Biology subjects

Kalthur, G.

Publications and source records attributed to Kalthur, G..

4 recordsLinked to original sources

bioRxiv2025

A Rare Multipotent Peg-like Epithelial Cell is a Candidate Cell-of-Origin for High-Grade Serous Ovarian Cancer

To illuminate the origins of high-grade serous ovarian cancer (HGSOC), the most lethal and common form of ovarian cancer, we have created a comprehensive living organoid biobank of human fallopian tube tissue, which is thought to be the origin of this cancer. Through optimized culture protocols and integrated multi-omic profiling--including single-cell RNA sequencing, chromatin accessibility (ATAC) analysis, proteomics, and secretomics--we assembled the largest molecular atlas of the fallopian tube epithelium to date. This resource revealed diverse epithelial lineages and regulatory networks, including a rare, multipotent epithelial subpopulation with hybrid epithelial-mesenchymal features. Spatially localized to the basal epithelium and resembling mesonephric developmental precursors, these cells exhibit transcriptomic and proteomic similarities to the mesenchyme-like subtype of HGSOC, implicating them as potential cells-of-origin. Their molecular identity is preserved in organoid models, enabling future mechanistic and translational studies. This resource, which advances fundamental understanding of epithelial hierarchy and cancer susceptibility, provides a platform to inform early detection and prevention strategies for aggressive forms of ovarian cancer. HighlightsO_LIEstablishment of a clinically annotated fallopian tube organoid biobank enables delineation of epithelial lineage hierarchies and differentiation capacity. C_LIO_LIMulti-omics integration defines robust, lineage-specific transcriptional and regulatory networks in the fallopian tube epithelium. C_LIO_LIA rare basal epithelial subpopulation with mesenchymal features aligns with a mesenchyme-like subtype of high-grade serous ovarian cancer. C_LIO_LIRare basal peg cells exhibit fetal mesonephric developmental transcriptional programs and are maintained ex-vivo in fallopian tube organoids. C_LI

cancer biology↗

bioRxiv2025

Receptor Tyrosine Kinase Profiling Identifies Chronic Constitutive Floodgate Oxidative Signaling in Glutathione-Independent Human Mammary Luminal Progenitor Cells

The human mammary epithelium contains a subset of luminal progenitor (LP) cells that are distinct from basal cells in both lineage potential and redox biology. LPs are uniquely equipped to tolerate oxidative stress through glutathione-independent mechanisms and have been implicated as candidate cells of origin in basal-like breast cancers. In this study, we identify the receptor tyrosine kinase (RTK) cKIT (CD117), as a defining feature of LPs and a key mediator of their expansion. cKIT is developmentally restricted to the LP compartment via Polycomb-mediated epigenetic repression in basal and luminal-committed cells. It is expressed in scattered epithelial cells within both ductal and alveolar regions of resting human mammary glands. Using RTK-engineered MCF10A models, we demonstrate that cKIT ligand/stem cell factor (SCF)-activated wildtype cKIT signaling is sufficient to drive proliferation in the absence of epidermal growth factor (EGF) and that cKIT is responsive not only to canonical ligands but also to hydrogen peroxide (H2O2). In primary human LPs, cKIT is rapidly phosphorylated upon exposure to SCF and H2O2, with concomitant AKT activation. These responses are enhanced when cKIT and EGFR signaling are co-engaged, suggesting a cooperative mitogenic program. In mammary gland, phosphorylation of the antioxidant enzyme PRDX1 is selectively detected in LPs, consistent with a floodgate model of redox signaling in which transient oxidative inactivation of peroxiredoxins (PRDXs) facilitates RTK signaling under elevated intracellular reactive oxygen species conditions. Clinically, elevated cKIT expression is associated with shorter progression-free survival in certain basal-like breast cancer, supporting a link between LP-like redox signaling states and aggressive tumor behavior. Together, these findings define a redox-integrated RTK signaling axis centered on cKIT that drives LP expansion and is associated with poor outcomes in a subset of basal breast cancers. This work establishes a mechanistic framework for targeting redox-responsive progenitor populations in both regenerative and oncologic context.

cancer biology↗

bioRxiv2024

Haploid Asexual Blastocyst Fitness Varies Across Mouse Strains Related to Efficiency of Exit From Totipotency

In vitro activation, both sexually and asexually, facilitates assessing the reproductive mode and fitness of mammalian oocytes. Herein, we present evidence of the enhancement of asexual haploid blastocyst fitness in one selectively-inbred Mus musculus population. We tracked sexually and asexually activated-oocytes as they exited totipotency and self-organized into blastocyst-stage embryos. We examined haploid and diploid parthenogenetic potential of activated-oocytes. Unexpectedly, [~]90% of selectively-inbred mouse oocytes that were asexually activated successfully generated haploid blastocysts, contrasting with [~]90% failure in randomly-outbred mice. Furthermore, by closely tracking the timeline of exit from totipotency, we propose a novel self-correcting totipotency clock, crucial for timely exit from totipotency and successful embryogenesis across mammals. Insufficiency in this self-correcting prerequisite, will alter the fitness landscape in different reproductive modes. Collectively, this work provides a quantitative framework to investigate the unknown disruptive evolutionary trajectories of reproductive modes and fitness of females in anisogamous species. HighlightsO_LISerendipitious discovery of disruptive evolution of haploid asexual reproductive mode and preimplantation embryogenetic fitness in FVB strain of mice. C_LIO_LINovel self-correcting totipotency clock regulates blastulation potential in mammals including humans and limits haploid asexual embryogenesis C_LIO_LIEvolution of haploid asexual reproductive mode and preimplantation embryogenetic fitness in FVB mouse is linked to a superior self-correcting totipotency clock lacking in other animals. C_LI Graphical Summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/608531v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@12b9f77org.highwire.dtl.DTLVardef@f2759forg.highwire.dtl.DTLVardef@84029org.highwire.dtl.DTLVardef@1ac7f42_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2024

Puberty Blocker and Aging Impact on Testicular Cell States and Function

Spermatogonial stem cell (SSC) acquisition of meiotogenetic state during puberty to produce genetically diverse gametes is blocked by drugs collectively referred as puberty blocker (PB). Investigating the impact of PB on juvenile SSC state and function is challenging due to limited tissue access and clinical data. Herein, we report largest clinically annotated juvenile testicular biorepository with all children with gender dysphoria on chronic PB treatment highlighting shift in pediatric patient demography in US. At the tissue level, we report mild-to-severe sex gland atrophy in PB treated children. We developed most extensive integrated single-cell RNA dataset to date (>100K single cells; 25 patients), merging both public and novel (52 month PB-treated) datasets, alongside innovative computational approach tailed for germ cells and evaluated the impact of PB and aging on SSC. We report novel constitutional ranges for each testicular cell type across the entire age spectrum, distinct effects of treatments on prepubertal vs adult SSC, presence of spermatogenic epithelial cells exhibiting post-meiotic-state, irrespective of age, puberty status, or PB treatment. Further, we defined distinct effects of PB and aging on testicular cell lineage composition, and SSC meiotogenetic state and function. Using single cell data from prepubertal and young adult, we were able to accurately predict sexual maturity based both on overall cell type proportions, as well as on gene expression patterns within each major cell type. Applying these models to a PB-treated patient that they appeared pre-pubertal across the entire tissue. This combined with the noted gland atrophy and abnormalities from the histology data raise a potential concern regarding the complete reversibility and reproductive fitness of SSC. The biorepository, data, and research approach presented in this study provide unique opportunity to explore the impact of PB on testicular reproductive health.

developmental biology↗