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Peer-reviewedCC BY 4.0Cancers

Organoid-Guided Synthetic Micropeptide Therapeutics to Target Ovarian Cancer Stem Cells

  • Bhavana Balayoganandh1
  • Naisarg Gamit2
  • Harshit Kallepalli1
  • Bhawna Dev3
  • Arun Dharmarajan4,5,6
  • Sudha Warrier7
7 affiliations
  1. 1Department of Biotechnology, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, Tamil Nadu, India
  2. 2Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560063, Karnataka, India
  3. 3Department of Radiology, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, Tamil Nadu, India
  4. 4Trichy SRM Medical College Hospital and Research Center, Trichy 621105, Tamil Nadu, India
  5. 5School of Human Sciences, Faculty of Life and Physical Sciences, The University of Western Australia, Perth, WA 6009, Australia
  6. 6Faculty of Health Sciences, Curtin Medical School, Curtin University, Perth, WA 6102, Australia
  7. 7Faculty of Life Sciences, Atria University, Bangalore 560024, Karnataka, India
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Abstract

Ovarian cancer remains the most lethal gynecological malignancy, largely due to high recurrence rates and the development of therapy-resistant disease. Cancer stem cells (CSCs) contribute to treatment failure by promoting chemoresistance through signaling pathways such as Wnt/β-catenin, Hedgehog, and Notch, as well as through dynamic interactions with the tumor microenvironment (TME). Ovarian CSC (OCSC)-associated biomarkers, including CD44, CD24, CD133, and ALDH, have expanded opportunities for specific tumor characterization and biomarker identification. Effective targeting of OCSCs requires experimental models that preserve cellular plasticity and hierarchical organization. Development of synthetic matrices and chemically defined media has improved the reproducibility and scalability of three-dimensional (3D) organoid cultures for preclinical drug testing. CSC-derived organoids, established by enriching cells positive for CSC markers directly from patient tumor material, provide a 3D platform for studying OCSC-associated phenotypes and therapeutic responses. This review examines current understanding of ovarian CSC biology and the development of OCSC-derived 3D organoid models that can recapitulate cellular architecture and patient-specific drug responses. These 3D organoid models provide a guided platform for evaluating emerging therapeutics, such as micropeptides encoded by short open reading frames or engineered from functional tumor-suppressor protein domains selected to target OCSCs. Their small size enables modulation of intracellular signaling and highly specific protein–protein interactions. We further review micropeptide stabilization strategies and tumor-targeted delivery systems designed to enhance bioavailability. This review highlights how integrating patient-specific OCSC-derived organoid models with engineered micropeptides may accelerate the development of personalized treatment strategies for ovarian cancer while improving the preclinical evaluation of novel therapies.

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Cite

BibTeXRIS
BibTeX
@article{balayoganandh2026organoidguided,
  title = {{Organoid-Guided Synthetic Micropeptide Therapeutics to Target Ovarian Cancer Stem Cells}},
  author = {Bhavana Balayoganandh and Naisarg Gamit and Harshit Kallepalli and Bhawna Dev and Arun Dharmarajan and Sudha Warrier},
  journal = {Cancers},
  year = {2026},
  month = oct,
  doi = {10.3390/cancers18203289},
  url = {https://www.mdpi.com/2072-6694/18/20/3289},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Organoid-Guided Synthetic Micropeptide Therapeutics to Target Ovarian Cancer Stem Cells
AU  - Bhavana Balayoganandh
AU  - Naisarg Gamit
AU  - Harshit Kallepalli
AU  - Bhawna Dev
AU  - Arun Dharmarajan
AU  - Sudha Warrier
PY  - 2026
DA  - 2026/10/01
JO  - Cancers
DO  - 10.3390/cancers18203289
UR  - https://www.mdpi.com/2072-6694/18/20/3289
AB  - Ovarian cancer remains the most lethal gynecological malignancy, largely due to high recurrence rates and the development of therapy-resistant disease. Cancer stem cells (CSCs) contribute to treatment failure by promoting chemoresistance through signaling pathways such as Wnt/β-catenin, Hedgehog, and Notch, as well as through dynamic interactions with the tumor microenvironment (TME). Ovarian CSC (OCSC)-associated biomarkers, including CD44, CD24, CD133, and ALDH, have expanded opportunities for specific tumor characterization and biomarker identification. Effective targeting of OCSCs requires experimental models that preserve cellular plasticity and hierarchical organization. Development of synthetic matrices and chemically defined media has improved the reproducibility and scalability of three-dimensional (3D) organoid cultures for preclinical drug testing. CSC-derived organoids, established by enriching cells positive for CSC markers directly from patient tumor material, provide a 3D platform for studying OCSC-associated phenotypes and therapeutic responses. This review examines current understanding of ovarian CSC biology and the development of OCSC-derived 3D organoid models that can recapitulate cellular architecture and patient-specific drug responses. These 3D organoid models provide a guided platform for evaluating emerging therapeutics, such as micropeptides encoded by short open reading frames or engineered from functional tumor-suppressor protein domains selected to target OCSCs. Their small size enables modulation of intracellular signaling and highly specific protein–protein interactions. We further review micropeptide stabilization strategies and tumor-targeted delivery systems designed to enhance bioavailability. This review highlights how integrating patient-specific OCSC-derived organoid models with engineered micropeptides may accelerate the development of personalized treatment strategies for ovarian cancer while improving the preclinical evaluation of novel therapies.
SN  - 2072-6694
ER  -