About

J. Kevin Foskett, PhD, is the Isaac Ott Professor of Physiology and a Professor in the Department of Cell and Developmental Biology at the University of Pennsylvania. He serves as the Chair of the Department of Physiology at the Perelman School of Medicine. His research interests focus on membrane transport and cell signaling, employing techniques that range from biophysical to molecular, biochemical, and physiological measurements. His laboratory specializes in the molecular physiology of intracellular calcium signaling, particularly the inositol trisphosphate receptor (InsP3R) calcium release channel, and its roles in normal and disease states such as epilepsy, Alzheimer's disease, and programmed cell death. Foskett's work has contributed to understanding how InsP3Rs generate complex calcium signals that regulate processes like mitosis, motility, secretion, and gene transcription, as well as their involvement in pathological conditions. His lab has developed novel techniques to study the properties of single InsP3R channels and their recombinant isoforms, and has made significant discoveries related to mitochondrial calcium uniporters, the molecular mechanisms of Alzheimer's disease, and cystic fibrosis-related ion transport. He is recognized internationally as a leader in the biophysics and cell biology of InsP3R channels and protein interactions, with ongoing research into the regulation of calcium signaling, protein interactions, and their implications for neurodegenerative diseases and cancer.

Research topics

• Biology
• Cell biology
• Chemistry
• Computer Science
• Biochemistry
• Psychology
• Communication
• Botany
• Telecommunications
• Biophysics
• Neuroscience

Selected publications

• Mitochondrial Ca²⁺ in Cancer Growth and Metabolism

  Journal of Cellular Physiology · 2025-09-01 · 1 citations

  reviewOpen accessSenior authorCorresponding

  ABSTRACT Cancer is a leading cause of death in developed countries, despite many breakthroughs in targeted small molecule and immunotherapeutic interventions. A deeper understanding of the characteristics and processes that underlie malignancy will enable us to develop more effective therapeutic options to improve patient outcomes. One particular area of interest is in cancer cell metabolism. Even as early as the 1920s, Otto Warburg recognized dysregulated metabolism in cancerous cells. Altered metabolism may provide targetable nutrient dependencies for further clinical development, either by nutrient restriction or pathway inhibition. More recently, researchers have observed an increasingly strong linkage between altered mitochondrial Ca 2+ homeostasis and tumor cell metabolism, with strong implications for therapeutic targeting. In this review, we summarize the literature surrounding mitochondrial Ca 2+ homeostasis, metabolism, and cancer, as well as providing a discussion of the potential for mitochondrial Ca 2+ modulation as an anticancer therapeutic modality.

  PublisherOA PDFDOI

• BPS2025 - Charcot-Marie-Tooth disease is associated with loss of high-(Ca2+) inhibition of h-IP3R-3 Ca2+-release channel activity

  Biophysical Journal · 2025-02-01

  articleSenior author
  PublisherDOI

• Selective Vulnerability of Cancer Cells by Inhibition of Ca2+ Transfer from Endoplasmic Reticulum to Mitochondria

  Cell Reports · 2025-06-01

  erratumOpen accessSenior author
  PublisherOA PDFDOI

• Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity

  Cell Reports · 2025-04-24 · 6 citations

  articleOpen accessSenior author

  <h2>Summary</h2> Endoplasmic reticulum to mitochondria Ca²⁺ transfer is important for cancer cell survival, but the role of mitochondrial Ca²⁺ uptake through the mitochondrial Ca²⁺ uniporter (MCU) in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in patients with PDAC. In isogenic murine PDAC models, <i>Mcu</i> deletion (<i>Mcu</i>^KO) ablated mitochondrial Ca²⁺ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. <i>Mcu</i> deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to-mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca²⁺ uptake reduced the expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGF-β. Snail re-expression and TGF-β treatment rescued deficits in <i>Mcu</i>^KO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.

  PublisherDOI

• BPS2025 - Kinetic modeling of nuclear large-conductance cationic channels

  Biophysical Journal · 2025-02-01

  articleSenior author
  PublisherDOI

• A mechanism of CALHM1 ion channel gating

  American Journal of Physiology-Cell Physiology · 2025-02-21 · 2 citations

  articleOpen accessSenior authorCorresponding

  -regulated large-pore ion channel that plays an essential role in taste perception. The mechanisms that regulate the opening and the closing of the channel are unknown. Here we explored the role of the amino-terminal region of the channel in gating regulation. Our data define the roles of the amino-terminus in channel gating, establishing components essential for the opening and closing of the CALHM1 channel gate.

  PublisherDOI

• The N-terminus is not the Ca2+-regulated gate in CALHM1 channels

  Biophysical Journal · 2024-02-01

  articleOpen accessSenior author
  PublisherOA PDFDOI

• A recurrent missense variant in <i>ITPR3</i> causes demyelinating Charcot-Marie-Tooth with variable severity

