Paper Reading
01
Francisco Sanchez-Vega, Marco Mina, Joshua Armenia, Walid K. Chatila, Augustin Luna, et al.
Cell.2018;173:321–337.
Cancer is a disease in which cells have acquired the ability to divide and grow uncontrollably, usually through genetic alterations in specific genes. An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights the significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), the authors analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFb signaling, p53 and b-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. This pathway landscape in The Cancer Genome Atlas is meant to provide a valuable resource for clinical oncologists, for cancer researchers and for a broad scientific community interested in cancer precision medicine.
https://doi.org/10.1016/j.cell.2018.03.035
02
TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion
Omar Khan, Josephine R. Giles, Sierra McDonald, Sasikanth Manne, Shin Foong Ngiow, et al.
Nature. 2019;571(7764):211-218.
Exhausted CD8 + T cells (TEX) in chronic infections and cancer have limited effector function, high inhibitory receptor co-expression and extensive transcriptional changes compared to the effector (T EFF) or memory (T MEM) CD8 + T cells. T EX are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T EX are a distinct immune subset, with a unique chromatin landscape compared to T EFF and T MEM. However, the mechanisms governing the transcriptional and epigenetic development of T EX remain unknown. Here, the authors identified the HMG-box transcription factor TOX as a central regulator of T EX. TOX is largely dispensable for T EFF and T MEM formation but is critical for exhaustion and without TOX T EX do not form. TOX is induced by calcineurin and NFAT2 and operates in a feed-forward loop to become calcineurin independent and sustained in T EX. Thus, robust TOX expression results in commitment to T EX by translating persistent stimulation into a distinct T EX transcriptional and epigenetic developmental program.
https://doi.org/10.1016/j.cmet.2019.06.014
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