About

Anil K. Rustgi, MD, is an Emeritus Professor of Medicine (Gastroenterology) at the University of Pennsylvania Perelman School of Medicine. He serves as the Chief of the Division of Gastroenterology and is the Director of the Digestive Diseases and Liver Clinical Center at the same institution. Dr. Rustgi is a member of the Cancer Center, specifically within the Center for Cancer Pharmacology and the Chemoprevention Program. He also directs the NIH Center for Molecular Studies in Digestive and Liver Diseases and the NIDDK Year Out Program for medical students at Penn. Additionally, he is a Co-Program Leader of the Tumor Biology Program at the Abramson Cancer Center and a director of the Joint Center for Digestive, Liver, and Pancreatic Medicine, which involves collaboration between the University of Pennsylvania and the Children's Hospital of Philadelphia. His research expertise focuses on oncogenes, tumor suppressor genes, tumor microenvironment, tumor metastasis, and the molecular genetics of gastrointestinal cancers, including colon, pancreatic, and upper GI cancers. His laboratory investigates the tissue-specific actions of oncogenes such as cyclin D1 and EGFR, and tumor suppressor genes like p53 and p120 catenin, particularly in the context of gastrointestinal cancers. Employing novel three-dimensional cell culture systems and genetically-engineered mouse models, his work aims to elucidate molecular mechanisms with the goal of improving molecular diagnostics and developing experimental therapeutics for patients.

Research topics

• Medicine
• Internal medicine
• Oncology
• Cancer research
• Biology
• Genetics
• Bioinformatics
• Cell biology
• Pathology
• Gastroenterology
• Surgery

Selected publications

• LIN28B-mediated PI3K/AKT pathway activation promotes metastasis in colorectal cancer models

  Journal of Clinical Investigation · 2025-01-14 · 13 citations

  articleOpen accessSenior author

  Colorectal cancer (CRC) remains a leading cause of cancer death because of metastatic spread. LIN28B is overexpressed in 30% of CRCs and promotes metastasis, yet its mechanisms remain unclear. In this study, we genetically modified CRC cell lines to overexpress LIN28B, resulting in enhanced PI3K/AKT pathway activation and liver metastasis in mice. We developed genetically modified mouse models with constitutively active Pik3ca that form intestinal tumors progressing to liver metastases with an intact immune system, addressing the limitations of previous Pik3ca-mutant models, including long tumor latency, mixed histology, and lack of distant metastases. The PI3Kα-specific inhibitor alpelisib reduced migration and invasion in vitro and metastasis in vivo. We present a comprehensive analysis of vertical inhibition of the PI3K/AKT pathway in CRC using the FDA-approved drugs alpelisib and capivasertib (an AKT inhibitor) in combination with LY2584702 (a ribosomal protein S6 kinase inhibitor) in CRC cell lines and mouse- and patient-derived organoids. Tissue microarrays from patients with CRC verified that LIN28B and PI3K/AKT pathway activation correlate with CRC progression. These findings highlight the critical role of the LIN28B-mediated PI3K/AKT pathway in CRC metastasis, the therapeutic potential of targeted inhibition, and the promise of patient-derived organoids in precision medicine in metastatic CRC.

  PublisherDOI

• Supplementary Figure Legends from Tumor-Derived CCL5 Recruits Cancer-Associated Fibroblasts and Promotes Tumor Cell Proliferation in Esophageal Squamous Cell Carcinoma

  2025-11-27

  articleOpen accessSenior author

  <p>Supplementary Figure Legends 1-4</p>

  PublisherDOI

• Supplementary Figures 1-6 from Tumor-Suppressive and Immune-Stimulating Roles of Cholesterol 25-hydroxylase in Pancreatic Cancer Cells

  2025-11-27

  articleOpen access

  <p>S1. Frequency of Pan-IN lesion types in KC versus KCC mice. S2. Re-expression of Ch25h in PDAC cell lines. S3. Presence of exogenous lipids diminishes effect of Ch25h re-expression in PDAC. S4. Re-expression of Ch25h does not affect Ras localization. S5. CH25H decreases autophagic flux in PDAC cells. S6. Ch25h slows PDAC tumor growth.</p>

  PublisherOA PDFDOI

• Supplementary Figure 1 from Tumor-Derived CCL5 Recruits Cancer-Associated Fibroblasts and Promotes Tumor Cell Proliferation in Esophageal Squamous Cell Carcinoma

