Jimpi Langthasa

All Publications

• Distinct Chemical Cues Reprogram Cellular and Multicellular Phenotypes in Ovarian Cancer Spheroids. Small (Weinheim an der Bergstrasse, Germany) Sreepadmanabh, M., Ganesh, M., Langthasa, J., Bhat, R., Bhattacharjee, T. 2025: e06120

  Abstract

  The self-organization of cellular collectives is crucial in development and cancer. Multicellular aggregation in cancer is associated with a higher efficiency of metastasis. However, it is not fully understood how mechanochemical microenvironmental cues affect the organization and stability of such ensembles. Here, using a model system of ovarian cancer spheroids, which temporally transit from solid, dysmorphic moruloids to structurally plastic, lumen-containing blastuloids, it is shown that the periodic volume fluctuations observed in blastuloids are driven by lumenal fluid influx and cell-cell junctional states. Furthermore, blastuloid cell states are reprogrammed, which enables them to rapidly recover from even complete structural disintegration and self-organize into fully lumenized ensembles. Using targeted chemical perturbations, two distinct cues are identified that regulate separate transition traits: calcium levels establish cell states cognate to, and pH regulates the fluctuation dynamics of blastuloid phenotypes. The work holds significant implications toward understanding mechanisms governing structural resilience and plasticity in complex cellular assemblies.

  View details for DOI 10.1002/smll.202506120

  View details for PubMedID 40955874

• VISTA immune checkpoint blunts radiotherapy-induced antitumor immune response. Cell reports Nambiar, D. K., Maddineni, S., Langthasa, J., Cao, H., Viswanathan, V., Liu, J., Islam, M. T., Mehta, N., Frank, J., Real, A., Cheunkarndee, T., Laseinde, E. E., Dharmadhikari, B., Thakkar, D., Boyd-Kirkup, J. D., Finegersh, A., Divi, V., Sunwoo, J. B., Aleman, J., Wang, X. J., Kong, C., Xing, L., Cochran, J. R., Le, Q. T. 2025; 44 (7): 115893

  Abstract

  Radiotherapy (RT) is a key treatment for solid neoplasms like head and neck cancer (HNC), but it can also activate and recruit immunosuppressive myeloid cells, causing treatment failure. In this study, we examine the role of V-domain immunoglobulin suppressor of T cell activation (VISTA) on myeloid cells during RT. We discovered high VISTA expression on myeloid cells in the tumor microenvironment (TME) of both murine and human HNC, with RT increasing VISTA+ myeloid cells in the TME and circulation. Compared to VISTA+/+ mice, VISTA-/- mice showed improved tumor control with RT, with their macrophages and neutrophils exhibiting antitumorigenic properties on sc-RNA-seq analysis, especially with RT. Combining anti-VISTA antibodies (active or silent Fc) with RT (fractionated or ablative) significantly decreased tumor volume compared to either treatment alone in multiple preclinical models (HNC, breast cancer, and colorectal cancer), enhancing systemic antitumor immune response with augmented intra-tumoral T cell function through myeloid repolarization. Targeting VISTA could improve the efficacy of RT.

  View details for DOI 10.1016/j.celrep.2025.115893

  View details for PubMedID 40580480

• Rheological transition driven by matrix makes cancer spheroids resilient under confinement. Life science alliance Dutt, T., Langthasa, J., Umesh, M., Mishra, S., Bothra, S., Vidhipriya, K., Vadaparty, A., Sen, P., Bhat, R. 2025; 8 (6)

  Abstract

  Cancer metastasis through confining peritoneal microenvironments is mediated by spheroids: clusters of disseminated cells. Ovarian cancer spheroids are frequently cavitated; such blastuloid morphologies possess an outer ECM coat. We investigated the effects of these spheroidal morphological traits on their mechanical integrity. Atomic force microscopy showed blastuloids were elastic compared with their prefiguring lumenless moruloid counterparts. Moruloids flowed through microfluidic setups mimicking peritoneal confinement, exhibited asymmetric cell flows during entry, were frequently disintegrated, and showed an incomplete and slow shape recovery upon exit. In contrast, blastuloids exhibited size-uncorrelated transit kinetics, rapid and efficient shape recovery upon exit, symmetric cell flows, and lesser disintegration. Blastuloid ECM debridement phenocopied moruloid traits including lumen loss and greater disintegration. Multiscale computer simulations predicted that higher intercellular adhesion and dynamical lumen make blastuloids resilient. Blastuloids showed higher E-cadherin expression, and their ECM removal decreased membrane E-cadherin localization. E-cadherin knockdown also decreased lumen formation and increased spheroid disintegration. Thus, the spheroidal ECM drives its transition from a labile viscoplastic to a resilient elastic phenotype, facilitating their survival within spatially constrained peritoneal flows.

  View details for DOI 10.26508/lsa.202402601

  View details for PubMedID 40147946

  View details for PubMedCentralID PMC11949850

• Salivary gland stem/progenitor cells: advancing from basic science to clinical applications. Cell regeneration (London, England) Langthasa, J., Guan, L., Jinagal, S. L., Le, Q. T. 2025; 14 (1): 4

  Abstract

  Salivary gland stem/progenitor cells (SSPCs) hold significant potential for regenerative medicine, especially for patients suffering from salivary gland dysfunction due to various causes such as radiation therapy, Sjögren's syndrome, and aging. This review provides a comprehensive overview of SSPCs, including their characteristics, isolation, culture techniques, differentiation pathways, and their role in tissue regeneration. Additionally, we highlight recent advances in cell- and tissue-based therapies, such as SSPC transplantation and bioengineered organ replacements. The challenges in translating SSPC research into effective clinical therapies are also discussed, alongside proposed solutions and future research directions.

