About

Todd William Ridky, M.D., Ph.D., is an Associate Professor of Dermatology and an Attending Physician at the Hospital of the University of Pennsylvania within the Department of Dermatology. His educational background includes a B.S. in Chemistry from the University of North Carolina at Chapel Hill (1992), a Ph.D. in Biochemistry from Case Western Reserve University (1997), and an M.D. from Case Western Reserve University School of Medicine (1999). He also completed a research mentor training certification at the University of Pennsylvania in 2022. Dr. Ridky's research focuses on epithelial biology, gene regulatory control of epidermal homeostasis, and epithelial oncogenesis. His laboratory employs genetically-defined, engineered epithelial tissues to study pathways involved in human cancer initiation, stromal invasion, tumor-stroma interactions, metastasis, and the maintenance of cancer stem cells. His work involves developing experimental human tissue systems based on normal primary human cells within a native 3-D environment, incorporating mesenchymal stroma and living stromal cells. These models allow for rapid genetic alterations and facilitate the study of cancer progression through systems biology approaches, genetic interventions, and targeted therapeutics. Dr. Ridky has contributed significantly to understanding the molecular mechanisms underlying skin and epithelial cancers, with a focus on translating these insights into potential therapeutic targets.

Research topics

• Biology
• Cancer research
• Chemistry
• Cell biology
• Molecular biology

Selected publications

• Stress vesicles link epidermal mechanotransduction to stem cell differentiation

  Nature Communications · 2026-01-23

  articleOpen access

  The skin exhibits extraordinary plasticity, enabling it to adapt to mechanical changes in the environment. While transient deformations are accommodated without lasting structural effects, sustained mechanical stress induces durable tissue changes. To investigate if these responses are mediated by shifts in epidermal stem cell fate, we employed two-photon intravital imaging to visualize epidermal cells in live skin subjected to acute mechanical forces. Mechanical force triggered the formation of intracellular “stress” vesicles within epidermal stem cells that filled with extracellular fluid and progressively enlarged, deforming the nucleus. Lineage tracing analyses revealed that the extent of nuclear deformation can predict cell fate outcomes. Moreover, mechanical stress caused sustained elevation of intracellular calcium in basal epidermal stem cells, and conditional deletion of the mechanosensitive ion channel Piezo1 disrupted calcium dynamics and increased stress vesicle formation. Using human skin xenografts, we demonstrated that stress vesicles are conserved in mammalian skin. Together, these findings identify stress vesicles as key mediators linking mechanical stress, calcium signaling, and epidermal stem cell fate. Using two-photon intravital imaging, the authors show that mechanical stress in skin triggers fluid-filled “stress vesicles” in epidermal cells, altering Piezo1-dependent calcium signals to drive stem cell differentiation and protect tissue integrity.

  PublisherDOI

• Figure 5 from LNS8801: An Enantiomerically Pure Agonist of the G Protein–Coupled Estrogen Receptor Suitable for Clinical Development

  2025-04-04

  preprintOpen accessSenior author

  <p>GPER staining in normal tissues. <b>A,</b> Representative images of GPER-positive staining areas in normal tissues, scale bar, 50 μm. <b>B,</b> Percentage of noncancerous tissue samples with GPER staining across normal tissues; epithelial tissues were quantitated with staining in the epithelial region of the tissue specifically, and denoted with (epi). WT, wildtype.</p>

  PublisherDOI

• Supplemental Table 2 from LNS8801: An Enantiomerically Pure Agonist of the G Protein–Coupled Estrogen Receptor Suitable for Clinical Development

  2025-05-13

  preprintOpen accessSenior author

  <p>Log-rank (Mantel-Cox) all comparisions of data in Figure 2 and 4.</p>

  PublisherDOI

• Data from LNS8801: An Enantiomerically Pure Agonist of the G Protein–Coupled Estrogen Receptor Suitable for Clinical Development

  2025-04-04

  preprintOpen accessSenior author

  <div>Abstract<p>Estrogen effects in tissue are mediated in part through activation of the surface estrogen receptor G protein–coupled estrogen receptor (GPER), a broadly expressed G protein–coupled receptor that affects a wide range of normal and pathologic processes, including metabolism, vascular health, inflammation, and cancer. A commonly used synthetic and specific GPER agonist, named G-1, antagonizes tumors by promoting cellular differentiation and enhancing tumor immunogenicity. G-1 is a racemic compound, and since its discovery, the question of whether both enantiomers display agonist activity or the agonist activity resides primarily in a single enantiomer has never been fully resolved. Herein, we disclose the isolation of the pure enantiomers of G-1 and determine that the desirable activity resides exclusively in one enantiomer, named LNS8801, whose configuration we have unambiguously determined by single-crystal X-ray structure analysis. Using preclinical models, we show that LNS8801 suppresses cancer in a GPER-dependent manner and that LNS8801 is efficacious when administered orally. Furthermore, we show that GPER is widely, but not ubiquitously, expressed in both normal and malignant human tissues. In addition, an attenuated response to LNS8801 is observed in a common germline coding variant in human GPER. These findings support ongoing human cancer trials with LNS8801 and suggest that the germline GPER genotype may serve as a predictive biomarker of therapeutic response.</p>Significance:<p>GPER is broadly expressed in human tissues and has tumor-suppressive activity. No FDA-approved agents selectively target GPER. LNS8801 is a synthetic, orally bioavailable, enantiomerically pure, GPER agonist with potent anticancer activity <i>in vivo</i>. LNS8801 response is attenuated by a common germline coding variant present in roughly half of humans.</p></div>

