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Using doxorubicin as a model drug, the study links increased glycocalyx sialylation with reduced drug cytotoxicity and diminished drug internalization, alongside altered single-cell metabolic phenotypes and enhanced glycolytic preference. Sialic acids are shown to directly block doxorubicin entry, while lipid droplet accumulation and metabolomic shifts support a dual defensive program with enzyme-expression roots.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/ketomimetic-nutrients-remodel-the-glycocalyx-and-trigger-a-metabolic-defense-in-breast-cancer-cells/369373/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/ketomimetic-nutrients-remodel-the-glycocalyx-and-trigger-a-metabolic-defense-in-breast-cancer-cells/369373.png","ImageObject",300,407,{"name":92,"@type":93},"Margaret","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-01","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",13,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What is the purpose of using ketomimetic nutrients in breast cancer cells?","Question",{"text":113,"@type":114},"To determine how a ketone body-rich, low-glucose medium remodels the glycocalyx and metabolic signature of breast cancer cells and how this influences their response to therapy.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does ketomimetic media affect doxorubicin treatment outcomes?",{"text":118,"@type":114},"Ketomimetic media enhance glycocalyx sialylation and protect breast cancer cells from doxorubicin, reducing cytotoxicity and drug internalization.",{"name":120,"@type":111,"acceptedAnswer":121},"What role do sialic acids play in the mechanism of drug defense?",{"text":122,"@type":114},"Enzymatic removal of glycocalyx sialic acids reveals a direct role as defense guards that block doxorubicin entry at the cellular membrane to curtail internalization.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},369373,1790452523,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},137451207643,"https://ap-avatar.wpscdn.com/davatar_3d24733baf745e90a7e4bdd5f77d97b2","Kamra etal. Cancer & Metabolism (2025) 13:18 [https://doi.org/10.1186/s40170-025-00385-3](https://doi.org/10.1186/s40170-025-00385-3)  \nCancer & Metabolism  \n RESEARCH Open Access  \nKetomimetic nutrients remodel  \nthe glycocalyx and trigger a metabolic defense in breast cancer cells  \nMohini Kamra1*, Yuan-I Chen1, Paula C. Delgado2, Erin H. Seeley3, Stephanie K. Seidlits 1, Hsin-Chih Yeh1,4, Amy Brock1 and Sapun H. Parekh 1*  \nAbstract  \nBackground While the triggers for the metastatic transformation of breast cancer (BC) cells remain unknown, recent evidence suggests that intrinsic cellular metabolism could be a crucial driver of migratory disposition and chemoresistance. Aiming to decipher the molecular mechanisms involved in BC cell metabolic maneuvering, we study how a ketomimetic (ketone body-rich, low glucose) nutrient medium can engineer the glycocalyx and metabolic signature of BC cells, to further maneuver their response to therapy.  \nMethods Doxorubicin (DOX) has been used as a model chemotherapeutic in this study. Bioorthogonal imaging was used to assess the degree of sialylation of the glycocalyx along with measurements of drug-induced cytotoxicity and drug internalization. Single cell label-free metabolic imaging has been performed, coupled with measurement of cellular proliferative and migratory abilities, and MS-based metabolomic screens. Transcriptomic analysis of crucial enzymes was performed using total RNA extraction and rt-qPCR.  \nResults We found an inverse correlation of glycocalyx sialylation with drug-induced cytotoxicity and drug internalization, where ketomimetic media enhanced sialylation and protected BC cells from DOX. These hypersialylated cells proliferated slower and migrated faster as compared to their counterparts receiving a high glucose media, while exhibiting a preference for glycolysis. These cells also showed pronounced lipid droplet accumulation coupled with an inversion in their metabolomic profile. Enzymatic removal of sialic acid moieties at the glycocalyx revealed for the first time, a direct role of sialic acids as defense guards, blocking DOX entry at the cellular membrane to curtail internalization. Interestingly, the non-cancerous mammary epithelial cells exhibited opposite trends and this differential pattern in cancer vs. normal cells was traced to its biochemical roots, i. e. the expression levels of key enzymes involved in sialylation and fatty acid synthesis.  \nConclusions Our findings revealed that a ketomimetic medium enhances chemoresistance and invasive disposition of BC cells via two main oncogenic pathways: hypersialylation and lipid synthesis. We propose that the crosstalk between these pathways, juxtaposed at the synthesis of the glycan precursor UDP-GlcNAc, furthers advancement of a metastatic phenotype in BC cells under ketomimetic conditions. Non-cancerous cells lack this dual defense machinery and end up being sensitized to DOX under ketomimetic conditions.  \n*Correspondence: Mohini Kamra[mkamra@utexas.edu](mkamra@utexas.edu)[ ](mkamra@utexas.edu)Sapun H. Parekh [sparekh@utexas.edu](sparekh@utexas.edu)  \nFull list of author information is available at the end of the article  \n© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your i","cbCaiuRaHU8jsvS9","https://ap.wps.com/l/cbCaiuRaHU8jsvS9","pdf",5910316,17,"English","# Background\n## Breast cancer metastasis and unknown triggers\n## Metabolic manipulation and the Warburg effect\n# Methods\n## Doxorubicin model and bioorthogonal imaging\n## Single-cell metabolic imaging, metabolomics, and rt-qPCR\n# Results\n## Glycocalyx sialylation versus cytotoxicity and drug internalization\n## Proliferation, migration, glycolysis preference, and lipid droplet accumulation\n## Sialic acids as defense guards blocking DOX entry\n## Differential responses in cancer versus normal cells\n# Conclusions\n## Hypersialylation and lipid synthesis as two oncogenic pathways","[{\"question\":\"What is the purpose of using ketomimetic nutrients in breast cancer cells?\",\"answer\":\"To determine how a ketone body-rich, low-glucose medium remodels the glycocalyx and metabolic signature of breast cancer cells and how this influences their response to therapy.\"},{\"question\":\"How does ketomimetic media affect doxorubicin treatment outcomes?\",\"answer\":\"Ketomimetic media enhance glycocalyx sialylation and protect breast cancer cells from doxorubicin, reducing cytotoxicity and drug internalization.\"},{\"question\":\"What role do sialic acids play in the mechanism of drug defense?\",\"answer\":\"Enzymatic removal of glycocalyx sialic acids reveals a direct role as defense guards that block doxorubicin entry at the cellular membrane to curtail internalization.\"}]","Ketomimetic nutrients remodel the glycocalyx and trigger a metabolic defense in breast cancer cells | PDF",1790182295,43]