Flexibility in the exchange of genetic material takes place between different organisms of the same or different species. This phenomenon is known to play a key role in the genetic, physiological, and ecological performance of the host. Exchange of genetic materials can cause both beneficial and/or adverse biological consequences. Horizontal gene transfer (HGT) or lateral gene transfer (LGT) as a general mechanism leads to biodiversity and biological innovations in nature. HGT mediators are one of the genetic engineering tools used for selective introduction of desired changes in the genome for gene/cell therapy purposes. HGT, however, is crucial in development, emergence, and recurrence of various human-related diseases, such as cancer, genetic-, metabolic-, and neurodegenerative disorders and can negatively affect the therapeutic outcome by promoting resistant forms or disrupting the performance of genome editing toolkits. Because of the importance of HGT and its vital physio- and pathological roles, here the variety of HGT mechanisms are reviewed, ranging from extracellular vesicles (EVs) and nanotubes in prokaryotes to cell-free DNA and apoptotic bodies in eukaryotes. Next, we argue that HGT plays a role both in the development of useful features and in pathological states associated with emerging and recurrent forms of the disease. A better understanding of the different HGT mediators and their genome-altering effects/potentials may pave the way for the development of more effective therapeutic and diagnostic regimes.

Tumor dormancy, a clinically undetectable state of cancer, makes a major contribution to the development of multidrug resistance (MDR), minimum residual disease (MRD), tumor outgrowth, cancer relapse, and metastasis. Despite its high incidence, the whole picture of dormancy-regulated molecular programs is far from clear. That is, it is unknown when and which dormant cells will resume proliferation causing late relapse, and which will remain asymptomatic and harmless to their hosts. Thus, identification of dormancy-related culprits and understanding their roles can help predict cancer prognosis and may increase the probability of timely therapeutic intervention for the desired outcome. Here, we provide a comprehensive review of the dormancy-dictated molecular mechanisms, including angiogenic switch, immune escape, cancer stem cells, extracellular matrix (ECM) remodeling, metabolic reprogramming, miRNAs, epigenetic modifications, and stress-induced p38 signaling pathways. Further, we analyze the possibility of leveraging these dormancy-related molecular cues to outmaneuver cancer and discuss the implications of such approaches in cancer treatment.

STAT5B is often mutated in hematopoietic malignancies. The most frequent STAT5B mutation, Asp642His (N642H), has been found in over 90 leukemia and lymphoma patients. Here, we used the Vav1 promoter to generate transgenic mouse models that expressed either human STAT5B or STAT5B^N642H in the hematopoietic compartment. While STAT5B-expressing mice lacked a hematopoietic phenotype, the STAT5B^N642H-expressing mice rapidly developed T cell neoplasms. Neoplasia manifested as transplantable CD8⁺ lymphoma or leukemia, indicating that the STAT5B^N642H mutation drives cancer development. Persistent and enhanced levels of STAT5B^N642H tyrosine phosphorylation in transformed CD8⁺ T cells led to profound changes in gene expression that were accompanied by alterations in DNA methylation at potential histone methyltransferase EZH2-binding sites. Aurora kinase genes were enriched in STAT5B^N642H-expressing CD8⁺ T cells, which were exquisitely sensitive to JAK and Aurora kinase inhibitors. Together, our data suggest that JAK and Aurora kinase inhibitors should be further explored as potential therapeutics for lymphoma and leukemia patients with the STAT5B^N642H mutation who respond poorly to conventional chemotherapy.

Induction of thrombosis in tumor vasculature represents an appealing strategy for combating cancer. Herein, we combined unique intrinsic coagulation properties of staphylocoagulase with new acquired functional potentials introduced by genetic engineering, to generate a novel bi-functional fusion protein consisting of truncated coagulase (tCoa) bearing an RGD motif on its C-terminus for cancer therapy. We demonstrated that free coagulase failed to elicit any significant thrombotic activity. Conversely, RGD delivery of coagulase retained coagulase activity and afforded favorable interaction of fusion proteins with prothrombin and α_vβ₃ endothelial cell receptors, as verified by in silico, in vitro, and in vivo experiments. Although free coagulase elicited robust coagulase activity in vitro, only targeted coagulase (tCoa-RGD) was capable of producing extensive thrombosis, and subsequent infarction and massive necrosis of CT26 mouse colon, 4T1 mouse mammary and SKOV3 human ovarian tumors in mice. Additionally, systemic injections of lower doses of tCoa-RGD produced striking tumor growth inhibition of CT26, 4T1 and SKOV3 solid tumors in animals. Altogether, the nontoxic nature, unique shortcut mechanism, minimal effective dose, wide therapeutic window, efficient induction of thrombosis, local effects and susceptibility of human blood to coagulase suggest tCoa-RGD fusion proteins as a novel and promising anticancer therapy for human trials.