  PublisherDOI

• Supplemental Figure 2 from LNS8801: An Enantiomerically Pure Agonist of the G Protein–Coupled Estrogen Receptor Suitable for Clinical Development

  2025-05-13

  preprintOpen accessSenior author

  <p>S2. LNS8801 is active in the WM46 human xenograft model.</p>

  PublisherDOI

• Supplemental Figure 1 from LNS8801: An Enantiomerically Pure Agonist of the G Protein–Coupled Estrogen Receptor Suitable for Clinical Development

  2025-04-04

  preprintOpen accessSenior author

  <p>S1. Validation of LNS8801 activity and necessity of GPER in HL-60 cells.</p>

  PublisherDOI

• Figure 1 from LNS8801: An Enantiomerically Pure Agonist of the G Protein–Coupled Estrogen Receptor Suitable for Clinical Development

  2025-04-04

  preprintOpen accessSenior author

  <p>G-1 is a racemic compound. <b>A,</b> Chemical structures of the enantiomers of racemic G-1, LNS8801, and LNS8812. <b>B,</b> Proliferation of YUMM1.7 melanoma cells treated with 500 nmol/L G-1, LNS8801, or LNS8812. <i>n</i> = 5 per group, * denotes significance by one-way ANOVA, α = 0.05. <b>C,</b> Proliferation of 2838c3 PDAC cells treated with 500 nmol/L G-1, LNS8801, or LNS8812. <i>n</i> = 5 per group, * denotes significance by one-way ANOVA, α = 0.05. The dotted line indicates the number of cells in each well at the start of the 4-day incubation.</p>

  PublisherDOI

• Figure 4 from LNS8801: An Enantiomerically Pure Agonist of the G Protein–Coupled Estrogen Receptor Suitable for Clinical Development

  2025-04-04

  preprintOpen accessSenior author

  <p>GPER is necessary, and genetic variation affects LNS8801 effects. <b>A,</b> Western blot demonstrating CRISPR-Cas9 GPER depletion and LNS8801 dose-response proliferation assay in YUMM1.7 cells (melanoma), <i>n</i> = 6 replicates per dose. <b>B,</b> Western blot demonstrating CRISPR-Cas9 GPER depletion and LNS8801 dose-response proliferation assay in 2838c3 cells (pancreatic cancer), <i>n</i> = 6 replicates per dose. <b>C,</b> Tumor volumes and (<b>D</b>) Kaplan–Meier survival curves measured over time in YUMM1.7 melanoma–bearing mice with GPER (GPER WT) and without GPER (GPER KO) treated with orally delivered vehicle or LNS8801 at 1 mg/kg, significance by log-rank (Mantel–Cox). To control for tumor size, treatment was started when tumor sizes were equal; day 7 and day 27 after tumor injection for GPER WT and GPER KO tumor-bearing mice, respectively. Additional statistical information for <b>F</b> is presented in Supplementary Table S2. <b>E,</b> CREB reporter assay of human melanocytes with CRISPR-Cas9 depleted GPER treated with LNS8801, significance by the Mann–Whitney test. <b>F,</b> CREB reporter assay of human melanocytes homozygous for consensus germline GPER (C/C) and heterozygous for variant germline GPER (C/V) treated with 50 nmol/L LNS8801, significance by the Mann–Whitney test.</p>

  PublisherDOI

• Supplemental Table 1 from LNS8801: An Enantiomerically Pure Agonist of the G Protein–Coupled Estrogen Receptor Suitable for Clinical Development

  2025-05-13

  preprintOpen accessSenior author

  <p>Off-target binding of LNS8801 and LNS8812 using Eurofins Discover X.</p>

  PublisherDOI

• Figure 3 from LNS8801: An Enantiomerically Pure Agonist of the G Protein–Coupled Estrogen Receptor Suitable for Clinical Development

  2025-04-04

  preprintOpen accessSenior author

  <p>MM-GBSA modeling of LNS8801 and LNS8812 binding to GPER.</p>

  PublisherDOI

Recent grants

• NIH Grant K08AR053195

  NIH · $598k · 2012

• NIH Grant R41CA228695

  NIH · $300k · 2019

• NIH Grant R01CA163566

  NIH · $1.6M · 2017

• NIH Grant F32CA099473

  NIH · $164k · 2006

• Using Nonclassical Estrogen Signaling to Prevent Melanoma

  NIH · $2.2M · 2019–2025

Frequent coauthors

• Christopher A. Natale

  134 shared

• J. Kevin Foskett

  University of Pennsylvania

  106 shared

• Miriam Doepner

  84 shared

• Inyoung Lee

  EuBiologics (South Korea)

  75 shared

• Sophia Mercado

  California University of Pennsylvania

  75 shared

• Jillian Weissenrieder

  University of Pennsylvania

  74 shared

• Ariana D. Majer

  74 shared

• Pamela J. Sung

  Roswell Park Comprehensive Cancer Center

  74 shared

Labs

• Ridky LabPI

Education

• M.D.,Ph.D.

  Case Western Reserve University

  1999

• B.S., Chemistry

  University of North Carolina at Chapel Hill

  1992

Awards & honors

• Society for Investigative Dermatology
• American Association for Cancer Research