  2025-11-27

  articleOpen accessSenior author

  <p>Confirmation of CCL5 knockout clones.</p>

  PublisherOA PDFDOI

• A generalizable cross-continent prediction of esophageal squamous cell carcinoma using the oral microbiome

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-24

  preprintOpen access

  Abstract Esophageal squamous cell carcinoma (ESCC) is a disease with limited tools for early screening and a poor prognosis. Symptoms typically appear late, and early cancer is hard to detect without endoscopic screening, which is inaccessible in most high-risk areas. Saliva is easily accessible, and its microbiome composition can serve as a marker for upper gastrointestinal tract disease. We studied the potential utility of an oral microbiome signature for ESCC in South Africa, a region with a high incidence of the disease. In a cohort of 48 ESCC patients and 110 controls, we found marked alterations in the oral microbiome in patients with ESCC, including significantly reduced alpha diversity and increased Fusobacterium nucleatum . We devised machine learning models that classify ESCC using microbiome data, finding good performance on held-out samples (area under receiver operating characteristic curve of 0.96), and demonstrated generalization to data across independent studies conducted in different geographic regions (0.64-0.81). Overall, our results demonstrate the potential of the oral microbiome to serve as a non-invasive screening tool for ESCC.

  PublisherOA PDFDOI

• Increased reflux secondary bile acids are associated with changes to the microbiome and transcriptome in Barrett’s esophagus

  Gut Microbes · 2025-08-22 · 8 citations

  articleOpen access

  showed the most associations with gene expression, including the oxidative phosphorylation pathway. We identified two distinct BE gene expression clusters independent of histology, bile acid, or microbiome composition. These findings suggest bile acids shape the BE microbiome and associate with gene expression changes potentially relevant to EAC development.

  PublisherOA PDFDOI

• Supplementary Figure 4 from Tumor-Derived CCL5 Recruits Cancer-Associated Fibroblasts and Promotes Tumor Cell Proliferation in Esophageal Squamous Cell Carcinoma

  2025-11-27

  preprintOpen accessSenior author

  <p>Targeted CCR5 inhibition replicates CCL5 loss with reduced tumor cell proliferation in vitro and in vivo.</p>

  PublisherOA PDFDOI

• Abstract LB092: Decoding tumor cell dynamics driven by mutant <i>TP53</i> gain-of-function activity in squamous cell carcinoma metastasis

  Cancer Research · 2025-04-25

  articleSenior author

  Abstract Mutations in the tumor suppressor gene TP53 correlate with poor prognosis and high metastasis rates, which account for more than 90% of cancer-related mortality worldwide. Our recent work, published in Cancer Discovery (PMC10841313), highlights that mutant TP53 may exhibit neomorphic gain-of-function (GOF) properties, driving squamous cell carcinoma (SCC) metastasis beyond its classic role via wild-type TP53 loss. To elucidate novel mutant p53-dependent mechanisms in promoting metastasis, we first focused on one of the most frequent TP53 mutations, human R175H (mouse homolog, R172H). Utilizing the L2-Cre (esophageal specific promoter), we generated LSL-Trp53 R172H/- , Trp53 -/- or Trp53 +/+ mice to isolate isogenic primary and metastatic tumor cells that vary in their p53 statuses. Using ex vivo and in vivo syngeneic models, we found that p53-R172H significantly enhances metastatic colonization in the lung compared to tumor cells with wild-type p53 or p53-null, suggesting GOF features of this mutant protein. Through our analysis of RNA-Seq, p53 ChIP-Seq, and H3K27ac CUT&amp;RUN-Seq on metastatic tumor cells, we identified mediators of the epithelial-to-mesenchymal transition (EMT) pathway as dominant effectors of p53-R172H-dependent lung metastasis. While most research efforts have traditionally focused on a single mutation, our studies now leverage to an evaluation of the mutant TP53 spectrum to assess how each specific mutation may contribute to unique pro-tumorigenic activities. Our analysis of aero-digestive SCC datasets from AACR Project Genie, TCGA, and tissue microarrays suggests that recurrently detected TP53 mutations are associated with differential patient survival rates and enriched molecular pathways. To investigate the extent of GOF properties and underlying mechanisms of distinct TP53 mutations, we endogenously introduced four frequently detected mutations (R175H, R248Q, R273H and R282W) into esophageal SCC (ESCC) mouse and human cells using state-of-the-art genome engineering approaches. This has allowed us to generate a physiologically relevant and isogenic model. Tumors harboring different TP53 mutations demonstrate varying degrees of enhanced invasion and metastatic abilities in comparison to TP53-deleted controls. Among these, TP53 R282W mutant tumor cells show a marked increase in lung metastases, accompanied by the enrichment of inflammatory response and interferon-alpha response pathways. Our molecular analyses of diverse TP53 mutations provide new insights into their GOF properties. TP53 mutations exhibit distinct clinical outcomes, as well as unique functional and mechanistic behaviors, emphasizing the need for allele-specific mutational analysis in therapeutic strategies. Identifying actionable downstream targets regulated by specific TP53 mutations could transform precision medicine efforts. Furthermore, this approach can be extended to key oncoproteins involved in critical signaling pathways, such as KRAS and PIK3CA. Citation Format: Gizem Efe, Katherine Cunningham, Raúl Navaridas, Karen Dunbar, Emily Esquea, Lois Resnick-Silverman, James J. Manfredi, Carol Prives, Anil K. Rustgi. Decoding tumor cell dynamics driven by mutant TP53 gain-of-function activity in squamous cell carcinoma metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB092.

