humanized mouse and cancer

Growing evidence demonstrates the key role of the gut microbiota in human health and disease. The recent success of microbiotherapy products to treat recurrent Clostridioides difficile infection has shed light on its potential in conditions associated with gut dysbiosis, such as acute graft-versus-host disease, intestinal bowel diseases, neurodegenerative diseases, or even cancer. However, the difficulty in defining a "good" donor as well as the intrinsic variability of donor-derived products' taxonomic composition limits the translatability and reproducibility of these studies...

Ploidy is relevant to numerous biological phenomena, including development, metabolism, and tissue regeneration. Single-cell RNA-seq and other omics studies are revolutionizing our understanding of biology, yet they have largely overlooked ploidy. This is likely due to the additional assay step required for ploidy measurement. Here, we developed a statistical method to infer ploidy from single-cell ATAC-seq data, addressing this gap. When applied to data from human and mouse cell atlases, our method enabled systematic detection of polyploidy across diverse cell types...

Cancer drug testing in animals is an extremely poor predictor of the drug's safety and efficacy observed in humans. Hence there is a pressing need for functional testing platforms that better predict traditional and immunotherapy responses in human, live tumor tissue or tissue constructs, and at the same time are compatible with the use of mouse tumor tissue to facilitate building more accurate disease models. Since many cancer drug actions rely on mechanisms that depend on the tumor microenvironment (TME), such platforms should also retain as much of the native TME as possible...

BACKGROUND: Osteosarcoma is a diverse and aggressive bone tumor. Driver genes regulating osteosarcoma initiation and progression remains incompletely defined. Zinc finger protein 692 (ZNF692), a kind of Krüppel C2H2 zinc finger transcription factor, exhibited abnormal expression in different types of malignancies and showed a correlation with the clinical prognosis of patients as well as the aggressive characteristics of cancer cells. Nevertheless, its specific role in osteosarcoma is still not well understood...

Our skin provides a physical and immunological barrier against dehydration and environmental insults ranging from microbial attacks, toxins and UV irradiation to wounding. Proper functioning of the skin barrier largely depends on the interplay between keratinocytes- the epithelial cells of the skin- and immune cells. Two spatially distinct populations of keratinocyte stem cells (SCs) maintain the epidermal barrier function and the hair follicle. These SCs are inherently long-lived, but cell death can occur within their niches and impacts their functionality...

Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT)...

We recently reported that resistance to PD-1-blockade in a refractory lung cancer-derived model involved increased collagen deposition and the collagen-binding inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), and thus we hypothesized that LAIR1 and collagen cooperated to suppress therapeutic response. Here, we report LAIR1 is associated with tumor stroma and is highly expressed by intratumoral myeloid cells in both human tumors and mouse models of cancer. Stroma-associated myeloid cells exhibit a suppressive phenotype and correlate with LAIR1 expression in human cancer...

PURPOSE: One of the main reasons for prostate cancer (PCa) recurrence is the difficulty in identifying and removing cancerous lesions during surgery. Accurately localizing and excising cancerous tissue remains a significant challenge. The second near-infrared window (NIR-II, 1000-1700 nm) fluorescence offers enhanced resolution, a high signal-to-noise ratio, and the potential for deeper tissue penetration. However, this technology is not currently employed for intraoperative imaging of PCa...

PURPOSE: It has long been thought that the carcinogenic effect of radiation resulted from the induction of oncogenic mutations which then led to an increase in the proportion of cancer-bearing individuals. However, even as early as the 1960s, there were indications that the carcinogenic effect of radiation might result from the induction of an earlier onset of cancer. Recently, the former notion was challenged by its inability to explain time-dependent decline of the relative risk following an exposure to radiation, and a parallel shift of mouse survival curves toward younger ages following an exposure to radiation...

L1 elements are retrotransposons currently active in mammals. Although L1s are typically silenced in most normal tissues, elevated L1 expression is associated with a variety of conditions, including cancer, aging, infertility and neurological disease. These associations have raised interest in the mapping of human endogenous de novo L1 insertions, and a variety of methods have been developed for this purpose. Adapting these methods to mouse genomes would allow us to monitor endogenous in vivo L1 activity in controlled, experimental conditions using mouse disease models...

Rationale: In recent years, nicotinamide adenine dinucleotide (NAD+ ) precursors (Npre) have been widely employed to ameliorate female reproductive problems in both humans and animal models. However, whether and how Npre plays a role in the male reproductive disorder has not been fully clarified. Methods: In the present study, a busulfan-induced non-obstructive azoospermic mouse model was used, and Npre was administered for five weeks following the drug injection, with the objective of reinstating spermatogenesis and fertility...

