About

Christopher Joachim Lengner, Ph.D., is a Professor of Cell and Developmental Biology at the University of Pennsylvania Perelman School of Medicine. He is a member of the Institute for Regenerative Medicine and the NIH P30 Center for Molecular Studies in Digestive and Liver Diseases at the University of Pennsylvania. He also serves as the Director of the Center for Animal Transgenesis at the University of Pennsylvania School of Veterinary Medicine and is a member of the Abramson Cancer Center. His research program aims to understand the molecular mechanisms that govern stem cell potency and how their dysregulation can contribute to disease onset and progression, including oncogenesis. His laboratory employs genetic, genomic, and single-cell analysis approaches in murine systems to address these questions, and utilizes human induced pluripotent cells and patient samples to translate findings into human systems. His work has identified novel pathways underlying somatic stem cell self-renewal and the development of hematopoietic and gastrointestinal cancers. Additionally, his research explores the hierarchical structure of the intestinal stem cell compartment and how perturbations in this hierarchy contribute to diseases such as cancer, chronic inflammation, and tissue regeneration following injury.

Research topics

• Cell biology
• Biology
• Genetics

Selected publications

• Electromagnetic field-inducible in vivo gene switch for remote spatiotemporal control of gene expression

  Cell · 2026-04-01

  article
  PublisherDOI

• APC coordinates GSK3 phosphorylation of SETD8 to suppress colorectal cancer

  Cell Reports · 2026-03-01

  articleOpen accessSenior author

  Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths. Mutations in the tumor-suppressor APC initiate CRC in part by preventing the glycogen synthase kinase 3 (GSK3) kinase from phosphorylating β-CATENIN, leading to its stabilization and transactivation of mitogenic target genes. While the importance of β-CATENIN phosphorylation by GSK3 is well established, APC regulation of GSK3 activity upon other targets is not understood. Here, we identify the H4K20 methyltransferase SETD8 as a target of APC-coordinated GSK3 phosphorylation in the intestinal epithelium. We find that phosphorylation by GSK3 restrains the oncogenic activity of SETD8, with loss of phosphorylation sensitizing mice to oncogenic insults. Mechanistically, loss of SETD8 phosphorylation in tumors results in a loss of H4K20 monomethylation (H4K20me1) deposition at oncogenic cholesterol biosynthesis and fetal intestinal genes, allowing for their activation in part through gain of YAP accessibility. These results underscore the importance of SETD8 in CRC and represent a novel β-CATENIN-independent oncogenic consequence of APC loss.

  PublisherDOI

• MAIT cell enrichment in Lynch syndrome is associated with immune surveillance and colorectal cancer risk

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-27 · 3 citations

  preprintOpen access

  ABSTRACT Tissue microenvironment characteristics associated with elevated risk of colorectal cancer (CRC) in Lynch syndrome (LS) are poorly characterized. We applied the multimodal single cell sequencing platform ExCITE-seq to define the colonic cellular composition and transcriptome of LS carriers with and without a history of CRC compared with general population controls. Our analysis revealed widespread remodeling in LS that included striking expansion of epithelial stem and progenitor cells, and loss of fibroblast populations. Although clonally expanded and terminally exhausted CD8 T cells were more prominent in individuals with a history of CRC, LS carriers without CRC displayed enrichment of cytotoxic mucosal-associated invariant T (MAIT) cells associated with CCL20 expression in epithelial progenitors, validated by orthogonal techniques including demonstration of a protective function in a murine model of CRC. These findings highlight cellular features that distinguish LS carriers and suggest a protective role of MAIT cells in human CRC surveillance.

  PublisherOA PDFDOI

• An Epigenetic Basis for Sustained Inflammatory Epithelial Progenitor Cell States in Crohn’s Disease

  Cellular and Molecular Gastroenterology and Hepatology · 2025-10-21 · 1 citations

  articleOpen access

  BACKGROUND & AIMS: Defining consequential differences in intestinal epithelial stem cells in healthy humans vs those with inflammatory bowel disease (Crohn's disease and ulcerative colitis) is essential for the development of much needed therapies to restore the epithelial barrier and maintain its fidelity. METHODS: We used single-cell transcriptomic and epigenomic approaches in matched patient tissues and organoids to investigate epithelial gene expression and function in children with no pathological diagnosis in the lower gastrointestinal tract and healthy adults compared with those with Crohn's disease. RESULTS: We identify an inflammatory secretory progenitor (ISP) cell state present almost exclusively in patients with Crohn's disease compared with healthy subjects. ISPs exhibit gene expression profiles consistent with normal secretory progenitor cells but concomitantly express a suite of distinguishing pro-inflammatory genes. Mechanistically, ISPs exhibit open chromatin at ISP gene loci. Although ISP-specific genes are not expressed in intestinal stem cells, their chromatin is accessible in Crohn's disease stem cells, suggesting that ISP genes are epigenetically poised in stem cells and subsequently transcriptionally activated in ISPs in the presence of inflammatory stimuli. Consistently, Crohn's disease colonoids exhibit sustained ISP gene expression that can be elicited further with pro-inflammatory cytokines or via co-culture with pro-inflammatory macrophages. CONCLUSIONS: We have defined differences in the epithelial stem and progenitor compartment of patients with Crohn's disease that suggest aberrant stem cell differentiation and inflammatory gene expression arise and persist during disease.

