Aru Rajeevan

All Publications

• p53: defender of lineage fidelity and foe of plasticity in cancer and regeneration. Trends in cancer Attardi, L. D., Rajeevan, A. 2026

  Abstract

  Although p53 plays a vital role in tumor suppression, the molecular programs underlying its tumor suppressor function remain incompletely understood. Recent work coupling genetically engineered mouse models and single-cell RNA sequencing has illuminated new aspects of p53 function in governing cell state changes. During both lung adenocarcinoma suppression and lung injury repair, p53 acts in a plastic transitional cell state to drive alveolar type 1 cell differentiation, while p53 deficiency causes transitional cell persistence and cancer progression or tissue damage. New insights into p53 function in injury repair in other tissues have also emerged, including in injury-induced intestinal revival stem cells. These studies underscore the importance of p53 in specific plastic states, where it coordinately enforces differentiation and restrains lineage infidelity during tissue healing and cancer suppression.

  View details for DOI 10.1016/j.trecan.2026.02.004

  View details for PubMedID 41887985

• p53 drives lung cancer regression through a TSC2/TFEB-dependent senescence program. Cancer discovery Wang, M., Bieging-Rolett, K. T., Kaiser, A. M., Brady, C. A., Lockhart, J. H., Ferreira, S., Nguyen, K. T., Rajeevan, A., Evans, S. A., Zhao, T., Raj, N., Elkrief, A., Tischfield, S. E., Ladanyi, M., Ozawa, M. G., Bui, N. Q., Chen, C. T., Flores, E. R., Attardi, L. D. 2025

  Abstract

  Pharmacological restoration of p53 tumor suppressor function is a conceptually appealing therapeutic strategy for the many deadly cancers with compromised p53 activity, including lung adenocarcinoma (LUAD). However, the p53 pathway has remained undruggable, partly because of insufficient understanding of how to drive effective therapeutic responses without toxicity. Here, we use mouse and human models to deconstruct the transcriptional programs and sequelae underlying robust therapeutic responses in LUAD. We show that p53 drives potent tumor regression by direct Tsc2 transactivation, leading to mTORC1 inhibition and TFEB nuclear accumulation, which in turn triggers lysosomal gene expression programs, autophagy, and cellular senescence. Senescent LUAD cells secrete factors to recruit macrophages, precipitating cancer cell phagocytosis and tumor regression. Collectively, our analyses reveal a surprisingly complex cascade of events underlying a p53 therapeutic response in LUAD and illuminate targetable nodes for p53 combination therapies, thus establishing a critical framework for optimizing p53-based therapeutics.

  View details for DOI 10.1158/2159-8290.CD-25-0525

  View details for PubMedID 41115251

• Broad misappropriation of developmental splicing profile by cancer in multiple organs. Nature communications Singh, A., Rajeevan, A., Gopalan, V., Agrawal, P., Day, C. P., Hannenhalli, S. 2022; 13 (1): 7664

  Abstract

  Oncogenesis mimics key aspects of embryonic development. However, the underlying mechanisms are incompletely understood. Here, we demonstrate that the splicing events specifically active during human organogenesis, are broadly reactivated in the organ-specific tumor. Such events are associated with key oncogenic processes and predict proliferation rates in cancer cell lines as well as patient survival. Such events preferentially target nitrosylation and transmembrane-region domains, whose coordinated splicing in multiple genes respectively affect intracellular transport and N-linked glycosylation. We infer critical splicing factors potentially regulating embryonic splicing events and show that such factors are potential oncogenic drivers and are upregulated specifically in malignant cells. Multiple complementary analyses point to MYC and FOXM1 as potential transcriptional regulators of critical splicing factors in brain and liver. Our study provides a comprehensive demonstration of a splicing-mediated link between development and cancer, and suggest anti-cancer targets including splicing events, and their upstream splicing and transcriptional regulators.

  View details for DOI 10.1038/s41467-022-35322-1

  View details for PubMedID 36509773

  View details for PubMedCentralID PMC9744839

• Peroxisome Proliferator Activated Receptor-Delta Controls Fat Oxidation in Alloreactive T Cells Waltz, G., Rajeevan, A., Dobbs, A., Denby, E., Byersdorfer, C. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-116727

  View details for Web of Science ID 000454837601185