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Research Highlight

 

Deciphering the Role of Sphingolipids and Gangliosides on Chemotherapy-mediated Unfolded Protein Response

 

Chemotherapy is a prime mode of treatment for cancer patients, and chemotherapeutic drugs cause numerous alterations in cellular signaling machinery like changes in sphingolipid and ganglioside metabolism, activation of unfolded protein response (UPR), generation of reactive oxygen species, and immunogenic cell death. In our earlier studies, we have shown that combination of doxorubicin with anti-angiogenic combretstatin-A4 and anti-inflammatory dexamethasone is highly effective in combating tumor progression by altering the sphingolipid metabolism through alternative splicing (Pal et al. ACS Central Sci., 2019). We also showed that combination of doxorubicin and the triterpenoid celastrol elevates expression of ceramide synthases with concurrent increase in the level of ceramides, thereby causing a synergistic apoptotic effect in a murine colon tumor model (Medatwal et al. Nanoscale 2020).

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Elucidating the Role  of Alternative Splicing of Sphingolipid Genes in Lipid Reprogramming during Breast Cancer Progression

 

Alternative splicing (AS) has emerged as a crucial post-transcriptional regulatory mechanism in many disease conditions including cancer. We identified AS events of sphingolipid and ganglioside genes in different breast cancer subtypes from The Cancer Genome Atlas (TCGA)-BRCA dataset. We successfully validated a Luminal B specific AS event in Ceramide Synthase 2 (CERS2) gene in breast cancer cell lines and tumor tissues in comparison to normal epithelial cells or adjoining normal tissue. We showed that AS of CERS2 reduces the functional protein and levels of very-long chain ceramides, and this imbalance contributes to increased cancer cell proliferation and migration (Pani et al. Cell Death Dis. 2021). 

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Identifying and Establishing Sphingolipids and Gangliosides as Possible Diagnostic and Prognostic Biomarkers for Breast Cancer and Liver Disease Progression

 

In collaboration with clinicians, we use tumor tissues, biopsy, and plasma samples from patients undergoing treatment for breast cancer and liver diseases for LC-MS/MS based qualitative and quantitative analysis of various types and classes of lipids. We aim to develop and validate sphingolipid/ganglioside/phospholipid/glycerolipid-based diagnostic biomarkers for different subtypes of breast cancer and liver diseases that will be robust enough to overcome the heterogeneity of the disease, help in early detection, capable of better prognosis, and provide scope to be developed as therapeutic targets. Correlation of the lipid profile/s with clinicopathological data, disease recurrence, and disease-free survival status will allow us to determine the impact of temporal changes in the lipid signature/s with disease progression and patient response to treatments. The lipid signature/s will then be further validated in a larger patient cohort, and clinicopathological correlations will be established before they can be used for diagnosis or prognosis of the disease (Kar et al. Int. J. Cancer 2023)​

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Development of Targeted and Immuno-modulatory Strategies for Breast Cancer Treatment

 

Our published study (Science Advances 2023, PMID: 37390205) explored the therapeutic relevance of sphingolipid modulation. A hydrogel-mediated local delivery system of docetaxel and carboplatin (DTX-CPT-Gel) was developed to treat TNBC models. LC-MS/MS lipidomics revealed that this therapy induced a ceramide-enriched environment, leading to activation of the PERK-mediated unfolded protein response (UPR). This molecular stress response facilitated apoptosis and immunogenic cell death (ICD), reprogramming the tumor immune microenvironment and enhancing CD8+ T cell-mediated anti-tumor immunity. The treatment not only regressed primary tumors but also prevented recurrence and cleared distant metastases. Together, these studies illustrate the dual role of sphingolipids in breast cancer—as diagnostic/prognostic biomarkers and as mediators of therapeutic immune activation. LC-MS-based lipidomics has proven to be a powerful platform for both biomarker discovery and mechanistic insight, supporting the development of targeted and immuno-modulatory strategies for breast cancer treatment.​

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Targeting Tumor Angiogenesis by Disrupting Sphingolipid (Ceramide-1-Phosphate) Synthesis

 

In our most recent study (Nanoscale, 2024, PMID: 38739006), we advanced our therapeutic exploration by developing engineered lipid–drug nanomicelles (DTX-CA4 NMs) designed to co-deliver docetaxel and combretastatin A4, targeting both tumor proliferation and angiogenesis. These nanomicelles were synthesized using lithocholic acid-based amphiphilic conjugates and optimized for esterase-responsive drug release within the tumor microenvironment. Using LC-MS/MS-based lipidomics, we demonstrated that DTX-CA4 NMs significantly impair ceramide-1-phosphate (C1P) production by downregulating ceramide kinase (CERK) at both transcript and protein levels. This metabolic interference was associated with a pro-apoptotic, anti-angiogenic, and immune-stimulatory shift in the tumor microenvironment. Treated mice exhibited enhanced infiltration and activation of CD8+ T cells, increased expression of granzyme B, and a favourable response to anti-PD-L1 checkpoint therapy. Moreover, DTX-CA4 NMs prevented tumor recurrence post-surgical resection and maintained protection upon rechallenge. These results underscore the central role of C1P suppression in augmenting antitumor immunity and highlight how LC-MS-guided lipidomic profiling is instrumental in mapping therapeutic mechanisms and validating sphingolipid metabolism as a druggable target.​

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News

 

  1. Featured in Vigyan Biopatrika first-author interviews https://biopatrika.com/2023/08/10/hydrogel-chemo-triple-neg-breast-cancer/

  2. Featured by India Bioscience, https://indiabioscience.org/news/2023/near-tumor-injection-of-a- new-nano-drug-exposes-an-eat-me-signal?x-craft-preview=vLVmMeQQB3&token=-HNl47G5RixtJXgjqqRkcTRIcA7GnFCt

  3. Invited article on “Journey of an Young Investigator“ covered by India Bioscience, DBT https://indiabioscience.org/columns/journey-of-a-yi/its-never-too-late-to-get-back-to-science

  4. Article featured in Hindu https://www.thehindu.com/sci-tech/science/nanomicelles-using-nanoparticles-for-cancer-treatment/article33426073.ece

  5. Featured by Bio Patrika https://biopatrika.com/2020/12/28/bp-0025-12-2020-sreekanth-and-animesh/

  6. Featured by Bio Patrika https://biopatrika.com/2021/03/05/interview-ptm-enzyme-tumor-breast-cancer/

  7. Featured by India Bioscience https://indiabioscience.org/news/2019/researchers-combat-tumour-growth-by-packing-three-drugs-into-a-single-biomaterial

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