In this study, we tested a novel approach of "repurposing" a biomarker typically associated with breast cancer for use in melanoma. HER2/neu is a well characterized biomarker in breast cancer for which effective anti-HER2/neu therapies are readily available. We constructed a lentivirus encoding c-erb-B2 (the animal homolog to HER2/neu). This was used to transfect B16 melanoma in vitro for use in an orthotopic preclinical mouse model, which resulted in expression of c-erb-B2 as a neoantigen target for anti-c-erb-B2 monoclonal antibody (7...

Lineage plasticity is a recognized hallmark of cancer progression that can shape therapy outcomes. The underlying cellular and molecular mechanisms mediating lineage plasticity remain poorly understood. Here, we describe a versatile in vivo platform to identify and interrogate the molecular determinants of neuroendocrine lineage transformation at different stages of prostate cancer progression. Adenocarcinomas reliably develop following orthotopic transplantation of primary mouse prostate organoids acutely engineered with human-relevant driver alterations (e...

Transcriptional profiling has become a common tool for investigating the nervous system. During analysis, differential expression results are often compared to functional ontology databases, which contain curated gene sets representing well-studied pathways. This dependence can cause neuroscience studies to be interpreted in terms of functional pathways documented in better studied tissues ( e . g ., liver) and topics ( e . g ., cancer), and systematically emphasizes well-studied genes, leaving other findings in the obscurity of the brain "ignorome"...

BACKGROUND: Nuclear mitotic apparatus protein 1 (NuMA1) is a cell cycle protein and upregulated in breast cancer. However, the role of NuMA1 in TNBC and its regulation in heterogenous populations remains elusive. METHODS: We performed CRISPR mediated deletion of NuMA1 in mouse TNBC cells, BF3M. FACS was utilized to isolate BCSCs, and bulk cells based on CD29 and CD61 markers. Cell viability, migration, and invasion ability of BCSCs and bulk cells was evaluated using MTT, wound healing and transwell invasion assays, respectively...

DNA methylation at cytosine bases of eukaryotic DNA (5-methylcytosine, 5mC) is a heritable epigenetic mark that can regulate gene expression in health and disease. Enzymes that metabolize 5mC have been well-characterized, yet the discovery of endogenously produced signaling molecules that regulate DNA methyl-modifying machinery have not been described. Herein, we report that the free radical signaling molecule nitric oxide (NO) can directly inhibit the Fe(II)/2-OG-dependent DNA demethylases ten-eleven translocation (TET) and human AlkB homolog 2 (ALKBH2)...

UNLABELLED: Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)--a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival...

Triple-negative breast cancer (TNBC) is thought to be an estradiol-independent, hormone therapy-resistant cancer because of lack of estrogen receptor alpha 66 (ERα66). We identified a membrane-bound splice variant, ERα36, in TNBC cells that responds to estrogen (E2 ) and may contribute to bone osteolysis. We demonstrated that the MDA-MB-231 TNBC cell line, which expresses ERα36 similarly to MCF7 cells, is responsive to E2 , forming osteolytic tumors in vivo. MDA-MB-231 cells activate osteoclasts in a paracrine manner...

Lynch syndrome (LS) is the most prevalent heritable form of colorectal cancer (CRC). Its early onset and high lifetime risk for CRC emphasize the necessity for effective chemoprevention. NFE2L2 (NRF2) is often considered a potential druggable target, and many chemopreventive compounds do induce NRF2. However, while NRF2 counteracts oxidative stress, it is also overexpressed in CRC and may promote tumorigenesis. Herein, we evaluated the role of NRF2 in prevention of LS-associated neoplasia. We found an increased levels of NRF2 in intestinal epithelia of mice with intestinal epithelial-specific Msh2 deletion (MSH2ΔIEC) as compared to C57BL/6 (wild type) mice, as well as an increase in downstream NRF2 targets Nqo1 and Gclc...

BACKGROUND: Mitochondrial dysfunction is a critical factor in the pathogenesis of acute kidney injury (AKI). Agents that ameliorate mitochondrial dysfunction hold potential for AKI treatment. The objective of this study was to investigate the impact of olesoxime, a novel mitochondrial-targeted agent, on cisplatin-induced AKI. METHODS: In vivo, a cisplatin-induced AKI mouse model was established by administering a single intraperitoneal dose of cisplatin (25 mg/kg) to male C57BL/6 mice for 72 hours, followed by gavage of either olesoxime or a control solution...