Glycosphingolipids are mediators of cancer plasticity through independent signaling pathways

Cumin, Cécile; Huang, Yen‐Lin; Rossdam, Charlotte; Ruoff, Felix; Posada-Céspedes, Susana; Liang, Ching-Yeu; Lombardo, Flavio; Coelho, Ruimário Inácio; Rimmer, Natalie; Konantz, Martina; López, Mónica Núñez; Alam, Salma; Schmidt, Alexander; Calabrese, Diego; Fedier, André; Vlajnic, Tatjana; Itzstein, Mark von; Templin, Markus F.; Buettner, Falk F. R.; Everest‐Dass, Arun; Heinzelmann‐Schwarz, Viola; Jacob, Francis

doi:10.1016/j.celrep.2022.111181

Cited by 37 publications

(19 citation statements)

References 95 publications

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“…Cellular responses to our bimodal treatment were also assessed using the zebrafish embryo tumor xenograft model. In this model, we transplanted COV362 MSLN high cells (carboplatin and paclitaxel-resistant) stably expressing dTomato fluorescent protein (COV362_Chili) into transgenic Tg(kdrl:eGFP) zebrafish embryos ( 35, 36 ). Zebrafish embryos were then exposed to birinapant in combination with paclitaxel or to the vehicle for 72 hours.…”

Section: Resultsmentioning

confidence: 99%

SMAC mimetics overcome apoptotic resistance in ovarian cancer through MSLN-TNF alpha axis

Coelho,

Seashore-Ludlow,

Schütz

et al. 2024

Preprint

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Resistance to chemotherapy and PARPi inhibitors remains a critical challenge in the treatment of epithelial ovarian cancer, mainly due to disabled apoptotic responses in tumor cells. Given mesothelin's pivotal role in ovarian cancer and its restricted expression in healthy tissues, we conducted a drug-screening discovery analysis across a range of genetically modified cancer cells to unveil mesothelin's therapeutic impact. We observed enhanced cell death in low mesothelin expressing cancer cells when exposed to a second mitochondria-derived activator of caspases (SMAC) mimetics, and demonstrated a compelling synergy when combined with chemotherapy in ex vivo patient-derived cultures and zebrafish tumor xenografts. Mechanistically, the addition of the SMAC mimetics drug birinapant to either carboplatin or paclitaxel triggered the activation of the Caspase 8-dependent apoptotic program facilitated by TNF alpha signaling. Multimodal analysis of neoadjuvant-treated patient samples further revealed an association between tumor-associated macrophages and the activation of TNF alpha-related pathways. Our proposed bimodal treatment shows promise in enhancing the clinical management of patients by harnessing the potential of SMAC mimetics alongside conventional chemotherapy.

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Section: Resultsmentioning

confidence: 99%

SMAC mimetics overcome apoptotic resistance in ovarian cancer through MSLN-TNF alpha axis

Coelho,

Seashore-Ludlow,

Schütz

et al. 2024

Preprint

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“…48 Elevations of sialic acid in cell-membrane glycans could contribute to cancer progression by dampening the immune response 49,50 or could enable migration after epithelial-mesenchymal transition (EMT). 51,52 In the immune system, changes in the glycosylation of membrane proteins and lipid rafts upon activation and differentiation of lymphocytes enable antigen recognition 53 and homing of immune cells. [54][55][56] Further investigations could show how metabolic shifts affect function through alterations in cell-membrane glycosylation.…”

Section: Discussionmentioning

confidence: 99%

Metabolomics and¹³C Labelled Glucose Tracing to Identify Carbon Incorporation into Aberrant Cell Membrane Glycans in Cancer

Reyes-Oliveras,

Ellis,

Sheldon

et al. 2024

Preprint

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Cell membrane glycans contribute to immune recognition, signaling, and cellular adhesion and migration, and altered membrane glycosylation is a feature of cancer cells that contributes to cancer progression. The uptake and metabolism of glucose and other nutrients essential for glycan synthesis could underlie altered membrane glycosylation, but the relationship between shifts in nutrient metabolism and the effects on glycans have not been directly examined. To address this possibility, we created a novel method that combines stable isotope tracing with metabolomics to enable direct observations of glucose allocation to nucleotide sugars and cell-membrane glycans. We compared the glucose allocation to membrane glycans of two pancreatic cancer cell lines that are genetically identical but have differing energy requirements. The 8988-S cells had higher glucose allocation to membrane glycans and intracellular pathways relating to glycan synthesis, but the 8988-T cells had higher glucose uptake and commitment of glucose to non-glycosylation pathways. The cells lines differed in requirements of glucose for energy production, resulting in differences in glucose bioavailability for glycan synthesis. The workflow demonstrated here enables studies on the effects of metabolic shifts on the commitment of media nutrients to cell-membrane glycans. The results support a flux-based regulation of glucose commitment glycosylation and a mode of metabolic control of cell functions such signaling, immune recognition, and adhesion and migration.