  PublisherDOI

• Tissue-Specific and NF-kappaB-Independent Xist RNA Localization Patterns in Female Intestinal, Blood, and Muscle Progenitors

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-02

  preprintOpen access

  ABSTRACT X-Chromosome Inactivation (XCI), driven by the expression of Xist RNA and the enrichment of various repressive epigenetic marks, results in the formation of a mostly inactive X chromosome (Xi) to equalize X-linked gene expression between sexes. Unexpectedly, in unstimulated female lymphocytes that are largely quiescent, these epigenetic features are largely absent but are restored by NF-κB signaling following their activation. To determine whether these epigenetic phenotypes correlate with quiescence or NF-κB activation in other tissues, we evaluated female progenitor and stem cells from intestine, blood, and muscle. Despite known NF-κB activation, intestinal progenitors have variable Xist RNA patterns, whereas blood progenitors and neutrophils show a strong correlation between NF-κB activation status and Xist RNA localization. In contrast, muscle satellite cells (SCs) and myoblasts exhibit Xist RNA accumulation at the Xi without NF-κB activation. Xist RNA localization patterns in SCs change with age, yet adult SCs have an Xi that is mostly transcriptionally silent while allowing expression of muscle-specific X-linked genes including Dmd . These findings reveal that female somatic cells employ diverse, tissue-specific epigenetic mechanisms to maintain X chromosome inactivation, enabling cell type specific Xi gene expression while preserving chromosome-wide silencing.

  PublisherOA PDFDOI

• Single-Cell RNA Sequencing and Inferred Protein Activity Analysis Reveal a Distinct Tumor Phenotype in Early-Onset Colorectal Cancer Patients

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-16

  preprintOpen access

  Colorectal cancer (CRC) diagnosed before age 50 years (early-onset CRC, EO-CRC) is rising at an alarming rate, yet its molecular and microenvironmental drivers remain poorly understood. EO-CRC is highly heterogeneous, and while subtle differences from late-onset CRC (LO-CRC) have been reported, their full extent remains unresolved due to the limited scope of previous studies. Here, we integrate public data with in-house clinical samples profiled by single-cell RNA sequencing (scRNA-seq) and multiplex immunofluorescence (mIF) to compare EO-CRC and LO-CRC. Additionally, we employ gene regulatory network-based protein activity inference (VIPER), enabling a more precise characterization of key regulatory proteins driving tumor-stroma interactions. Our analysis reveals that EO-CRC and LO-CRC have a largely similar immune composition, challenging previous reports of an "immune-cold" phenotype in EO-CRC. However, we identify distinct stromal differences, including a significant enrichment of fibroblasts in EO-CRC. Notably, we define a previously unrecognized epithelial subpopulation in EO-CRC, marked by high expression of toll-like receptor 4 (TLR4) and C-C chemokine receptor type 5 (CCR5)-key mediators of inflammation-driven tumor progression and fibroblast recruitment. These findings suggest that EO-CRC may be driven by a tumor-intrinsic inflammatory phenotype with enhanced stromagenesis, providing new insights into potential mechanisms underlying its increasing incidence in young adults.

  PublisherOA PDFDOI

• Forward genetic screening in engineered colorectal cancer organoids identifies regulators of metastasis

  Proceedings of the National Academy of Sciences · 2025-11-11 · 1 citations

  articleOpen accessCorresponding

  Metastatic outgrowth requires that cancer cells delaminate from the primary tumor, intravasate, survive in circulation, extravasate, migrate to, and proliferate at a distal site. Recurrent genetic drivers of metastasis remain elusive, suggesting that unlike the early steps of oncogenesis, metastasis drivers may be variable. We develop a framework for identifying metastasis regulators using CRISPR/Cas9-based screening in a genetically defined organoid model of colorectal adenocarcinoma. We conduct in vitro screens for invasion and migration alongside orthotopic, in vivo screens for gain of metastasis in a syngeneic mouse model. We identify CTNNA1 and BCL2L13 as bona fide metastasis-specific suppressors which do not confer any selective advantage in primary tumors. CTNNA1 loss promotes cell invasion and migration, and BCL2L13 loss promotes anchorage-independent survival and non-cell-autonomous changes to macrophage polarization. This study demonstrates proof of principle that large-scale genetic screening can be performed in tumor-organoid models in vivo and identifies novel regulators of metastasis.

  PublisherDOI

• Aberrant neural stem cell quiescence is the gateway to autism development linked to Arid1b

  Molecular Psychiatry · 2025-08-30 · 1 citations

  article
  PublisherDOI

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

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

  articleOpen access

  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

• MAIT cell enrichment in Lynch syndrome is associated with immune surveillance and colorectal cancer risk

  Research Square · 2025-08-25

  preprintOpen access
  PublisherOA PDFDOI

Recent grants

• NIH Grant R21AG054209

  NIH · $443k · 2018

• NIH Grant F32CA119647

  NIH · $145k · 2009

• Cell type and molecular determinants of colorectal cancer initiation downstream of APC inactivation

  NIH · $3.7M · 2017–2023

• The basis for and function of enteroendocrine lineage plasticity in the intestinal DNA damage response

  NIH · $3.3M · 2016–2024

Frequent coauthors

• Rudolf Jaenisch

  Whitehead Institute for Biomedical Research

  47 shared

• Ning Li

  University of Pennsylvania

  40 shared

• Kathryn E. Hamilton

  38 shared

• F. Brad Johnson

  37 shared

• Michael G. Kharas

  Memorial Sloan Kettering Cancer Center

  34 shared

• Zhengquan Yu

  30 shared

• Yuhua Tian

  25 shared

• Ben Z. Stanger

  University of Pennsylvania

  25 shared

Labs

• Lengner LabPI

Education

• Ph.D.

  University of Massachusetts Department of Cell Biology

  2005

• BS

  Worcester Polytechnic Institute

  1998