bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.03.17.484800

Dietary Induced Dynamic Plasticity of Intestinal Stem Cells and the Mucosa in Elevating Risk for Tumor Development

Choi, J.·Zhang, X.·Li, W.·Houston, M.·Peregrina, K.·Dubin, R.·Ye, K.·Augenlicht, L.
View original source ↗Export metadata ↓

Abstract

NWD1, a purified rodent diet establishing mouse exposure to key nutrients recapitulating levels that increase risk for intestinal cancer, reproducibly causes sporadic intestinal and colonic tumors in the mouse, reflecting human etiology, incidence, frequency and lag with developmental age. Complex NWD1 reprogramming of stem cells and lineages was deconvolved by bulk and scRNAseq, scATACseq, functional genomics and imaging. NWD1 extensively, rapidly, and reversibly reprogrammed Lgr5hi stem cells, epigenetically down-regulating Ppargc1a expression, altering mitochondrial structure and function. This suppressed Lgr5hi stem cell functions and developmental maturation of Lgr5hi cell progeny as cells progressed through progenitor cell compartments, recapitulated by Ppargc1a genetic inactivation in Lgr5hi cells in vivo. Mobilized Bmi1+, Ascl2hi cells adapted lineages to the nutritional environment and elevated antigen processing and presentation pathways, especially in mature enterocytes, causing chronic, pro-tumorigenic low-level inflammation. There were multiple parallels between NWD1 remodeling of stem cells and lineages with pathogenic mechanisms in human inflammatory bowel disease, also pro-tumorigenic. Moreover, the shift to alternate stem cells reflects that the balance between Lg5 positive and negative stem cells in supporting human colon tumors is determined by environmental influences. Stem cell and lineage plasticity in response to nutrients supports historic concepts of homeostasis as a continual adaptation to environment, with the human mucosa likely in constant flux in response to changing nutrient exposures. Thus, although oncogenic mutations provide a competitive advantage to intestinal epithelial cells in clonal expansion, the competition is on a playing field dynamically sculpted by the nutritional environment, influencing which cells dominate in mucosal maintenance and tumorigenesis.

Source connections

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Choi, J., Zhang, X., Li, W., Houston, M., Peregrina, K., Dubin, R., Ye, K., Augenlicht, L.. 2022-03-19. Dietary Induced Dynamic Plasticity of Intestinal Stem Cells and the Mucosa in Elevating Risk for Tumor Development. https://doi.org/10.1101/2022.03.17.484800

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Glycolysis and interferon transcription in melanoma immunotherapy

Glycolysis and interferon signalling have both been associated with responses to PD-1 blockade, but their joint transcriptional relationship with treatment outcome remains uncertain. We examined whether a state with high glycolysis and low interferon- response was associated with reduced disease control in melanoma. Fixed Hallmark gene sets were scored by single-sample gene set enrichment analysis in GSE91061, GSE78220 and an additional Liu cohort. Disease control analyses included 47, 26 and 100 patients. Conditional odds ratios for the joint state were 6.06 (exact 95% confidence interval, 1.04 to 65.61), 0.35 (0.026 to 3.11) and 1.03 (0.39 to 2.73), respectively. Holm-adjusted P values for the two initial comparisons were 0.073 and 0.365. The additional exploratory P value was 1.000. Continuous models and analyses that omitted each patient in turn did not provide consistent evidence of an adverse association. IFN scores were negatively correlated with DNA-derived tumour purity in 102 patients (Spearman {rho} = -0.671). Among 40 patients with paired biopsies, disease control was associated with higher on-treatment IFN scores after baseline adjustment, although the paired subset had lower baseline glycolysis than patients without paired profiles. In patient-level single-cell analyses, the baseline CD8 T cell correlation weakened when an alternative rank score used a common gene background. The defined joint state was not consistently associated with poorer disease control across cohorts. Bulk IFN scores were related to tumour purity, and cellular correlations were sensitive to scoring choices. These transcriptomic results do not measure pyruvate concentration, glycolytic flux or STAT1 pyruvylation.

cancer biology↗
bioRxiv2026

Psychoneuroimmunology of Viral Hepatitis and Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Hepatocellular carcinoma (HCC) and viral hepatitis (VH) are recognized primarily as hepatic diseases, yet they impose a substantial neuropsychiatric disorders (NPDs) encompassing depression, anxiety, cognitive impairment, and fatigue. Whether these manifestations reflect psychological reactions or biologically grounded psychoneuroimmune dysfunction remains poorly understood. Here, we present a pre-registered systematic review and meta-analysis (PROSPERO 2026 CRD420251081757) synthesizing evidence from 24 studies combining psychosocial outcomes with immune dysregulation markers across HCC and VH populations. Bibliometric and network analyses identified a growing psychoneuroimmunology research hub linking cytokine signaling, microglial activation, blood-brain barrier (BBB) disruption, and gut-liver-brain axis dysregulation to the neuropsychiatric phenotype of these diseases. Meta-analysis revealed a pooled hazard ratio (HR) of 1.92 (95% CI: 1.09-3.39) for adverse outcomes in HCC and a pooled HR of 2.28 (95% CI: 1.48-3.52) for depression associated to genetic variants in VH. TNF-a, but not IL-6, showed a tendency toward lower levels in VH patients with versus without NPDs, suggesting differential inflammatory roles. The literature, however, remains fragmented by heterogeneous designs and a paucity of longitudinal data. A psychoneuroimmunological approach, integrating immune, endocrine, neural, and psychosocial dimensions, is essential for capturing the full systemic impact of HCC and VH and should inform future mechanistic research and multidisciplinary clinical strategies.

cancer biology↗
bioRxiv2026

Nutrient Availability as a Driver of Transcriptome Reprogramming in Osteosarcoma

Background: Gene expression in mammalian cells is intricately regulated by environmental and metabolic cues. Among these, nutrient availability represents a key feature of the tumor microenvironment and has recently emerged as a potent modulator of oncogenic signaling networks. In this study, we employed a cell-line model of osteosarcoma, a rare but highly aggressive bone malignancy affecting both humans and dogs. We demonstrate that altering the concentration of a single nutrient can profoundly reprogram gene expression in osteosarcoma cells, revealing a previously underexplored phenomenon: nutrient-dependent gene regulation. This finding highlights potential opportunities for therapeutic intervention and underscores the broader implications of metabolic regulation for personalized medicine and nutrition. Methods/Results: We performed bulk RNA sequencing of an established osteosarcoma cell line cultured under varying concentrations of two key nutrients, glucose and glutamine. Differential gene expression analysis revealed a pronounced nutrient-dependent transcriptional response. The identified genes were functionally associated with pathways involved in cancer, development, nervous system regulation, metabolism, cellular signaling, and immune responses. We identified seven distinct expression patterns, one of which exhibited a striking correlation with cell growth rate and resembled a FOS-like transcriptional signature. Notably, the proto-oncogene FOS was among the identified genes and displayed a strong growth-rate-dependent expression pattern. Conclusion/Impact: Our findings demonstrate that modulation of nutrient availability profoundly reshapes the gene expression landscape of osteosarcoma cells, revealing nutrient-responsive targets with potential therapeutic relevance. This work expands our understanding of metabolic regulation in cancer and suggests that nutrient-based interventions may provide a controllable means of influencing tumor progression. Beyond oncology, such approaches may also have broader implications for developmental biology, autoimmune disorders, and nervous system function. More broadly, this study highlights the potential of metabolic interventions as a strategy for targeted modulation of gene expression programs.

cancer biology↗