Veena Padmanaban, Ph.D.

Summary of Research:

Metastasis remains the principal cause of cancer mortality, yet the biological mechanisms that enable tumor cells to survive dissemination and colonize distant organs remain incompletely understood. The Padmanaban laboratory investigates a fundamental and underappreciated regulator of this process: the peripheral sensory nervous system. We study how solid tumors co-opt sensory neurons at primary and distant sites and how neuronal plasticity governs metastatic survival and colonization.

During my postdoctoral work, we demonstrated that sensory neurons innervate primary breast tumors and are required for their metastatic spread. We identified a tumor-driven neuropeptide signaling axis in which cancer cells stimulate substance P release from sensory nerves, activating an innate RNA-sensing pathway within tumor cells to enhance cancer cell invasion, growth, and metastasis. These findings establish peripheral sensory nerves as active regulators of metastatic competence and reveal neural signaling as a therapeutically actionable vulnerability, with pharmacologic blockade of this pathway significantly impairing tumor progression in preclinical models.

Building on this foundation, our laboratory advances three interconnected research directions. First, we define mechanisms of cancer-induced neuronal reprogramming: identifying how tumor-derived cues convert quiescent sensory neurons into metastasis-promoting states and uncovering the transcriptional programs that drive this transition. Second, we determine how organ-specific sensory innervation shapes metastatic niches, investigating how neural remodeling in tissues such as lung, liver, and bone influences metastatic seeding, dormancy, and outgrowth. Third, we dissect neuro-immune integration in metastasis, defining how nerve-derived signals coordinate innate immune responses and inflammation to regulate tumor progression across tissue contexts. Through these efforts, we aim to establish peripheral nerve co-option as a mechanistic driver of metastatic disease and to identify neural dependencies that can be disrupted to prevent lethal cancer progression.

List of publications:

1. Padmanaban V., Keller I., Seltzer E., Ostendorf B., Kerner Z., Tavazoie S.F., Neuronal substance-P drives breast cancer growth and metastasis via an extracellular RNA/ TLR7 axis. Nature (2024). https://doi.org/10.1038/s41586-024-07767-5.

Featured in: Ledford H., Nature (2024).
Featured in: Villenueva T.M., Nature Rev Drug Discovery (2024).
Featured in: Malireddi R.K.S. & Kanneganti T., Trends in Immun (2024).

2. Padmanaban V., Krol I., Suhail Y., Szczerba B.M., Aceto N., Bader J.S., Ewald A.J., E-cadherin is required for metastasis in multiple models of breast cancer, Nature (2019), 573 (439-444). https://doi.org/10.1038/s41586-019-1526-3.

Featured in: Gomis R.R., Nature (2019), 573 (353-354).
Featured in: O’Driscoll L., New England Journal of Medicine (2020), 383 (871-873).
Featured in: Shen M., and Kang Y., Developmental Cell (2019), 51(4) 417-419.

3. Padmanaban V., Cheung K.J., Grasset E.M., Neumann N.M., Fraser A.K., Henriet E., Matsui W., Tran P.T., Georgess D., Ewald A.J., Organotypic culture assays for murine and human primary and metastatic-site tumors, Nature Protocols(2020). https://doi.org/10.1038/s41596-020-0335-3.
4. Padmanaban V., Tsehay Y., Cheung K.J., Ewald A.J., Bader J.S., Between-tumor and within-tumor heterogeneity in invasive potential, PLoS Computational Biology (2020), https://doi.org/10.1371/journal.pcbi.1007464.
5. Liu X., Mei W., Padmanaban V., Alwaseem H., Molina H., Passarelli M.C., Tavora B., Tavazoie S.F. A pro-metastatic tRNA fragment drives Nucleolin oligomerization and stabilization of its bound metabolic mRNAs. Molecular Cell (2022), 82 (14), 2536-2538.
6. Georgess D., Padmanaban V., Sirka O.K., Coutinho K., Choi A., Frid G., Neumann N.M., Inoue T., Ewald A.J., Twist-1 induced epithelial dissemination requires PKD1 signaling, JCB (2020), 80 2(204-218).
7. Chan I., Knutsdottir H., Ramakrishnan G., Padmanaban V., Warrier M., Ramirez J.C., Zhang H., Jaffee E., Bader J.S., Ewald A.J., Cancer cells educate natural killer cells to a metastasis-promoting cell state, JCB(2020), 219 (9): e202001134.
8. Cheung K.J., Padmanaban V., Silvestri V., Schipper K., Cohen J.D., Fairchild A.N., Gorin M.A., Verdone J.E., Pienta K.J., Ewald A.J., Polyclonal breast cancer metastases arise from collective tumor cell clusters, PNAS (2016), 113 7(854-863).