What happens in the early, still undetectable human malignancy is unknown because direct observations are impractical. Here we present and validate a “Big Bang” model, whereby tumors grow predominantly as a single expansion producing numerous intermixed sub-clones that are not subject to stringent selection, and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors revealed the absence of selective sweeps, uniformly high intra-tumor heterogeneity (ITH), and sub-clone mixing in distant regions, as postulated by our model. We also verified the prediction that most detectable ITH originates from early private alterations, and not from later clonal expansions, thus exposing the profile of the primordial tumor. Moreover, some tumors appear born-to-be-bad, with sub-clone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH with significant clinical implications.

Knowledge about the impact of different geographical environments on rhesus macaque gut microbiota is limited. In this study, we compared the characteristics of gut microbiota in six different Chinese rhesus macaque populations, including Hainan, Nanning, Guizhou, Xichang, Jianchuan and Tibet. Through the composition analysis of operational taxonomic units (OTUs), we found that there were significant differences in the abundance of core overlapping OTUs in the six Chinese groups. Specifically, the Tibet population exhibited the highest gut microbial diversity and the most unique OTUs. Statistically significant differences in the composition of gut microbiota among the six groups at phylum and family level were evident. Specifically, Tibet had higher abundances of Firmicutes and lower abundances of Bacteroidetes than the other geographical groups, and the higher abundance of Firmicutes in the Tibetan group was mainly caused by a significant increase in the family Ruminococcaceae and Christensenellaceae. Phylogenetic investigation of communities by reconstruction of unobserved state analysis showed that the enrichment ratio for environmental information processing and organismal systems was the highest in the Tibet population. Additionally, our results suggested that in the adaptation process of rhesus macaques to different geographical environments, the abundance of the core common flora of the intestinal microbes had undergone varying degree of change and produced new and unique flora, both of which helped to reshape the gut microbiota of rhesus macaques. In particular, this change was more obvious for animals in the high-altitude environments.

Alternative polyadenylation (APA) is an important post-transcriptional regulatory mechanism and involved in many diseases, including cancer. CFIm25, a subunit of the cleavage factor I encoded by NUDT21, is required for 3'RNA cleavage and polyadenylation. Although it has been recently reported to be involved in glioblastoma tumor suppression, its roles and the underlying functional mechanism remain unclear in other types of cancer. In this study, we characterized NUDT21 in hepatocellular carcinoma (HCC). Reduced expression of NUDT21 was observed in HCC tissue compared to adjacent non-tumorous compartment. HCC patients with lower NUDT21 expression have shorter overall and disease-free survival times than those with higher NUDT21 expression after surgery. Knockdown of NUDT21 promotes HCC cell proliferation, metastasis, and tumorigenesis, whereas forced expression of NUDT21 exhibits the opposite effects. We then performed global APA site profiling analysis in HCC cells and identified considerable number of genes with shortened 3'UTRs upon the modulation of NUDT21 expression. In particular, we further characterized the NUDT21-regulated genes PSMB2 and CXXC5. We found NUDT21 knockdown increases usage of the proximal polyadenylation site in the PSMB2 and CXXC5 3' UTRs, resulting in marked increase in the expression of PSMB2 and CXXC5. Moreover, knockdown of PSMB2 or CXXC5 suppresses HCC cell proliferation and invasion. Taken together, our study demonstrated that NUDT21 inhibits HCC proliferation, metastasis and tumorigenesis, at least in part, by suppressing PSMB2 and CXXC5, and thereby provided a new insight into understanding the connection of HCC suppression and APA machinery.

Intratumoral mutational heterogeneity (ITH) or the presence of different private mutations in different parts of the same tumor is commonly observed in human tumors. The mechanisms generating such ITH are uncertain. Here we find ITH can be remarkably well-structured by measuring point mutations, chromosome copy numbers and DNA passenger methylation from opposite sides and individual glands of a 6 cm human colorectal adenoma. ITH was present between tumor sides and individual glands, but the private mutations were side specific and subdivided the adenoma into two major subclones. Furthermore, ITH disappeared within individual glands because the glands were clonal populations composed of cells with identical mutant genotypes. Despite mutation clonality, the glands were relatively old, diverse populations when their individual cells were compared for passenger methylation and by FISH. These observations can be organized into an expanding star-like ancestral tree with co-clonal expansion, where many private mutations and multiple related clones arise during the first few divisions. As a consequence, most detectable mutational ITH in the final tumor originates from the first few divisions. Much of the early history of a tumor, especially the first few divisions, may be embedded within the detectable ITH of tumor genomes.

Background: Artemin is a cancer stem cell (CSC) and metastatic factor in mammary carcinoma. Results: Artemin promotes trastuzumab resistance by enhancing the cancer stem cell-like population in mammary carcinoma. Conclusion: Artemin mediates acquired resistance to trastuzumab in mammary carcinoma. Significance: Functional antagonism of Artemin may enhance trastuzumab sensitivity and reverse acquired resistance to trastuzumab in mammary carcinoma.