Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer

Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry, we reveal a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC tumors (LS-SCLCs). Compared to localized non-small cell lung cancers, LS-SCLCs have similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Furthermore, copy number loss of IFN-γ pathway genes is frequently observed and positively correlates with CNA burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression are associated with longer overall survival (OS), while higher CNA burden is associated with shorter OS in patients with LS-SCLC

PRMT6-dependent CRAF/ERK signaling regulates cancer stem cell plasticity in liver cancer

Hepatocellular carcinoma (HCC), the major type of liver cancer, remains one of the most prevalent and deadliest cancer types in the world. Contemporary challenge in treating HCC has been the common therapy resistance and recurrence after therapy, all of which have been reported to be associated with stemlike behavior of cancer cells. Our group has previously identified a functional liver cancer stem cell (CSC) subset marked by the CD133 cell surface phenotype. Utilizing a PCR array encompassing diverse human chromatin modifiers, protein arginine methyltransferase 6 (PRMT6) was found to be differentially down regulated in CD133+ liver CSCs of human HCC cells as well as CD133 enriched chemoresistant hepatospheres as compared to their counterparts. Clinically, reduced PRMT6 expression was detected in HCC specimens and correlated with a higher risk of metastasis. PRMT6 negatively regulated diverse in vitro cancer stem cell properties of HCC cells including self-renewal, therapy resistance, metastasis and expression of CSC and pluripotency markers. In addition, PRMT6 also suppressed in vivo tumor initiation and serial transplantation. Surprising, contrary to its usual localization in the nucleus as a chromatin modification enzyme mediating histone H3R2 methylation, we found PRMT6 to be predominantly expressed in the cytoplasm in normal liver and HCC cells. Through tandem affinity purification and subsequent mass spectrometry profiling, we identified CRAF, a serine/threonine-protein kinase, as a novel cytoplasmic protein partner of PRMT6. Binding of PRMT6 to CRAF inhibited its kinase activity through site-specific arginine methylation, resulting in inhibition of ERK mediated CSC plasticity in HCC, demonstrated through in vivo / in vitro methylation assays, kinase assay and functional rescue experiments with the ERK inhibitor U0126. The link between PRMT6, ERK and cancer stemness was further substantiated in primary human normal liver and HCC organoids with or without PRMT6 modulated. Taken together, we found PRMT6 to be down-regulated in the liver CSC subset and to be functionally involved in regulating liver CSC plasticity via an unprecedented role in the cytoplasm through suppression of CRAF/ERK cascade

Cell-cell Interaction, Cell Polarity, And The Blood-testis Barrier

The study of polarity and its role in cell–cell interactions, such as spermatid polarity and adhesion in the seminiferous epithelium, and blood–testis barrier (BTB) in the testis during the epithelial cycle of spermatogenesis in recent years has yielded some unexpected and interesting observations. Similar to other polarized tissues, Sertoli and germ cells in the seminiferous epithelium express many of the component proteins of the Par-, Scribble- and Crumb-based polarity protein complexes. These polarity proteins are working in concert with non-receptor protein kinases, adhesion proteins, and cytoskeletons to confer spermatid and Sertoli cell polarity, and these proteins are also involved in germ cell transport in the epithelium during the epithelial cycle. In this review, we summarize the latest findings in the field. Based on the available data in the literature, it is increasingly clear that polarity proteins are crucial in (1) conferring spermatid and Sertoli cell polarity, (2) regulating spermatid adhesion and transport, and (3) regulating BTB dynamics in the testis during the epithelial cycle. We also highlight specific areas of research that deserve attention in future years. This information should be helpful to investigators in other blood–tissue and epithelial barriers in the field