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Khatib, A.

Publications and source records attributed to Khatib, A..

8 recordsLinked to original sources

Dihydropyrimidines sustain aggressive cancer states by stabilizing DPYSL2

Cancer cell states are governed by coordinated signaling and metabolic networks, yet the mechanisms coupling metabolic activity to oncogenic signaling remain poorly understood. Here, we identify dihydropyrimidines (DHPs), metabolites generated during pyrimidine catabolism, as "signaling metabolites" that sustain aggressive cancer cell states. Depletion of DHPs, either by knockout of the pyrimidine catabolic enzyme DPYD or by expression of the DHP-degrading enzyme DPYS, suppressed STAT3 signaling and attenuated mesenchymal and inflammatory transcriptional programs. Mechanistically, DHPs stabilized DPYSL2, a JAK1-interacting adaptor protein required for efficient STAT3 activation. Structural modeling and thermal stability analyses further support a direct interaction between DHPs and DPYSL2. Accordingly, high DPYD expression was associated with EMT, inflammatory signaling, and poor-prognosis breast cancer subtypes across patient cohorts. Ultimately, our findings establish pyrimidine catabolism as a direct regulator of signaling competence and identify DHPs as signaling-active metabolites that couple cellular metabolic state to oncogenic transcriptional programs and mesenchymal identity.

cancer biology↗

A Systematic Review of the Distribution and Prevalence of Viruses Detected in the Peromyscus maniculatus Species Complex (Rodentia: Cricetidae)

The North American Deermouse, Peromyscus maniculatus, is one of the most widespread and abundant mammals on the continent. It is of public health interest as a known host of several viruses that are transmissible to humans and can cause illness, including the acute respiratory disease Hantavirus pulmonary syndrome (HPS). However, recent taxonomic studies indicate that P. maniculatus is a complex of multiple species, raising questions about how to identify and interpret three decades of hantavirus monitoring data. We conducted a systematic review investigating the prevalence and spatial distribution of viral taxa detected in wild populations allocated to P. maniculatus. From the 49 relevant studies published from 2000 to 2022, we extracted and analyzed spatial occurrence data to calculate weighted populational prevalences for hantaviruses. We found that detection efforts have been concentrated in the Western United States and Mexico with a focus on the spread of Sin Nombre virus (Orthohantavirus sinnombreense), the primary causative agent of HPS. There are significant gaps in the existing literature both geographically and in regard to the types of viruses being sampled. These results are significantly impacted by a recent taxonomic split of P. maniculatus into four species, and we were able to update 94% of hantavirus observations to reflect this change. Investigating the uncertain, and likely multiple, phylogenetic histories of these viral hosts should be a key emphasis of future modeling efforts. Author SummaryUnderstanding the interactions of viruses with mammal hosts is critical for monitoring disease spread and identifying species or geographic areas at high risk for future zoonotic disease outbreaks. However, much of the data scientists have collected about viruses in mammals remains fragmented in published literature and is not available in an up-to-date, standardized format online. We conducted a systematic review of virus observations in one of the most abundant, widespread group of rodent species in North America, the Peromyscus maniculatus (North American Deermouse) species complex. We extracted and analyzed the spatial distribution of 62,421 observations reporting the results of tests for viruses in the Hantaviridae, Arenaviridae, and Flaviviridae families. We find that conclusions about reservoir host status may be impacted by recent taxonomic proposals that split P. maniculatus into four distinct species, and we show how the taxonomic identifications of 94% of the reported observations can be updated using expert-generated maps of the ranges for the proposed new species. We also highlight the uneven geographic sampling of viruses in the rodent populations and major gaps that remain in our knowledge.

ecology↗

The metabolic enzyme EXT1 is sufficient to induce the epithelial-mesenchymal transition program in cancers

