About

Eric S. Witze, Ph.D., is an Associate Professor of Cancer Biology and an Assistant Investigator at the Abramson Family Cancer Research Institute at the University of Pennsylvania's Perelman School of Medicine. His research focuses on the regulation of cell signaling in cancer, particularly through protein palmitoylation in response to non-canonical Wnt signaling pathways. His laboratory investigates how Wnt control of cell polarity influences cancer progression, with specific attention to melanoma and other cancers. Dr. Witze's work has elucidated mechanisms by which Wnt5a signaling induces cell polarity phenotypes, including the polarized localization of cell adhesion molecules such as MCAM, which is palmitoylated and undergoes depalmitoylation upon Wnt5a activation. His research has identified the enzyme APT1 as a key mediator in this process, with Wnt5a signaling inducing phosphorylation of APT1, thereby increasing its activity and promoting metastatic behavior in melanoma cells. Additionally, his lab studies the palmitoyl-transferase DHHC20, which palmitoylates the epidermal growth factor receptor (EGFR), and how its inhibition affects receptor activation and cancer cell dependence on EGFR signaling. His work has demonstrated that loss of palmitoylation can activate EGFR and transform cells, providing insights into potential therapeutic strategies for cancers with EGFR mutations or resistance to inhibitors.

Research topics

• Cell biology
• Biology
• Chemistry
• Cancer research
• Computational biology

Selected publications

• A selective S-acyltransferase inhibitor suppresses tumor growth

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-07-22 · 2 citations

  preprintOpen accessSenior authorCorresponding

  S-acyltransferases play integral roles in essential physiological processes including regulation of oncogenic signaling pathways. While discovered over 40 years ago the field still lacks specific S-acylation inhibitors thus the potential benefit of pharmacologically targeting S-acyltransferases for human disease is still unknown. Here we report the identification of an orally bioavailable acyltransferase inhibitor SD-066-4 that inhibits the acyltransferase ZDHHC20. We identified a specific alanine residue that accommodates the methyl group of SD-066-4, thus providing isoform selectivity. SD-066-4 stably reduces EGFR S-acylation in Kras mutant cells and blocks the growth of Kras mutant lung tumors extending overall survival. We find that lung cancer patients harboring deletions in ZDHHC20 or ZDHHC14 concurrent with Kras alterations have a significant survival benefit, underscoring the translational importance of these enzymes.

  PublisherOA PDFDOI

• Chemical Methods from A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles

  2023-04-03

  preprintOpen access

  <p>Supplemental Chemical Methods</p>

  PublisherOA PDFDOI

• Chemical Methods from A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles

  2023-04-03

  preprintOpen access

  <p>Supplemental Chemical Methods</p>

  PublisherDOI

• Data from A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles

  2023-04-03

  preprintOpen access

  <div>Abstract<p>Lysosomes serve dual roles in cancer metabolism, executing catabolic programs (i.e., autophagy and macropinocytosis) while promoting mTORC1-dependent anabolism. Antimalarial compounds such as chloroquine or quinacrine have been used as lysosomal inhibitors, but fail to inhibit mTOR signaling. Further, the molecular target of these agents has not been identified. We report a screen of novel dimeric antimalarials that identifies dimeric quinacrines (DQ) as potent anticancer compounds, which concurrently inhibit mTOR and autophagy. Central nitrogen methylation of the DQ linker enhances lysosomal localization and potency. An <i>in situ</i> photoaffinity pulldown identified palmitoyl-protein thioesterase 1 (PPT1) as the molecular target of DQ661. PPT1 inhibition concurrently impairs mTOR and lysosomal catabolism through the rapid accumulation of palmitoylated proteins. DQ661 inhibits the <i>in vivo</i> tumor growth of melanoma, pancreatic cancer, and colorectal cancer mouse models and can be safely combined with chemotherapy. Thus, lysosome-directed PPT1 inhibitors represent a new approach to concurrently targeting mTORC1 and lysosomal catabolism in cancer.</p><p><b>Significance:</b> This study identifies chemical features of dimeric compounds that increase their lysosomal specificity, and a new molecular target for these compounds, reclassifying these compounds as targeted therapies. Targeting PPT1 blocks mTOR signaling in a manner distinct from catalytic inhibitors, while concurrently inhibiting autophagy, thereby providing a new strategy for cancer therapy. <i>Cancer Discov; 7(11); 1266–83. ©2017 AACR.</i></p><p><i>See related commentary by Towers and Thorburn, p. 1218</i>.</p><p><i>This article is highlighted in the In This Issue feature, p. 1201</i></p></div>

  PublisherDOI

• Supplemental Figures S1-S7 and Supplemental Table S1 from A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles

  2023-04-03

  preprintOpen access

  <p>Supplemental Figures and Table</p>

  PublisherDOI

• Supplemental Figures S1-S7 and Supplemental Table S1 from A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles

  2023-04-03

  preprintOpen access

  <p>Supplemental Figures and Table</p>

  PublisherOA PDFDOI

• Chemical probe mediated visualization of protein S-palmitoylation in patient tissue samples

