Research Areas
The Cai lab focuses on understanding how the transcription process is regulated in normal and cancer cells. We are intrigued by the discoveries in our lab that many transcription factors involved in cancers can form small, liquid-like condensates in the nucleus to activate transcription. Our results are consistent with an emerging and paradigm-shifting view in biology: many biochemical reactions inside the living cell are organized in liquid-like condensates formed by weak protein and nucleic acid interactions. This implies that the material states as well as the components of cellular assemblies matter for their functions. We develop and employ many cutting-edge imaging tools in the lab, such as super resolution microscopy, single particle tracking, and optogenetics. By studying these condensates, we hope to understand how transcription is differentially organized in normal and cancer cells, and how we can target these condensates for cancer therapies.
There are three main research directions in the Cai lab:
1. Phase separation of the Hippo pathway.
The Hippo pathway plays a critical role in regulating cell proliferation during organismal development. It contains the kinase cascade involving MST/LATS in the cytoplasm, and the transcription effectors YAP/TAZ and TEAD in the nucleus. However, the spatial and temporal organization of these components remains unclear. We were the first to discover that YAP, a key Hippo effector, forms biomolecular condensates while mediating transcription. We later also found that TEAD and the upstream Hippo kinases form condensates with diverse and differing functions. By studying these condensates, we uncovered crucial insights into how the Hippo pathway utilizes phase separation to rapidly respond to cellular stress and activate gene transcription essential for cell survival.
a. Cai D, Feliciano D, Dong P, Flores E, Gruebele M, Porat-Shliom N, Sukenik S, Liu Z, Lippincott-Schwartz J. Phase separation of YAP reorganizes genome topology for long-term YAP target gene expression. Nat Cell Biol. 2019 Dec;21(12):1578-1589. doi: 10.1038/s41556-019-0433-z. Epub 2019 Dec 2. PubMed PMID: 31792379; PubMed Central PMCID: PMC8259329.
b. Bonello TT, Cai D, Fletcher GC, Wiengartner K, Pengilly V, Lange KS, Liu Z, Lippincott-Schwartz J, Kavran JM, Thompson BJ. Phase separation of Hippo signalling complexes. EMBO J. 2023 Mar 15;42(6):e112863. doi: 10.15252/embj.2022112863. Epub 2023 Feb 20. PubMed PMID: 36807601; PubMed Central PMCID: PMC10015380.
c. Hao S, Lee YJ, Benhamou Goldfajn N, Flores E, Liang J, Fuehrer H, Demmerle J, Lippincott-Schwartz J, Liu Z, Sukenik S, Cai D. YAP condensates are highly organized hubs. iScience. 2024 Jun 21;27(6):109927. doi: 10.1016/j.isci.2024.109927. eCollection 2024 Jun 21. PubMed PMID: 38784009; PubMed Central PMCID: PMC11111833.
d. Liang J, Wang Y, Demmerle J, He BJ, Ricketts CJ, Linehan WM, Zang C, Cai D. TEAD1 condensates are transcriptionally inactive storage sites on the pericentromeric heterochromatin. bioRxiv. 2025:2025.05.02.651992. doi: 10.1101/2025.05.02.651992.
2. Biomolecular condensates in cancer.
We were among the first to propose that biomolecular condensates play a crucial role in cancer formation and progression. A significant proportion of cancer-related mutations occur in disordered protein domains, which do not adopt rigid structures. These disordered regions often form diverse biomolecular condensates, essential for various cellular processes. Our lab focuses on papillary and translocation renal cell carcinoma as models to study condensates formed by Hippo pathway transcription factors and TFE3 fusion oncoproteins. Understanding the components and functions of these cancer-related condensates will offer critical insights for developing condensate-targeting cancer therapies.
a. So CL, Lee YJ, Vokshi BH, Chen W, Huang B, De Sousa E, Gao Y, Portuallo ME, Begum S, Jagirdar K, Linehan WM, Rebecca VW, Ji H, Toska E, Cai D. TFE3 fusion oncoprotein condensates drive transcriptional reprogramming and cancer progression in translocation renal cell carcinoma. Cell Rep. 2025 Apr 22;44(4):115539. doi: 10.1016/j.celrep.2025.115539. Epub 2025 Apr 11. PubMed PMID: 40222010.
b. Cai D, Liu Z, Lippincott-Schwartz J. Biomolecular Condensates and Their Links to Cancer Progression. Trends Biochem Sci. 2021 Jul;46(7):535-549. doi: 10.1016/j.tibs.2021.01.002. Epub 2021 Feb 10. PubMed PMID: 33579564.
c. Magesh S, Cai D. Roles of YAP/TAZ in ferroptosis. Trends Cell Biol. 2022 Sep;32(9):729-732. doi: 10.1016/j.tcb.2022.05.005. Epub 2022 Jun 11. PubMed PMID: 35701310; PubMed Central PMCID: PMC10153635.
3. Dynamic interactome of membrane-less organelles.
Membrane-less organelles (MLOs) perform diverse and important functions inside cells. However, how they interact with each other to carry out these functions collectively is unknown. We proposed a paradigm-shifting idea that the dynamic interactome of MLOs are shaped by cellular states, which in turn determines cellular functions. By devising a novel “Rainbow Nucleus” multi-spectral imaging tool, we mapped the first interactome of five MLOs inside the nucleus, and discovered specific functional interactions among these MLOs. We envision that this new field of MLOs interactome research will provide essential insights into cellular organization, and generate new tools to alter these interactions to modulate cell function in physiology and diseases.
a. Ye S, Benhamou Goldfajn N, So CL, Inoue T, Cai D. Rainbow Nucleus Charts Dynamic Interactome of Membrane-less Organelles. bioRxiv. 2025:2025.05.14.654140. doi: 10.1101/2025.05.14.654140.
b. Liang J, Cai D. Membrane-less compartments in the nucleus: Separated or connected phases? Curr Opin Cell Biol. 2023 Oct;84:102215. doi: 10.1016/j.ceb.2023.102215. Epub 2023 Aug 11. Review. PubMed PMID: 37574634; PubMed Central PMCID: PMC10528681.