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“…They are comprised of ceramide backbones and glycans that remain outside of the membrane and participate in cell adhesion, cell-cell interaction, and migration. [52][53][54][55]. Increased production of GSLs in tumors with abundant B. theta suggests that availability of glycans for nutrition may underlie outgrowth of the bacterium.…”

Section: Biological Processes Correlated With Abundances Of B Theta A...mentioning

confidence: 99%

Intratumoral Microbiome of Adenoid Cystic Carcinomas and Comparison with other Head and Neck Cancers

Karpinets,

Mitani,

Chang

et al. 2024

Preprint

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Background: Adenoid cystic carcinoma (ACC) is a rare, slow growing yet aggressive head and neck malignancy. Despite its clinical significance, our understanding of the cellular evolution and microenvironment in ACC remains limited. Methods: We investigated the intratumoral microbiome of 50 ACC tumors and 33 adjacent normal tissues using 16S rRNA gene sequencing. This allowed us to characterize the bacterial communities within ACC and explore potential associations between the bacterial community structure, clinical characteristics, and tumor molecular features obtained through RNA sequencing. Results: Bacterial composition in ACC displayed significant differences compared to adjacent normal salivary tissue and exhibited diverse levels of species richness. We identified two main microbial subtypes within ACC: oral-like and gut-like. Oral-like microbiomes, characterized by higher diversity and abundance of genera like Neisseria, Leptotrichia, Actinomyces, Streptococcus, Rothia, and Veillonella (commonly found in healthy oral cavities), were associated with the less aggressive ACC-II molecular subtype and improved patient outcomes. Notably, we identified the same oral genera in oral cancer and in head and neck squamous cell carcinomas. In both cancers, they were part of shared oral communities associated with more diverse microbiome, less aggressive tumor phenotype, and better survival. Conversely, gut-like microbiomes in ACC, featuring low diversity and colonization by gut mucus layer-degrading species like Bacteroides, Akkermansia, Blautia, Bifidobacterium, and Enterococcus, were associated with poorer outcomes. Elevated levels of Bacteroides thetaiotaomicron were independently associated with significantly worse survival, regardless of other clinical and molecular factors. Furthermore, this association positively correlated with tumor cell biosynthesis of glycan-based cell membrane components. Conclusions: Our study uncovers specific intratumoral oral genera as potential pan-cancer biomarkers for favorable microbiomes in ACC and other head and neck cancers. These findings highlight the pivotal role of the intratumoral microbiome in influencing ACC prognosis and disease biology.

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Glycosphingolipids are mediators of cancer plasticity through independent signaling pathways

Cited by 37 publications

References 95 publications

SMAC mimetics overcome apoptotic resistance in ovarian cancer through MSLN-TNF alpha axis

SMAC mimetics overcome apoptotic resistance in ovarian cancer through MSLN-TNF alpha axis

Metabolomics and¹³C Labelled Glucose Tracing to Identify Carbon Incorporation into Aberrant Cell Membrane Glycans in Cancer

Intratumoral Microbiome of Adenoid Cystic Carcinomas and Comparison with other Head and Neck Cancers

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Glycosphingolipids are mediators of cancer plasticity through independent signaling pathways

Cited by 37 publications

References 95 publications

SMAC mimetics overcome apoptotic resistance in ovarian cancer through MSLN-TNF alpha axis

SMAC mimetics overcome apoptotic resistance in ovarian cancer through MSLN-TNF alpha axis

Metabolomics and13C Labelled Glucose Tracing to Identify Carbon Incorporation into Aberrant Cell Membrane Glycans in Cancer

Intratumoral Microbiome of Adenoid Cystic Carcinomas and Comparison with other Head and Neck Cancers

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Metabolomics and¹³C Labelled Glucose Tracing to Identify Carbon Incorporation into Aberrant Cell Membrane Glycans in Cancer