  Frontiers in Physiology · 2023-02-21 · 4 citations

  articleOpen accessSenior authorCorresponding

  While protein palmitoylation has been studied for decades, our understanding of its clinical importance is minimal compared to other post translational modifications. As a result of the inherent challenges preventing the production of antibodies to palmitoylated epitopes we are unable to correlate levels of protein palmitoylation in biopsied tissues at a meaningful resolution. The most common method for detecting palmitoylated proteins without metabolic labelling is through chemical labeling of palmitoylated cysteines with the acyl-biotinyl exchange (ABE) assay. We have adapted the ABE assay to detect protein palmitoylation in formalin fixed paraffin embedded (FFPE) tissue sections. The assay is sufficient to detect subcellular regions of cells with increased labeling which indicates areas enriched in palmitoylated proteins. To visualize specific palmitoylated proteins in both cultured cells and in FFPE preserved tissue arrays we have integrated the ABE assay with a proximity ligation assay (ABE-PLA). Our findings demonstrate for the first time that FFPE preserved tissues can be labelled with unique chemical probes to detect either areas enriched in palmitoylated proteins or the localization of specific palmitoylated proteins using our ABE-PLA methodology.

  PublisherOA PDFDOI

• Data from A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles

  2023-04-03

  preprintOpen access

  <div>Abstract<p>Lysosomes serve dual roles in cancer metabolism, executing catabolic programs (i.e., autophagy and macropinocytosis) while promoting mTORC1-dependent anabolism. Antimalarial compounds such as chloroquine or quinacrine have been used as lysosomal inhibitors, but fail to inhibit mTOR signaling. Further, the molecular target of these agents has not been identified. We report a screen of novel dimeric antimalarials that identifies dimeric quinacrines (DQ) as potent anticancer compounds, which concurrently inhibit mTOR and autophagy. Central nitrogen methylation of the DQ linker enhances lysosomal localization and potency. An <i>in situ</i> photoaffinity pulldown identified palmitoyl-protein thioesterase 1 (PPT1) as the molecular target of DQ661. PPT1 inhibition concurrently impairs mTOR and lysosomal catabolism through the rapid accumulation of palmitoylated proteins. DQ661 inhibits the <i>in vivo</i> tumor growth of melanoma, pancreatic cancer, and colorectal cancer mouse models and can be safely combined with chemotherapy. Thus, lysosome-directed PPT1 inhibitors represent a new approach to concurrently targeting mTORC1 and lysosomal catabolism in cancer.</p><p><b>Significance:</b> This study identifies chemical features of dimeric compounds that increase their lysosomal specificity, and a new molecular target for these compounds, reclassifying these compounds as targeted therapies. Targeting PPT1 blocks mTOR signaling in a manner distinct from catalytic inhibitors, while concurrently inhibiting autophagy, thereby providing a new strategy for cancer therapy. <i>Cancer Discov; 7(11); 1266–83. ©2017 AACR.</i></p><p><i>See related commentary by Towers and Thorburn, p. 1218</i>.</p><p><i>This article is highlighted in the In This Issue feature, p. 1201</i></p></div>

  PublisherDOI

• Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis

  Open Biology · 2021-10-01 · 43 citations

  reviewOpen accessSenior authorCorresponding

  The epidermal growth factor receptor (EGFR) is an essential driver of oncogenic signalling, and EGFR inhibitors are some of the earliest examples of successful targeted therapies in multiple types of cancer. The tractability of EGFR as a therapeutic target is overshadowed by the inevitable drug resistance that develops. Overcoming resistance mechanisms requires a deeper understanding of EGFR regulation in cancer cells. In this review, we discuss our recent discovery that the palmitoyltransferase DHHC20 palmitoylates EGFR on the C-terminal domain and plays a critical role in signal regulation during oncogenesis. Inhibiting DHHC20 expression or mutating the palmitoylation site on EGFR alters the EGF-induced signalling kinetics from a transient signal to a sustained signal. The change in signalling is accompanied by a decrease in cell proliferation in multiple human cancer cell lines. Our in vivo studies demonstrate that ablating the gene Zdhhc20 by CRISPR/Cas9-mediated inhibition in a mouse model of oncogenic Kras-driven lung adenocarcinoma potently inhibits tumorigenesis. The negative effect on tumorigenesis is mediated by EGFR since the expression of a palmitoylation-resistant mutant form of EGFR also inhibits Kras-driven lung adenocarcinoma. Finally, reducing EGFR palmitoylation increases the sensitivity of multiple cancer cell lines to existing inhibitors of EGFR and downstream signalling effector pathways. We will discuss the implications of these effects and strategies for targeting these new vulnerabilities.

  PublisherDOI

• Author response for "Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis"

  2021-09-09

  peer-reviewSenior author
  PublisherDOI

Recent grants

• Understanding Wnt5a regulation of protein depalmitoylation during cell migration

  NIH · $1.5M · 2014–2020

• Understanding Wnt5a regulation of protein depalmitoylation during cell migration

  NIH · $332k · 2014–2019

• NIH Grant F32CA112847

  NIH · $143k · 2008

Frequent coauthors

• Natalie G. Ahn

  Comer Children's Hospital

  18 shared

• Donita C. Brady

  17 shared

• Elizabeth S. Litman

  George Washington University

  13 shared

• Ronen Marmorstein

  12 shared

• Kristin B. Runkle

  University of Pennsylvania

  12 shared

• Julie S. Barber-Rotenberg

  University of Pennsylvania

  12 shared

• Gretchen Argast

  10 shared

• Zhi Wei

  Ansteel (China)

  9 shared