Squishy spheroids and crafty cells: chemically controlling morphological stability and plasticity
Research Summary: Our work identifies an elegant regulatory framework capturing how complex multicellular ensembles transition between morphologically-distinct forms, and how environmental chemical cues influence the stability of these structures.
Researcher Spotlight
Sreepadmanabh M is a final year graduate student with Dr. Tapomoy Bhattacharjee at NCBS, Bangalore. He works at the interface of soft matter biophysics, mechanobiology, and bioengineering. His PhD research pioneers an understanding of complex environments as active regulators of living matter across biological scales.
Linkedin: https://www.linkedin.com/in/sreepadmanabh/
Twitter: @padmanabh97
Instagram: @the_critical_hippo
Lab: Dr. Tapomoy Bhattacharjee, National Centre for Biological Sciences, Tata Institute of Fundamental Research
Linkedin: https://www.linkedin.com/in/tapomoy-bhattacharjee-1858932b/
Twitter: @tapomoy89 and @ESoftbio
Instagram: @tapomoyb
What was the core problem you aimed to solve with this research?
Ovarian cancer – particularly high-grade serous ovarian carcinoma – is one of the most aggressive and challenging pathologies. Clinically, this often presents enigmatic forms, where metastatic cells organize into solid, morula-like masses or hollow, blastula-like ECM-covered masses. Whether and how these morphologically-distinct ensembles alter disease progression remains an open question. Moreover, the mechanistic determinants guiding the cellular reprogramming necessary to achieve such spatially well-defined aggregate organizations remain unclear.
How did you go about solving this problem?
We use self-aggregating ovarian cancer (OVCAR3, OVCAR4, and COV362) cells cultured in suspension to form spheroids. We apply dozens of controlled chemical perturbations by altering calcium levels and pH to test the responses of these structures to varying environmental cues. We combine volumetric live-cell imaging, 3D segmentation, and quantitative measurements of fluid flux and volume fluctuations to characterize the dynamic behavior of these multicellular ensembles. We also trigger complete structural disruptions using chemical stresses to test the self-driven recoverability of spheroidal structures, as well as to quantify the extent of cellular reprogramming induced by collective organization.
We first showed that blastuloids undergo dramatic fluid flux-driven cycles of collapses and recoveries. From this, we went on to find that calcium-dependent cell-cell adhesion determines the structural integrity of blastuloids, as well as influences the transition between solid moruloids and hollow blastuloids. Further, we discovered that acidic pH stabilizes the blastuloids, whereas, basic pH destabilizes and induces a collapse to moruloid-like forms. We also report that these transitions are reversible, which contributes to the morphological plasticity of these structures. Importantly, we find that organization of cells into such collective forms imparts a form of “structural memory” which contributes towards the structural resilience of these multicellular ensembles.
How would you explain your research outcomes (Key findings) to the non-scientific community?
Our study discovers that simple environmental chemical cues – calcium and pH – exert a profound influence on the transitions between structurally-distinct multicellular forms, as well as re-program cells within such collectives. We also demonstrate a remarkable “structural memory” for the individual cells within multicellular aggregates, which enables accelerated recovery of collective organizations even after catastrophic disruptions. Hence, this work holds immense value towards identifying regulatory mechanisms controlling both single cell states and multicellular organisation, as well as understanding how specialized cell populations emerge within multicellular ensembles.
“Our findings highlight how cancer’s spread is not only controlled by genetic changes but also by the chemical makeup of its environment.” – Dr. Tapomoy Bhattacharjee, NCBS
What are the potential implications of your findings for the field and society?
Our findings hold fundamental implications for understanding the plasticity, spatial organization, and structural resilience of self-aggregating multicellular collectives. We would like to understand how these ensemble transitions affect sub-cellular organelle functioning, and further investigate how individual cell states are determined within a collective. From a translational perspective, it would be interesting to explore how drug resistance mechanisms vary between structurally-distinct spheroids.
What was the exciting moment during your research?
One surprising outcome was the high degree of resilience exhibited by blastuloids – even after complete disintegration, the cells could spontaneously re-organize into fully-lumenized ensembles, suggesting an inherent “structural memory”. Incredibly, these recoveries occurred on much shorter time scales (<2 days), whereas, forming blastuloids from scratch actually requires ~7 days. This was a completely unexpected and exciting observation, which gave us direct evidence that individual cells undergo some form of reprogramming as a consequence of the collective organization, which enables them to rapidly recover the original structures.
Paper reference: Distinct Chemical Cues Reprogram Cellular and Multicellular Phenotypes in Ovarian Cancer Spheroids. M Sreepadmanabh, Meenakshi Ganesh, Jimpi Langthasa, Ramray Bhat, Tapomoy Bhattacharjee. Small (2025). https://doi.org/10.1002/smll.202506120
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