  Brain · 2024-06-24 · 3 citations

  articleOpen access

  Charcot-Marie-Tooth (CMT) disease is a neuromuscular disorder affecting the peripheral nervous system. The diagnostic yield in demyelinating CMT (CMT1) is typically ∼80%-95%, of which at least 60% is due to the PMP22 gene duplication. The remainder of CMT1 is more genetically heterogeneous. We used whole exome and whole genome sequencing data included in the GENESIS database to investigate novel causal genes and mutations in a cohort of ∼2670 individuals with CMT neuropathy. A recurrent heterozygous missense variant p.Thr1424Met in the recently described CMT gene ITPR3, encoding IP3R3 (inositol 1,4,5-trisphosphate receptor 3), was identified. This previously reported p.Thr1424Met change was present in 33 affected individuals from nine unrelated families from multiple populations, representing an unusual recurrence rate at a mutational hotspot, strengthening the gene-disease relationship (gnomAD v4 allele frequency 1.76 × 10-6). Sanger sequencing confirmed the co-segregation of the CMT phenotype with the presence of the mutation in autosomal dominant and de novo inheritance patterns, including a four-generation family with multiple affected second-degree cousins. Probands from all families presented with slow nerve conduction velocities, matching the diagnostic category of CMT1. Remarkably, we observed a uniquely variable clinical phenotype for age at onset and phenotype severity in p.Thr1424Met carrying patients, even within families. Finally, we present data supportive of a dominant-negative effect of the p.Thr1424Met mutation with associated changes in protein expression in patient-derived cells.

  PublisherOA PDFDOI

• Abstract C113: The mitochondrial calcium uniporter supports epithelial to mesenchymal transition of pancreatic ductal adenocarcinoma

  Cancer Research · 2024-01-16

  articleSenior author

  Abstract In spite of many new developments in cancer treatments and targeted therapies over the past few decades, outcomes for pancreatic ductal adenocarcinoma (PDAC) patients continue to be poor. Calcium signaling and mitochondrial function are known to contribute to cancer outcomes in many paradigms, yet much remains unknown in the context of PDAC. The mitochondrial Ca2+ uniporter, MCU, is the main route by which mitochondria can take up Ca2+ into the mitochondrial matrix, where it drives metabolic activity in the tricarboxylic acid cycle and promotes ATP synthesis by the electron transport chain. Our previous work suggests that Ca2+ flux from the endoplasmic reticulum (ER) into the mitochondria at mitochondria-associated membranes (MAMs) may be important to drive malignancy. Here, we show that MCU expression is associated with poor outcomes in PDAC patients and disease progression in murine organoid models of cancer development. Further, deletion of Mcu in murine KPC cells results in ablation of mitochondrial Ca2+ uptake, which reduces growth, proliferation, and clonogenicity. Tumor growth and metastatic colonization are also reduced in orthotopic implantation models, with some KPCY-McucKO models failing to develop primary lesions. This suggests that MCU, and thus mitochondrial Ca2+, play an important role in tumor growth. Critically, we here elucidate a heretofore unknown relationship between ER-to-mitochondrial Ca2+ flux through Mcu and epithelial to mesenchymal transition (EMT), an important process that contributes to poor outcomes in PDAC. To this end, McucKO associates with reduced basal Snail expression and reduced TGFβ secretion, and McucKO clones have a more epithelial morphology than their isogenic, Mcu-expressing counterparts. Both stable expression of Snail and treatment with TGFβ are able to rescue growth, mobility, and clonogenic deficits in McucKO cell lines to levels comparable to isogenic, Mcu-expressing cell lines. Uptake assays, metabolomics, isotope tracing, and mRNA-Seq have enabled us to elucidate metabolic and transcriptional rewiring induced by Snail and TGFβ treatment which may promote cell survival and proliferation despite the lack of Mcu. This work has important implications for potential targeting of Ca2+ signaling in the context of PDAC. Citation Format: Jillian S. Weissenrieder, Jason Pitarresi, Natalie Weinmann, Rebecca Drager, Usha Paudel, Anil Rustgi, Ben Stanger, J. Kevin Foskett. The mitochondrial calcium uniporter supports epithelial to mesenchymal transition of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C113.

  PublisherDOI

• Mitochondrial Ca ²⁺ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-08-09 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Endoplasmic reticulum to mitochondria Ca 2+ transfer is important for cancer cell survival, but the role of mitochondrial Ca 2+ uptake through the mitochondrial Ca 2+ uniporter (MCU) in pancreatic adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in PDAC patients. In isogenic murine PDAC models, Mcu deletion ( Mcu KO ) ablated mitochondrial Ca 2+ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. Mcu deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to-mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca 2+ uptake reduced expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGFβ. Snail re-expression and TGFβ treatment rescued deficits in Mcu KO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R21NS072775

  NIH · $436k · 2013

• NIH Grant R01MH059937

  NIH · $5.0M · 2016

• NIH Grant R01GM056328

  NIH · $4.5M · 2012

• Molecular physiology of CALHM ion channels

  NIH · $2.7M · 2020–2026

• Role of CALHM1 ion channel in taste transduction

  NIH · $2.0M · 2013–2019

Frequent coauthors

• Todd W. Ridky

  California University of Pennsylvania

  106 shared

• Christopher A. Natale

  105 shared

• Jillian Weissenrieder

  University of Pennsylvania

  81 shared

• Pamela J. Sung

  Roswell Park Comprehensive Cancer Center

  75 shared

• Martin Carroll

  University of Pennsylvania

  74 shared

• Miriam Doepner

  74 shared

• Sophia Mercado

  California University of Pennsylvania

  74 shared

• Inyoung Lee

  EuBiologics (South Korea)

  74 shared

Labs

• Foskett LabPI

Education

• B.S.

  Duke University

  1974

• M.S.

  University of South Carolina

  1977

• Ph.D.

  University of California at Berkeley

  1981