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Open access publications by faculty, postdocs, and graduate students in the Department of Biological Sciences
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- ItemThe v8-10 variant isoform of CD44 is selectively expressed in the normal human colonic stem cell niche and frequently is overexpressed in colon carcinomas during tumor development(Cancer Biology & Therapy, 2023-04-02) Boman, Bruce M.; Viswanathan, Vignesh; Faceya, Caroline O. B.; Fields, Jeremy Z.; Stave, James W.CD44 protein and its variant isoforms are expressed in cancer stem cells (CSCs), and various CD44 isoforms can have different functional roles in cells. Our goal was to investigate how different CD44 isoforms contribute to the emergence of stem cell (SC) overpopulation that drives colorectal cancer (CRC) development. Specific CD44 variant isoforms are selectively expressed in normal colonic SCs and become overexpressed in CRCs during tumor development. We created a unique panel of anti-CD44 rabbit genomic antibodies to 16 specific epitopes that span the entire length of the CD44 molecule. Our panel was used to comprehensively investigate the expression of different CD44 isoforms in matched pairs (n = 10) of malignant colonic tissue and adjacent normal mucosa, using two (IHC & IF) immunostaining approaches. We found that: i) CD44v8–10 is selectively expressed in the normal human colonic SC niche; ii) CD44v8–10 is co-expressed with the SC markers ALDH1 and LGR5 in normal and malignant colon tissues; iii) colon carcinoma tissues frequently (80%) stain for CD44v8–10 while staining for CD44v6 was less frequent (40%). Given that CD44v8–10 expression is restricted to cells in the normal human colonic SC niche and CD44v8–10 expression progressively increases during CRC development, CD44v8–10 expression likely contributes to the SC overpopulation that drives the development and growth of colon cancers. Since the CD44 variant v8–10 epitope is located on CD44’s extracellular region, it offers great promise for targeted anti-CSC treatment approaches.
- ItemDynamic bioinspired coculture model for probing ER+ breast cancer dormancy in the bone marrow niche(Science Advances, 2023-03-08) Pradhan, Lina; Moore, DeVonte; Ovadia, Elisa M.; Swedzinski, Samantha L.; Cossette, Travis; Sikes, Robert A.; van Golen, Kenneth; Kloxin, April M.Late recurrences of breast cancer are hypothesized to arise from disseminated tumor cells (DTCs) that reactivate after dormancy and occur most frequently with estrogen receptor–positive (ER+) breast cancer cells (BCCs) in bone marrow (BM). Interactions between the BM niche and BCCs are thought to play a pivotal role in recurrence, and relevant model systems are needed for mechanistic insights and improved treatments. We examined dormant DTCs in vivo and observed DTCs near bone lining cells and exhibiting autophagy. To study underlying cell-cell interactions, we established a well-defined, bioinspired dynamic indirect coculture model of ER+ BCCs with BM niche cells, human mesenchymal stem cells (hMSCs) and fetal osteoblasts (hFOBs). hMSCs promoted BCC growth, whereas hFOBs promoted dormancy and autophagy, regulated in part by tumor necrosis factor–α and monocyte chemoattractant protein 1 receptor signaling. This dormancy was reversible by dynamically changing the microenvironment or inhibiting autophagy, presenting further opportunities for mechanistic and targeting studies to prevent late recurrence.