Carcinomas often exhibit aggressive characteristics, such as enhanced migration abilities, through the execution of the epithelial-mesenchymal transition (EMT) program. Heparan sulfate (HS) is a polysaccharide expressed on the surface of aggressive cancer cells, which acts as a co-receptor to stimulate EMT-associated signaling pathways. However, despite HS role in cancer aggressiveness, the mechanisms governing its EMT-dependent biosynthesis remains poorly understood. Here, we characterized the HS chain elongation enzyme, exostosin glycosyltransferase 1 (EXT1), as an essential component of the EMT program. We identified an EMT-dependent expression of EXT1 and its selective upregulation in aggressive tumor subtypes and cell lines. Overexpression of EXT1 in epithelial cells is sufficient to induce HS biosynthesis, cell migration, and invasion, form tumors in mice, and activate the STAT3 pathway. Moreover, its knockout in aggressive cells significantly inhibited their EMT-associated characteristics. These findings demonstrate a cellular mechanism by which metabolic processes regulate signaling pathways to govern cell state.

cancer biology↗

Depletion of FH, an essential TCA cycle enzyme, drives proliferation in a two-step model

Several tumor suppressor genes do not follow the canonical function of cell cycle repressors. For example, fumarate hydratase (FH) is an evolutionary conserved TCA cycle enzyme that reversibly catalyzes the hydration of fumarate to L-malate and has a moonlight function in the DNA damage response (DDR). Interestingly, despite this enzymes essential role in central carbon metabolism, FH is inactive or absent in several tumors, such as hereditary leiomyomatosis and renal cell cancer (HLRCC). Accordingly, FH has a contradictory cellular function, as it is pro-survival through its role in the TCA cycle, yet its loss can drive tumorigenesis. These observations have supported the role of FH as a tumor suppressor. Here, we solved this contradiction by determining the molecular mechanisms that allow the cells to survive and even proliferate upon FH loss. We found that the cells response to FH loss is separated into two distinct time frames based on cell proliferation and DNA damage repair. During the early stages of FH loss, the cells proliferation and DNA damage repair are inhibited. However, over time the cells overcome the FH loss and form knockout clones, indistinguishable from WT cells in their proliferation rate. Due to the FH loss effect on DNA damage repair, we assumed that the recovered cells bear adaptive mutations. Therefore, we applied whole-exome sequencing to identify such mutated genes systematically. Indeed, we identified recurring mutations in genes belonging to the central oncogenic signaling pathways, such as JAK/STAT, which we validated to be impaired in FH-KO clones. Intriguingly, we demonstrated that these adaptive mutations are responsible for FH-KO cell proliferation under TCA cycle malfunction.

cancer biology↗

Pluripotency-Independent Induction of Human Trophoblast Stem Cells from Fibroblasts

Recent studies demonstrated that human trophoblast stem-like cells (hTS-like cells) can be derived from naive embryonic stem cells or be induced from somatic cells by the pluripotency factors, OSKM. This raises two main questions; (i) whether human induced TSCs (hiTSCs) can be generated independently to pluripotent state or factors and (ii) what are the mechanisms by which hTSC state is established during reprogramming. Here, we identify GATA3, OCT4, KLF4 and MYC (GOKM) as a pluripotency-independent combination of factors that can generate stable and functional hiTSCs, from both male and female fibroblasts. By using single and double knockout (KO) fibroblasts for major pluripotency genes (i.e. SOX2 or NANOG/PRDM14) we show that GOKM not only is capable of generating hiTSCs from the KO cells, but rather that the efficiency of the process is increased. Through H3K4me2 and chromatin accessibility profiling we demonstrate that GOKM target different loci and genes than OSKM, and that a significant fraction of them is related to placenta and trophoblast function. Moreover, we show that GOKM exert a greater pioneer activity compared to OSKM. While GOKM target many specific hTSC loci, OSKM mainly target hTSC loci that are shared with hESCs. Finally, we reveal a gene signature of trophoblast-related genes, consisting of 172 genes which are highly expressed in blastocyst-derived TSCs and GOKM-hiTSCs but absent or mildly expressed in OSKM-hiTSCs. Taken together, these results imply that not only is the pluripotent state, and SOX2 specifically, not required to produce functional hiTSCs, but that pluripotency-specific factors actually interfere with the acquisition of the hTSC state during reprogramming.

