoplastic cells from metastatic versus primary tumor samples. Of note, once tumoral samples were normalized vs. non-tumoral colorectal tissue, only three mRNAS (i.e.: DEFB1, COL12A and PTGER3) and one miRNA (i.e.: miR-572) emerged as significantly deregulated in the liver metastases vs. the primary tumor. Canonical pathways found to be specifically deregulated in liver metastatic samples included multiple genes related with intercellular adhesion and the metastatic processes (e.g., IGF1R, PIK3CA, PTEN and EGFR), endocytosis (e.g., the PDGFRA, SMAD2, ERBB3, PML and FGFR2), and cell cycle (e.g., SMAD2, CCND2, E2F5 and MYC). Our results also highlight the activation of genes associated with the TGFβ signaling pathway, which thereby emerge as candidate genes to play an important role in CRC tumor metastasis.
Project description:Lung adenocarcinoma (LADC) is the most common subtype of non-small cell lung cancer (NSCLC). One major feature of disease progression is the metastatic spread to the central nervous system (CNS). Treatment regimens for brain metastases are limited, thus distant metastases remain the leading cause of tumour-associated deaths globally. The central aim of this paper was to investigate the differences of LADC and brain metastases with reference to fast and slowly progressing patients. Additionally, we elucidated the differences between patients with single versus multiple brain metastases.