  PublisherDOI

• Supplementary Table 1 from Tumor-Suppressive and Immune-Stimulating Roles of Cholesterol 25-hydroxylase in Pancreatic Cancer Cells

  2025-11-27

  supplementary-materialsOpen access

  &lt;p&gt;Supplementary Table 1: List of oligonucleotides used for qPCR&lt;/p&gt;

  PublisherDOI

• Colibactin-producing <i>E. coli</i> promote carcinogenesis of gastroesophageal adenocarcinoma and simultaneously induce autophagy and differentiation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-11

  preprintOpen access

  ABSTRACT Background &amp; Aims Gastroesophageal adenocarcinoma (GEAC) is a malignancy of the gastroesophageal junction (GEJ) and is associated with reflux of gastroduodenal contents and Barrett’s Esophagus (BE). A shift towards gram-negative bacteria in the microbiota of the GEJ additionally promotes inflammation and likely carcinogenesis. Enterobacteriaceae are enriched in advanced stages of GEAC development, and members of this family can produce colibactin, a genotoxin implicated in DNA damage and tumor progression. We aimed to validate these observations and investigate the effect of E. coli with or without colibactin production on GEAC-carcinogenesis. Methods Bacteria were profiled in human biopsies with imaging and 16S rRNA gene sequencing. Organoids of our L2-IL1B mouse model of GEAC were exposed to E. coli with colibactin (CoPEC) and without colibactin production (noCoPEC) via organoid microinjection. The phenotypic and transcriptomic changes in the organoids after the coculture with E. coli were evaluated via histology and single-cell RNA sequencing. Results In human specimens, we observed an infiltration of bacteria in GEJ-tissue upon tumor formation and detected Enterobacteriaceae in one third of BE-patients. CoPEC-injected organoids exhibited high rates of proliferation and DNA damage, and an upregulation of cancer-associated genes and pathways. Furthermore, genes and pathways associated with immune activation, defense mechanisms, metabolic reprogramming, autophagy and differentiation were upregulated in CoPEC-injected organoids. Conclusion In addition to the enrichment of Enterobacteriaceae in the GEJ-tissue of patients at late stages of GEAC, we show that the exposure of colibactin-producing E. coli to murine BE-organoids promotes genetic instability and proliferation, and the activation of cancer-associated pathways, while also activating autophagy and enhancing intercellular homeostasis. This indicates that colibactin-producing E. coli have a dual effect on early stages of GEAC-carcinogenesis. GRAPHICAL ABSTRACT

  PublisherOA PDFDOI

Recent grants

• Networks for functional regulation of pancreatic acinar-ductal metaplasia and epithelial plasticity

  NIH · $8.3M · 2002–2026

• NIH Grant R01DK053377

  NIH · $784k · 2002

• NIH Grant R56DK056645

  NIH · $320k · 2014

• NIH Grant K08CA001586

  NIH · $331k · 1995

• Mechanisms of Esophageal Carcinogenesis

  NIH · $48.5M · 2003–2024

Frequent coauthors

• Hiroshi Nakagawa

  253 shared

• Andres J. Klein‐Szanto

  180 shared

• J. Alan Diehl

  151 shared

• Oliver G. Opitz

  Heidelberg University

  120 shared

• Meenhard Herlyn

  111 shared

• Timothy C. Wang

  Columbia University

  99 shared

• Tatiana A. Karakasheva

  91 shared

• Yasir Suliman

  University of Freiburg

  87 shared

Education

• MD, Medicine

  Duke University School of Medicine

  1984

• BS, Molecular Biology & Biophysics

  Yale University

  1980