Peripheral blood MФ–cancer cell fusion hybrids identified in cancer patients correlate with disease stage and overall survival.

Given the implications of tumor dynamics for precision medicine, there is a need to systematically characterize the mode of evolution across diverse solid tumor types. In particular, methods to infer the role of natural selection within established human tumors are lacking. By simulating spatial tumor growth under different evolutionary modes and examining patterns of between-region subclonal genetic divergence from multi-region sequencing (MRS) data, we demonstrate that it is feasible to distinguish tumors driven by strong positive subclonal selection from those evolving neutrally or under weak selection, as the latter fail to dramatically alter subclonal composition. We developed a classifier based on measures of between-region subclonal genetic divergence and projected patient data into model space, revealing different modes of evolution both within and between solid tumor types. Our findings have broad implications for how human tumors progress, accumulate intra-tumor heterogeneity, and ultimately how they may be more effectively treated.

Pneumocystis is a fungal genus that contains multiple species. One member of the genus that has not been formally analysed for its phylogenetic relationships and possible species status is the Pneumocystis found in laboratory mice, Pneumocystis murina sp. nov. (type strain ATCC PRA-111 T =CBS 114898 T ), formerly known as Pneumocystis carinii f. sp. muris. To advance research in this area, approximately 3000 bp of additional DNA sequence were obtained from the locus encoding rRNAs. This sequence and others were used to determine genetic distances between P. murina and other members of the genus. These distances indicated that P. murina DNA is most similar to that of the species of Pneumocystis found in laboratory rats. Nevertheless, P. murina is at least as diverged from these other Pneumocystis species as species in other fungal genera are from each other. The 18S rRNA gene sequence divergence exhibited by P. murina could not be ascribed to accelerated evolution of this gene as similar levels of divergence were observed at seven other loci. When five genes were used to construct phylogenetic trees for five Pneumocystis taxa, including P. murina, all the trees had the same topology, indicating that genes do not flow among these taxa. The gene trees were all strongly supported by statistical tests. When sequences from the rRNA-encoding locus were used to estimate the time of divergence of P. murina, the results indicated that P. murina is as old as the mouse. Taken together, these data support previous recognition of multiple species in the genus and indicate that P. murina is a phylogenetic species as well.

Metastatic progression defines the final stages of tumor evolution and underlies the majority of cancer-related deaths. The heterogeneity in disseminated tumor cell populations capable of seeding and growing in distant organ sites contributes to the development of treatment resistant disease. We recently reported the identification of a novel tumor-derived cell population, circulating hybrid cells (CHCs), harboring attributes from both macrophages and neoplastic cells, including functional characteristics important to metastatic spread. These disseminated hybrids outnumber conventionally defined circulating tumor cells (CTCs) in cancer patients. It is unknown if CHCs represent a generalized cancer mechanism for cell dissemination, or if this population is relevant to the metastatic cascade. Herein, we detect CHCs in the peripheral blood of patients with cancer in myriad disease sites encompassing epithelial and non-epithelial malignancies. Further, we demonstrate that in vivo-derived hybrid cells harbor tumor-initiating capacity in murine cancer models and that CHCs from human breast cancer patients express stem cell antigens, features consistent with the potential to seed and grow at metastatic sites. Finally, we reveal heterogeneity of CHC phenotypes reflect key tumor features, including oncogenic mutations and functional protein expression. Importantly, this novel population of disseminated neoplastic cells opens a new area in cancer biology and renewed opportunity for battling metastatic disease.