Biology subjects

Khan, C.

Publications and source records attributed to Khan, C..

5 recordsLinked to original sources

bioRxiv2026

Tumor-Associated Macrophages Promote Brain Metastasis

Brain metastasis affects 20-40% of cancer patients and remains largely incurable, yet how metastatic cells engage and remodel brain-barrier interfaces is poorly understood. This gap stems in large part from the scarcity of genetically tractable in vivo systems that can resolve tumor-host interactions in their native context. Although tumor-associated macrophages (TAMs) dominate the brain metastatic microenvironment, their causal contribution to colonization has been difficult to establish. Here, we develop the adult Drosophila brain as a platform to address these questions, using allograft transplantation of lgl-/- neural stem cell-derived tumors. We find that tumors colonize the brain surface and deform it through collective, sheet-like invasion, recapitulating features of human leptomeningeal disease without parenchymal infiltration. While tumors compromise both functional and structural integrity of blood-brain barrier, they fail to breach the basement membrane (BM), which we identify as the principal barrier restricting invasion. Critically, tumors recruit TAMs to the metastasized tumor, and genetic depletion of TAMs markedly reduces brain metastasis without affecting initial dissemination. This establishes a causal role for macrophages in brain colonization, potentially through BM remodeling. Together, these findings reveal a conserved, macrophage-dependent mechanism of brain metastasis and provide a genetically accessible model that fills a critical gap in the field.

Cancer Biology↗

bioRxiv2026

A MOPD II-associated Pericentrin variant disrupts PACT domain dimerization and pericentriolar material recruitment

Centrosome dysfunction is linked to developmental disorders affecting brain and body size, including microcephaly and primordial dwarfism. However, the cellular mechanisms underlying these rare conditions remain poorly understood. In this study, we investigate a rare variant of the centrosome-associated protein Pericentrin, which was discovered in a single family with Majewski/microcephalic osteodysplastic primordial dwarfism type II (MOPD II). Unlike the majority of pathogenic PCNT variants that cause severe protein truncation, the p.Lys3154del variant ({Delta}K3154) involves a single amino acid deletion in the proteins only conserved functional domain, providing a unique opportunity to explore PCNT function in MOPD II. To model PCNT{Delta}K3154, we examined the effects of Drosophila Pericentrin-like protein (PLP) carrying an orthologous deletion (Plp{Delta}R). Our results show that plp{Delta}R animals exhibit smaller tissues that recapitulate MOPD II phenotypes. Behavioral assays revealed defects in climbing and mechanosensation, suggesting impaired sensory cilia function. We also found that Plp{Delta}R cells exhibit accelerated mitosis, increased apoptosis, and reduced pericentriolar material recruitment. In silico structural modeling, yeast two-hybrid, and co-immunoprecipitation experiments show that Plp{Delta}R produces a protein that disrupts PLP dimerization and PLP interaction with Asterless, another centrosome protein. Overall, modeling the human MOPD II patient variant PCNT{Delta}K3154 in Drosophila reveals how a single amino acid deletion affects biological processes from the molecular level to the organismal level. Our work offers new insights into the defective cellular mechanisms underlying MOPD II in patients with the PCNT{Delta}K3154 variant, potentially linking the etiology of the disease in these individuals to the loss of a single protein-protein interaction.

cell biology↗

bioRxiv2022

The DNA Damage response and cell competition are p53- and Xrp1-dependent processes that suppress hyperplastic aneuploidy

Model organisms may help understand how p53 suppresses tumorigenesis in mammals. In Drosophila, the primary transcriptional target of p53 is the gene encoding the bZip AT-hook protein Xrp1, which is another transcription factor. We report that Xrp1 mediated multiple functions of p53 in the DNA damage response (DDR), contributing to p53-dependent gene transcription and DNA damage-induced apoptosis. In addition to this role as a p53 effector, a p53-independent role for Xrp1 in cell competition has been described. Cell competition can remove cells whose genome has been altered by DNA damage and repair. During cell competition, Xrp1 is induced by RpS12, which acts as a sensor of defective ribosome biogenesis. RpS12-dependent cell competition began as the DDR wound down, and was even more prominent if p53 function was reduced. Such p53 inhibition resulted in persistence of DNA damage revealed by {gamma}H2Av accumulation. Thus, Xrp1 limited the accumulation of abnormal cells resulting from genotoxicity through both the acute, p53-dependent DDR, and also from subsequent cell competition that removes cells where DNA repair did not restore the normal genome. Both these processes might contribute to the tumor suppressor function of p53 in mammals.

developmental biology↗

bioRxiv2021

The transcription factor Xrp1 orchestrates both reduced translation and cell competition upon defective ribosome assembly or function

Ribosomal Protein (Rp) gene haploinsufficiency affects overall translation rate, leads to cell elimination by competition with wild type cells in mosaic tissues, and sometimes leads to accumulation of protein aggregates. The changes in ribosomal subunit levels observed are not sufficient for these effects, which all depend on the AT-hook, bZip domain protein Xrp1. In Rp+/- cells, Xrp1 reduced global translation through PERK-dependent phosphorylation of eIF2. eIF2 phosphorylation was sufficient to reduce translation in, and also enable cell competition of, otherwise wild type cells. Unexpectedly, however, many other defects reducing ribosome biogenesis or function (depletion of TAF1B, eIF2, eIF4G, eIF6, eEF2, eEF11, or eIF5A), also increased eIF2 phosphorylation and enabled cell competition. In all cases this was through the Xrp1 expression that was induced, placing Xrp1 as the downstream instigator of cell competition that also contributed to overall translation deficits. In the absence of Xrp1, translation differences between cells were not themselves sufficient to trigger cell competition. Thus, Xrp1, which is shown here to be a sequence-specific transcription factor, is the master regulator that triggers cell competition and other consequences of multiple ribosomal stresses.

developmental biology↗

bioRxiv2017

Somatic developmental defects in dmrad51/spnA mutant show low temperature sensitivity with enhanced genomic damages and cell death

Homologous Recombination (HR) is one of the key pathways to repair Double Strand Breaks (DSBs). Rad51 serves an important function of catalysing strand exchange between two homologous chromosomes in the HR pathway. In higher organisms, Rad51 function is indispensable with its absence leading to early embryonic lethality, thus precluding any mechanistic probing of the system. In contrast, absence of Drosophila rad51 (Dmrad51/spnA) has been associated with defects in female germline causing ventralization of the egg, without any reported detrimental consequences to Drosophila somatic tissues. In this study, we have performed a systematic analysis of somatic development of dmrad51 null mutant flies by using genetic complementation between multiple dmrad51 alleles. Our current study, for the first time, uncovers the requirement of Dmrad51 in somatic tissue maintenance at both larval and pupal stages. Also, we show that dmrad51 mutant exhibit patterning defects in abdominal cuticle in the stripes and bristles, while there appears to be only subtle defects in the adult wing and eye. Interestingly, dmrad51 null mutant and other alleles show discernible phenotype of low temperature sensitivity, suggesting a role for Dmrad51 in temperature sensitive cellular processes, which thus presents an elegant system for probing temperature sensitive cellular/tissue responses that ensue when a mutation leads to the loss of protein expression (null mutant) rather than its altered protein structure.

developmental biology↗