cell biology↗

Dihydropyrimidinase-like 2 (DPYSL2) regulates breast cancer migration via a JAK/STAT3/vimentin axis

The intricate neuronal wiring during development requires cytoskeletal reorganization orchestrated by signaling cues. Considering that cytoskeletal remodeling is a hallmark of cell migration, we inquired whether metastatic cancer cells exploit the axon guidance proteins to migrate. Indeed, in breast cancer patients, we found a significant correlation between the mesenchymal markers and the expression of dihydropyrimidinase-like 2 (DPYSL2), a regulator of cytoskeletal dynamics in growing axons. Strikingly, DPYSL2 knockout in mesenchymal-like cells profoundly inhibited cell migration, invasion, stemness features, tumor growth rate, and metastasis. Next, we aimed to decode the molecular mechanism underlying this phenomenon and revealed an interaction between DPYSL2 and Janus kinase 1 (JAK1). This binding is crucial for triggering signal transducer and activator of transcription 3 (STAT3) and subsequently expressing vimentin, the pro-migratory intermediate filament. Collectively, we identified DPYSL2 as a molecular link between oncogenic signaling pathways and cytoskeletal reorganization in migrating breast cancer cells. Statement of significanceThis study shows that the axon guidance adaptor protein DPYSL2 is essential for promoting breast cancer migration. Specifically, this protein interacts with JAK1 to govern STAT3 signaling and subsequently vimentin expression.

cancer biology↗

LncRNA PAINT is Associated with Aggressive Prostate Cancer and Dysregulation of Slug and Related Genes

Long non-coding RNAs (lncRNAs) play regulatory roles in cellular processes and their aberrant expression may drive cancer progression. Here we report the function of a lncRNA PAINT (Prostate Cancer Associated Intergenic Non-Coding Transcript) in promoting prostate cancer (PCa) progression. Upregulation of PAINT was noted in advanced stage and metastatic PCa. Inhibition of PAINT decreased cell proliferation, S-phase progression, increased expression of apoptotic markers, and improved sensitivity to docetaxel and Aurora kinase inhibitor VX-680. Inhibition of PAINT decreased cell migration and reduced expression of Slug and Vimentin. Ectopic expression of PAINT suppressed E-cadherin, increased S-phase progression and cell migration. PAINT expression in PCa cells induced larger colony formation and higher expression of mesenchymal markers. Transcriptome analysis followed by qRT-PCR validation showed differentially expressed genes involved in epithelial mesenchymal transition (EMT), apoptosis and drug resistance in PAINT-expressing cells. Our study establishes an oncogenic function of PAINT in PCa.

cancer biology↗

Glutathione Peroxidase 8 (GPX8)-IL6 axis is essential in maintaining breast cancer mesenchymal stem-like state and aggressive phenotype

Metabolic reprogramming as a downstream result of oncogenic signaling pathways has been described as a hallmark of cancer. Here, we describe a reverse scenario in which a metabolic enzyme regulates cancer cell behavior by triggering a signaling pathway. We find that glutathione peroxidase 8 (GPX8), a poorly characterized redox enzyme that resides in the endoplasmic reticulum, is upregulated during the epithelial-to-mesenchymal (EMT) program in HMLE and A549 cells. In cancer patients, high tumor levels of GPX8 correlate with mesenchymal markers and poor patient outcome. Strikingly, GPX8 knockout in mesenchymal-like cells results in an epithelial-like morphology, downregulation of EMT characteristics, loss of cancer stemness features, and impeded tumor initiation in mice. We determine the mechanism governing this reduction in cancer aggressiveness is through the repression of crucial autocrine factors, in particular, interleukin-6 (IL-6). Specifically, GPX8 knockout impairs IL-6-driven activation of the JAK-STAT3 signaling pathway, a critical regulator of a cancer-aggressive state. Altogether, we uncover the GPX8-IL-6 axis as a novel metabolic-inflammatory pathway that acts as a robust EMT activator and program to induce aggressive cancer cell characteristics.

cancer biology↗