Biology subjects

Radhakrishnan, S.

Publications and source records attributed to Radhakrishnan, S..

4 recordsLinked to original sources

bioRxiv2026

Hepatobiliary Progenitor-like Reprogramming in Liver Metastases

Metastatic progression requires cancer cells to adapt to the unique constraints of distant organ microenvironments, yet the mechanisms that drive organ-specific adaptations remain poorly understood. Here, we show that the liver actively rewrites metastatic cancer cell identity, driving tumor cells toward a hepatobiliary progenitor-like state. Through integrated transcriptomic, proteomic, metabolomic, and epigenomic analyses of patient-derived rapid-autopsy samples and experimental models, we identify this state as selectively enriched in liver metastases. It is characterized by co-activation of hepatic and biliary/progenitor regulators HNF4A and SOX9 and is observed across multiple epithelial cancers, indicating a conserved response to the hepatic niche. Mechanistically, hepatocyte-derived TGF-{beta} and hypoxia converge to activate a HIF-1-ACLY axis, increasing nuclear acetyl-coenzyme A availability and histone acetylation at hepatic lineage regulatory elements to drive hepatobiliary reprogramming. This coordinated niche-response program can be captured transcriptionally and is associated with inferior overall survival. Disruption of this pathway suppresses hepatic reprogramming and impairs liver metastatic fitness. These findings identify the liver as an active determinant of metastatic cell fate, linking microenvironmental signaling to metabolic and chromatin remodeling programs that enable lineage plasticity. More broadly, they reveal organ-specific reprogramming as a fundamental principle of metastasis and a therapeutic vulnerability in liver metastases.

cancer biology↗

bioRxiv2024

Targeting transcription factors through an IMiD independent zinc finger domain

Immunomodulatory imide drugs (IMiDs) degrade specific C2H2 zinc finger degrons in transcription factors, making them effective against certain cancers. SALL4, a cancer driver, contains seven C2H2 zinc fingers in four clusters, including an IMiD degron in zinc finger cluster two (ZFC2). Surprisingly, IMiDs do not inhibit growth of SALL4 expressing cancer cells. To overcome this limit, we focused on a non-IMiD degron, SALL4 zinc finger cluster four (ZFC4). By combining AlphaFold and the ZFC4-DNA crystal structure, we identified a potential ZFC4 drug pocket. Utilizing an in silico docking algorithm and cell viability assays, we screened chemical libraries and discovered SH6, which selectively targets SALL4-expressing cancer cells. Mechanistic studies revealed that SH6 degrades SALL4 protein through the CUL4A/CRBN pathway, while deletion of ZFC4 abolished this activity. Moreover, SH6 led to significant 62% tumor growth inhibition of SALL4+ xenografts in vivo and demonstrated good bioavailability in pharmacokinetic studies. In summary, these studies represent a new approach for IMiD independent drug discovery targeting C2H2 transcription factors in cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/574032v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@b8e4e8org.highwire.dtl.DTLVardef@bc6f01org.highwire.dtl.DTLVardef@11bbe85org.highwire.dtl.DTLVardef@791cb1_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Addition of soluble fiber in low fat purified diets improves gut and metabolic health compared to traditional AIN diets

BackgroundPurified diets (PDs) contain refined ingredients with one main nutrient, allowing for greater control relative to grain-based diets (GBDs), which contain unrefined grains and animal byproducts. Traditional PDs like the AIN-76A (76A) and AIN-93G (93G) can negatively impact metabolic and gut health when fed long-term, in part due to lower total fiber, no soluble fiber, and higher sucrose content. ObjectiveTwo studies were conducted to determine how PDs with reduced sucrose and increased fiber (soluble and insoluble) influence metabolic and gut health in mice compared to traditional AIN PDs or GBDs. MethodsIn study 1, C57Bl/6N mice consumed a GBD (5002), 76A, 93G, or 2 Open standard PDs (OSDs) with reduced sucrose and higher fiber for 88 days. Body composition and metabolic parameters were assessed. In study 2, C57Bl/6N mice consumed either 2 GBDs (5001 or 5002) or OSDs with different types/levels of fiber for 14 days. Microbiome alterations and predicted functional metagenomic changes were measured. ResultsOSD marginally influenced body weight and adiposity, but improved glucose tolerance relative to 93G (p = 0.0131) and 76A (p = 0.0014). Cecal and colonic weights were lower in mice fed cellulose-based PDs compared to those fed GBDs and soluble fiber PDs. Soluble fiber diets reduced alpha diversity and showed similar beta diversity, which differed from cellulose fed PDs and GBDs. Certain genera associated with improved gut health such as Bifidobacteria and Akkermansia were significantly elevated by soluble fibers PDs (p[≤]0.01). Some metabolic pathways related to carbohydrate and fatty acid metabolism were affected by PDs. ConclusionPDs formulated with lower sucrose and increased fiber content, particularly soluble fiber, blunted elevations in metabolic parameters and favorably impacted microbiota and metagenome in C57BL/6N mice.

physiology↗

bioRxiv2020

Unearthing the genes of plant-beneficial marine yeast - Wickerhamomyces anomalus strain MSD1

The de novo genome of unique marine yeast, Wickerhamomyces anomalus isolated from seaweed along Indian coast is presented. The genome assembly was carried out using MaSurCA assembler that generated a data size [~]14.3 mb from short and long reads obtained from Illumina Hiseq 4000 and GridION-X5 respectively. This assembled genome data were used for predicting genes using Augustus gene prediction tool that reported 6720 genes and proteins. The gene sequences were used to unravel the metabolic pathway analysis using KAAS database. The protein sequences were used for secondary analysis to predict the presence of signal peptides using SignalP tool, predicting protein family, domains using Pfam tool and prediction of transmembrane helices in proteins using TMHMM tool. Presence of genes involved in plant growth-promotion and regulation (PGPR) including siderophore and IAA production, iron and sulfur transformation, zinc and phosphate solubilization, nitrogen fixation, synthesis of anti-bacterial and volatile organic compound (VOCs), were assigned. Additionally, acid and alkaline phosphatases, ACC deaminases and lytic enzymes such as {beta}-glucanases, proteases and chitinases involved in pathogen suppression, are also reported. The study elucidates comprehensive understanding of PGP attributes of MSD1 and its potential use in agriculture as bio-fertilizer /bio-stimulant.

genomics↗