  View details for DOI 10.1186/s13619-025-00221-5

  View details for PubMedID 39856475

  View details for PubMedCentralID 5980780

• Gold-siRNA supraclusters enhance the anti-tumor immune response of stereotactic ablative radiotherapy at primary and metastatic tumors. Nature biotechnology Jiang, Y., Cao, H., Deng, H., Guan, L., Langthasa, J., Colburg, D. R., Melemenidis, S., Cotton, R. M., Aleman, J., Wang, X. J., Graves, E. E., Kalbasi, A., Pu, K., Rao, J., Le, Q. T. 2024

  Abstract

  Strategies to enhance the anti-tumor immune response of stereotactic ablative radiotherapy (SABR) at primary tumors and abscopal sites are under intensive investigation. Here we report a metabolizable binary supracluster (BSCgal) that combines gold nanoclusters as radiosensitizing adjuvants with small interfering RNA (siRNA) targeting the immunosuppressive mediator galectin-1 (Gal-1). BSCgal comprises reversibly crosslinked cationic gold nanoclusters and siRNA complexes in a polymer matrix that biodegrades over weeks, facilitating clearance (90.3% in vivo clearance at 4 weeks) to reduce toxicity. The particle size well above the renal filtration threshold facilitates passive delivery to tumors. Using mouse models of head and neck cancer, we show that BSCgal augments the radiodynamic and immunotherapeutic effects of SABR at the primary and metastatic tumors by promoting tumor-inhibitory leukocytes, upregulating cytotoxic granzyme B and reducing immunosuppressive cell populations. It outperforms SABR plus Gal-1 antagonists, chemoradiation drug cisplatin or PD-1 inhibitor. This work presents a translatable strategy to converge focal radiosensitization with targeted immune checkpoint silencing for personalized radioimmunotherapy.

  View details for DOI 10.1038/s41587-024-02448-0

  View details for PubMedID 39448881

  View details for PubMedCentralID 6053911

• Targeting metabolic fluxes reverts metastatic transitions in ovarian cancer. iScience Arora, G., Banerjee, M., Langthasa, J., Bhat, R., Chatterjee, S. 2023; 26 (11): 108081

  Abstract

  The formation of spheroids during epithelial ovarian cancer progression is correlated with peritoneal metastasis, disease recurrence, and poor prognosis. Although metastasis has been demonstrated to be driven by metabolic changes in transformed cells, mechanistic associations between metabolism and phenotypic transitions remain ill-explored. We performed quantitative proteomics to identify protein signatures associated with three distinct phenotypic morphologies (2D monolayers and two geometrically distinct three-dimensional spheroidal states) of the high-grade serous ovarian cancer line OVCAR-3. We obtained disease-driving phenotype-specific metabolic reaction modules and elucidated gene knockout strategies to reduce metabolic alterations that could drive phenotypic transitions. Exploring the DrugBank database, we identified and evaluated drugs that could impair such transitions and, hence, cancer progression. Finally, we experimentally validated our predictions by confirming the ability of one of our predicted drugs, the neuraminidase inhibitor oseltamivir, to inhibit spheroidogenesis in three ovarian cancer cell lines without any cytotoxic effects on untransformed stromal mesothelia.

  View details for DOI 10.1016/j.isci.2023.108081

  View details for PubMedID 37876796

  View details for PubMedCentralID PMC10590820

• Extracellular matrix mediates moruloid-blastuloid morphodynamics in malignant ovarian spheroids. Life science alliance Langthasa, J., Sarkar, P., Narayanan, S., Bhagat, R., Vadaparty, A., Bhat, R. 2021; 4 (10)

  Abstract

  Ovarian cancer metastasizes into peritoneum through dissemination of transformed epithelia as multicellular spheroids. Harvested from the malignant ascites of patients, spheroids exhibit startling features of organization typical to homeostatic glandular tissues: lumen surrounded by smoothly contoured and adhered epithelia. Herein, we demonstrate that cells of specific ovarian cancer lines in suspension, aggregate into dysmorphic solid "moruloid" clusters that permit intercellular movement, cell penetration, and interspheroidal coalescence. Moruloid clusters subsequently mature into "blastuloid" spheroids with smooth contours, a temporally dynamic lumen and immotile cells. Blastuloid spheroids neither coalesce nor allow cell penetration. Ultrastructural examination reveals a basement membrane-like extracellular matrix coat on the surface of blastuloid, but not moruloid, spheroids. Quantitative proteomics reveals down-regulation in ECM protein Fibronectin-1 associated with the moruloid-blastuloid transition; immunocytochemistry also confirms the relocalization of basement membrane ECM proteins: collagen IV and laminin to the surface of blastuloid spheroids. Fibronectin depletion accelerates, and enzymatic basement membrane debridement impairs, lumen formation, respectively. The regulation by ECM dynamics of the morphogenesis of cancer spheroids potentially influences the progression of the disease.

  View details for DOI 10.26508/lsa.202000942

  View details for PubMedID 34376568

  View details for PubMedCentralID PMC8358442

• The glycobiology of ovarian cancer progression: phenotypic switches and microenvironmental influences J Langthasa, P Sarkar, R Bhat Phenotypic switching: implications in biology and medicine Langthasa, J. 2020