- ItemLimiting Mrs2-dependent mitochondrial Mg2+ uptake induces metabolic programming in prolonged dietary stress(Cell Reports, 2023-03-28) Madaris, Travis R.; Venkatesan, Manigandan; Maity, Soumya; Stein, Miriam C.; Vishnu, Neelanjan; Venkateswaran, Mridula K.; Davis, James G.; Ramachandran, Karthik; Uthayabalan, Sukanthathulse; Allen, Cristel; Osidele, Ayodeji; Stanley, Kristen; Bigham, Nicholas P.; Bakewell, Terry M.; Narkunan, Melanie; Le, Amy; Karanam, Varsha; Li, Kang; Mhapankar, Aum; Norton, Luke; Ross, Jean; Aslam, M. Imran; Reeves, W. Brian; Singh, Brij B.; Caplan, Jeffrey; Wilson, Justin J.; Stathopulos, Peter B.; Baur, Joseph A.; Madesh, MuniswamyHighlights: • Mitochondrial Mg2+ channel Mrs2 rheostats MCU Ca2+ signals to maintain bioenergetic circuit • DNL precursor and cellular Mg2+ chelator citrate curbs HIF1α signal and oxidative metabolism • Lowering mMg2+ mitigates prolonged dietary-stress-induced obesity and metabolic syndrome • Mrs2 channel blocker CPACC reduces lipid accumulation and promotes browning and weight loss Summary The most abundant cellular divalent cations, Mg2+ (mM) and Ca2+ (nM-μM), antagonistically regulate divergent metabolic pathways with several orders of magnitude affinity preference, but the physiological significance of this competition remains elusive. In mice consuming a Western diet, genetic ablation of the mitochondrial Mg2+ channel Mrs2 prevents weight gain, enhances mitochondrial activity, decreases fat accumulation in the liver, and causes prominent browning of white adipose. Mrs2 deficiency restrains citrate efflux from the mitochondria, making it unavailable to support de novo lipogenesis. As citrate is an endogenous Mg2+ chelator, this may represent an adaptive response to a perceived deficit of the cation. Transcriptional profiling of liver and white adipose reveals higher expression of genes involved in glycolysis, β-oxidation, thermogenesis, and HIF-1α-targets, in Mrs2−/− mice that are further enhanced under Western-diet-associated metabolic stress. Thus, lowering mMg2+ promotes metabolism and dampens diet-induced obesity and metabolic syndrome. Graphical abstract Available at: https://doi.org/10.1016/j.celrep.2023.112155
- ItemRNA localization to the mitotic spindle is essential for early development and is regulated by kinesin-1 and dynein(Journal of Cell Science, 2023-03-06) Remsburg, Carolyn M.; Konrad, Kalin D.; Song, Jia L.Mitosis is a fundamental and highly regulated process that acts to faithfully segregate chromosomes into two identical daughter cells. Localization of gene transcripts involved in mitosis to the mitotic spindle might be an evolutionarily conserved mechanism to ensure that mitosis occurs in a timely manner. We identified many RNA transcripts that encode proteins involved in mitosis localized at the mitotic spindles in dividing sea urchin embryos and mammalian cells. Disruption of microtubule polymerization, kinesin-1 or dynein results in lack of spindle localization of these transcripts in the sea urchin embryo. Furthermore, results indicate that the cytoplasmic polyadenylation element (CPE) within the 3′UTR of the Aurora B transcript, a recognition sequence for CPEB, is essential for RNA localization to the mitotic spindle in the sea urchin embryo. Blocking this sequence results in arrested development during early cleavage stages, suggesting that RNA localization to the mitotic spindle might be a regulatory mechanism of cell division that is important for early development.
- ItemLens Epithelial Explants Treated with Vitreous Humor Undergo Alterations in Chromatin Landscape with Concurrent Activation of Genes Associated with Fiber Cell Differentiation and Innate Immune Response(Cells, 2023-02-03) Upreti, Anil; Padula, Stephanie L.; Tangeman, Jared A.; Wagner, Brad D.; O’Connell, Michael J.; Jaquish, Tycho J.; Palko, Raye K.; Mantz, Courtney J.; Anand, Deepti; Lovicu, Frank J.; Lachke, Salil A.; Robinson, Michael L.Lens epithelial explants are comprised of lens epithelial cells cultured in vitro on their native basement membrane, the lens capsule. Biologists have used lens epithelial explants to study many different cellular processes including lens fiber cell differentiation. In these studies, fiber differentiation is typically measured by cellular elongation and the expression of a few proteins characteristically expressed by lens fiber cells in situ. Chromatin and RNA was collected from lens epithelial explants cultured in either un-supplemented media or media containing 50% bovine vitreous humor for one or five days. Chromatin for ATAC-sequencing and RNA for RNA-sequencing was prepared from explants to assess regions of accessible chromatin and to quantitatively measure gene expression, respectively. Vitreous humor increased chromatin accessibility in promoter regions of genes associated with fiber differentiation and, surprisingly, an immune response, and this was associated with increased transcript levels for these genes. In contrast, vitreous had little effect on the accessibility of the genes highly expressed in the lens epithelium despite dramatic reductions in their mRNA transcripts. An unbiased analysis of differentially accessible regions revealed an enrichment of cis-regulatory motifs for RUNX, SOX and TEAD transcription factors that may drive differential gene expression in response to vitreous.