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Ahtiainen, M.

Publications and source records attributed to Ahtiainen, M..

2 recordsLinked to original sources
bioRxiv2022

Pan-cancer scale screening reveals NRF2 associated immunoevasive characteristics in non-small cell lung cancer and squamous malignancies

The NRF2 pathway is frequently activated in various cancer types, yet a comprehensive analysis of its effects across different malignancies is currently lacking. We developed a robust NRF2 activity metric and utilized it to conduct a pan-cancer wide analysis of oncogenic NRF2 signaling. We identified a distinct immunoevasive phenotype where high NRF2 activity is associated with low interferon-gamma (IFN{gamma}), HLA-I expression and T-cell infiltration spanning non-small cell lung cancer (NSCLC) and squamous malignancies of head and neck area, cervix and esophagus. In squamous cell cancers, NRF2 overactive tumors comprise a molecular phenotype with SOX2/TP63 amplification, TP53 mutation and CDKN2A loss. These immune-cold NRF2 hyperactive diseases are associated with upregulation of immunomodulatory NAMPT, WNT5A, SPP1, SLC7A11 and SLC2A1 that represent candidate NRF2 target genes, suggesting direct modulation of the tumor immune milieu. Based on single-cell mRNA data, coupled with a priori information on intercellular ligand-receptor interactions, cancer cells of this subtype exhibit decreased expression of IFN{gamma} responsive ligands, and increased expression of immunosuppressive ligands NAMPT, SPP1 and WNT5A that mediate signaling in intercellular crosstalk. As we observed differential cytokine mRNA expression with IFN{gamma} treatment in NSCLC adenocarcinoma subtype, we explored the cytokine secretome in vitro. We found that secreted neutrophil chemoattractants interleukin-8 (CXCL8) and ENA-78 (CXCL5) are elevated in NRF2 overactive cells, suggesting contribution of immunosuppressive neutrophils in NRF2 driven immune escape. Importantly, as overactive NRF2 is associated with immune-cold characteristics, our results highlight the utility of NRF2 pathway activation as a putative biomarker for stratifying immune-checkpoint blockade responders and non-responders across NSCLC and squamous cancers. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/489654v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@1f45782org.highwire.dtl.DTLVardef@9d40d0org.highwire.dtl.DTLVardef@a31a5org.highwire.dtl.DTLVardef@1418220_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗
bioRxiv2022

Systemic circulating microRNA landscape in Lynch syndrome

MicroRNAs (miRs) are non-coding RNA-molecules that regulate gene expression. Global circulating miR (c-miR) expression patterns (c-miRnome) change with carcinogenesis in various sporadic cancers. Therefore, aberrantly expressed c-miRs could have diagnostic, predictive and prognostic potential in molecular profiling of cancers. c-miR functions in carriers of inherited pathogenic mismatch-repair gene variants (path_MMR), also known as Lynch syndrome (LS), have remained understudied. LS cohort provides an ideal population for biomarker mining due to increased lifelong cancer risk and excessive cancer occurrence. Using high-throughput sequencing and bioinformatic approaches, we conducted an exploratory analysis to characterize systemic c-miRnomes of path_MMR carriers. Our discovery cohort included 81 healthy path_MMR carriers and 37 non-LS controls. Our analysis also included cancer cohort comprised of 13 path_MMR carriers with varying cancers and 24 sporadic rectal cancer patients. We showed for the first time that c-miRnome can discern healthy path_MMR carriers from non-LS controls but does not distinguish healthy path_MMR carriers from cancer patients with or without path_MMR. Our c-miR expression analysis combined with in silico tools suggest ongoing alterations of biological pathways shared in LS and sporadic carcinogenesis. We observed that these alterations can produce a c-miR signature which can be used to track oncogenic stress in cancer-free path_MMR carriers. Thus, c-miRs hold potential in monitoring which cancer patients would require more intensive surveillance or clinical management. SignificanceC-miRnome can discern between healthy persons with or without path_MMR but does not distinguish healthy path_MMR carriers from cancer patients with or without path_MMR, indicating an ongoing alteration of biological pathways that can be used to track oncogenic stress at cancer-free state.

cancer biology↗