Biology subjects

Ghuwalewala, S.

Publications and source records attributed to Ghuwalewala, S..

5 recordsLinked to original sources

bioRxiv2023

Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma

The distal region of the uterine (Fallopian) tube is commonly associated with high-grade serous carcinoma (HGSC), the predominant and most aggressive form of ovarian or extra-uterine cancer. Specific cell states and lineage dynamics of the adult tubal epithelium (TE) remain insufficiently understood, hindering efforts to determine the cell of origin for HGSC. Here, we report a comprehensive census of cell types and states of the mouse uterine tube. We show that distal TE cells expressing the stem/progenitor cell marker Slc1a3 can differentiate into both secretory (Ovgp1+) and ciliated (Fam183b+) cells. Inactivation of Trp53 and Rb1, whose pathways are commonly altered in HGSC, leads to elimination of targeted Slc1a3+ cells by apoptosis, thereby preventing their malignant transformation. In contrast, pre-ciliated cells (Krt5+, Prom1+, Trp73+) remain cancer-prone and give rise to serous tubal intraepithelial carcinomas and overt HGSC. These findings identify transitional pre-ciliated cells as a previously unrecognized cancer-prone cell state and point to pre-ciliation mechanisms as novel diagnostic and therapeutic targets.

cancer biology↗

bioRxiv2023

Single-cell transcriptomics of adult skin VE-cadherin expressing lineages during hair cycle

Adult skin homeostasis involves global reorganization of dermal lineages at different stages of the mouse hair growth cycle. Vascular endothelial cadherin (VE-cadherin encoded by Cdh5) expressing cells from blood and lymphatic vasculature structures are known to remodel during the adult hair cycle. Here we employ single-cell RNA-sequencing (scRNA-seq) 10x-genomics analysis of FACS-sorted VE-cadherin expressing cells marked via Cdh5-CreER genetic labeling at resting (telogen) and growth (anagen) stage of hair cycle. Our comparative analysis between the two stages uncovers a persistent Ki67+ proliferative EC population and documents changes in EC population distribution and gene expression. Global gene expression changes in all the analyzed populations revealed bioenergetic metabolic changes that may drive vascular remodeling during HF growth phase, alongside a few highly restricted cluster-specific gene expression differences. This study uncovers active cellular and molecular dynamics of adult skin endothelial lineages during hair cycle that may have broad implications in adult tissue regeneration and for understanding vascular disease.

cell biology↗

bioRxiv2022

Transit-amplifying progenitor with maturation-dependent behavior contributes to epidermal renewal

Transit-amplifying progenitor populations with phased behavior have long been postulated as essential to epidermal renewal, but not experimentally observed in vivo. Here we identify a population with bi-phasic behavior using CreER genetic cell-marking in mice for long-term lineage tracing and clonal analysis. Nascent, highly expressing Aspm cells undergo an amplification-phase followed by a timed transition into an extinction-phase, with near complete loss of descending cells from skin. Generalized birth-death modeling of Aspm-CreER and a Dlx1-CreER population that behaves like a stem cell demonstrates neutral competition for both populations, but neutral drift only for the stem cells. This work identifies a long-missing class of non-self-renewing epidermal progenitors with bi-phasic behavior that appears time-dependent as the lineage matures, indicative of a transit-amplifying cell. This has broad implications for understanding cell fate decisions and tissue renewal mechanisms. One-sentence summaryWe identify a long-missing class of non-self-renewing epidermal progenitors with bi-phasic and maturation-dependent behavior in vivo.

developmental biology↗

bioRxiv2022

Epidermal basal domains organization highlights skin robustness to environmental exposure

Adult interfollicular epidermis (IFE) renewal is likely orchestrated by physiological demands of its complex tissue architecture comprising spatial and cellular heterogeneity. Mouse tail and back skin display two kinds of basal IFE spatial domains that regenerate at different rates. Here we elucidate the molecular and cellular states of basal IFE domains by marker expression and single cell transcriptomics in mouse and human skin. We uncover two paths of basal cell differentiation that reflect in part the IFE spatial domain organization. We unravel previously unrecognized similarities between mouse tail IFE basal domains defined as scales and interscales versus human rete ridges and inter-ridges, respectively. Second, our basal IFE transcriptomics and gene targeting in mice provide evidence supporting a physiological role of IFE domains: adaptation to differential UV exposure. We identify Sox6 as a novel UV-induced and interscale/inter-ridge basal IFE-domain transcription factor, important for IFE proliferation and survival. The spatial, cellular, and molecular organization of IFE basal domains underscores skin adaptation to environmental exposure and its unusual robustness in adult homeostasis. Synopsis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/481662v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1565ee8org.highwire.dtl.DTLVardef@170f3e1org.highwire.dtl.DTLVardef@9b67adorg.highwire.dtl.DTLVardef@b3ba40_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2018

MiR-146a-dependent regulation of CD24/AKT/β-catenin axis drives stem cell phenotype in oral cancer

Cancer stem cells (CSCs) are known to potentiate tumor initiation and maintenance in Oral Squamous Cell Carcinoma (OSCC). Increasing evidences suggest that CD44highCD24low population in OSCC are potential CSCs. MicroRNAs (miRNAs) have emerged as crucial players in tumor development. However, their role in maintenance of OSCC stem cells remains unclear. Here we report that CD44highCD24low population within OSCC cells and primary HNSCC tumors have an elevated expression of miR-146a. Moreover, over-expression of miR-146a results in enhanced stemness phenotype by augmenting CD44highCD24low population. We demonstrate that miR-146a induces stemness by stabilizing {beta}-catenin with concomitant loss of E-cadherin and CD24. Interestingly, CD24 is identified as a novel functional target of miR-146a and ectopic expression of CD24 abrogates miR-146a driven potential CSC phenotype. Mechanistic analysis reveals that higher CD24 levels inhibit AKT phosphorylation leading to {beta}-catenin degradation. Using stably expressing miR-146a/CD24 OSCC cell lines, we also validate that the miR-146a/ CD24/AKT loop significantly alters tumorigenic ability in vivo. Furthermore, we confirmed that {beta}-catenin trans-activates miR-146a, thereby forming a positive feedback loop contributing to stem cell maintenance. Collectively, our study demonstrates that miR-146a regulate CSCs in OSCC through CD24-AKT-{beta}-catenin axis.\n\nHighlightsO_LIMiR-146a induces cancer stem cell characteristics in OSCC by targeting CD24\nC_LIO_LICD24 abrogates miR-146a mediated stemness via {beta}-catenin degradation in non-CSCs\nC_LIO_LIAkt/Wnt pathway is critical for sustenance of miR-146a driven potential CSCs\nC_LIO_LIThe miR-146a/CD24/AKT loop significantly alters tumorigenic ability in vivo\nC_LI

cancer biology↗