Rodent Histopathology Core

The Rodent Histopathology Core provides technical, professional, and educational services on non-human, primarily rodent tissues. The Core offers high-quality mouse dissection, tissue processing, slide preparation from paraffin-embedded and frozen tissues, routine and specialized histological staining, and expert interpretation of slides. The ultimate goal of the Core is to support investigator research that leads to the identification of pathologic processes in non-human models that can be directly translatable to human disease.

Publication Acknowledgement

If research supported by this core facility results in publication, please acknowledge this support by including the following in your publication(s):

We thank Harvard Cancer Consortium in Boston, MA, for the use of the Rodent Histopathology Core, which provided ______________________________ service. Harvard Cancer Consortium is supported in part by a NCI Cancer Center Support Grant # NIH 5 P30 CA06516.

Technical Services Offered:

• Whole Mouse Necropsy
• Tissue Trimming and Cassetting
• Tissue Processing and Embedding
• Paraffin and Frozen Sectioning
• Conventional Staining
• Specialty Histological Staining
  • Bacteria, Fungi, and Inclusion Bodies
  • Carbohydrate and Mucoproteins
  • Connective Tissue and Muscle
  • Cytoplasmic Granules
  • Fats and Lipids
  • Hematologic and Nuclear Elements
  • Nerve Cells and Fibers
  • Pigments and Minerals

Professional Services Offered:

• Slide Review
• Written Report 
• Slide Scoring

Systemic and skin-limited delayed-type drug hypersensitivity reactions associate with distinct resident and recruited T cell subsets

Principal Investigators: Sherrie J Divito (BWH)

Abstract: Delayed-type drug hypersensitivity reactions are major causes of morbidity and mortality. The origin, phenotype, and function of pathogenic T cells across the spectrum of severity require investigation. We leveraged recent technical advancements to study skin-resident memory T cells (TRMs) versus recruited T cell subsets in the pathogenesis of severe systemic forms of disease, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), and skin-limited disease, morbilliform drug eruption (MDE). Microscopy, bulk transcriptional profiling, and single-cell RNA-sequencing (scRNA-Seq) plus cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) plus T cell receptor sequencing (TCR-Seq) supported clonal expansion and recruitment of cytotoxic CD8+ T cells from circulation into skin along with expanded and nonexpanded cytotoxic CD8+ skin TRM in SJS/TEN. Comparatively, MDE displayed a cytotoxic T cell profile in skin without appreciable expansion and recruitment of cytotoxic CD8+ T cells from circulation, implicating TRMs as potential protagonists in skin-limited disease. Mechanistic interrogation in patients unable to recruit T cells from circulation into skin and in a parallel mouse model supported that skin TRMs were sufficient to mediate MDE. Concomitantly, SJS/TEN displayed a reduced Treg signature compared with MDE. DRESS demonstrated recruitment of cytotoxic CD8+ T cells into skin as in SJS/TEN, yet a pro-Treg signature as in MDE. These findings have important implications for fundamental skin immunology and clinical care. J Clin Invest. 2024 Jul 23;134(17):e178253., PMID 39042477

Contribution of the Core: RHP provided tissue processing, sectioning and H&E staining. SHL provided IHC/IF staining.

EED Maintains the Small Cell Lung Cancer Neuroendocrine Phenotype and Drives Lung Cancer Histological Transformation.

Principal Investigators: Matthew G Oser (DFCI), Sabina Signoretti (BWH), Matthew L. Freedman (DFCI)

Abstract: Lung cancer histological subtypes include lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC). While typically distinct, combined LUAD/SCLC histology tumors occur, and LUAD can transform into SCLC as a resistance mechanism to targeted therapies, especially in EGFR -Mutant LUADs with RB1 / TP53 -inactivation. Although PRC2 complex expression increases during this transformation, its functional role has remained unclear. Using CRISPR-based autochthonous immunocompetent GEMMs, we demonstrate that inactivation of EED, the core PRC2 scaffolding subunit, impairs SCLC tumorigenesis and drives histological transformation from ASCL1-positive SCLC to LUAD through a transient NEUROD1-positive intermediate state. Mechanistically, EED loss de-represses bivalent genes co-marked by H3K27me3 and H3K4me3, including LUAD oncogenic RAS, PI3K, and MAPK pathway genes, to promote transformation to LUAD. Consistently, these same signaling genes are bivalently repressed in human SCLC patient-derived xenograft (PDX) tumors, suggesting a conserved PRC2-dependent mechanism to repress LUAD lineage oncogenic signaling to maintain the SCLC neuroendocrine identity. In a complementary EGFR -mutant LUAD GEMM with RB1/TP53 inactivation, EED was required for LUAD-to-SCLC transformation and distant metastasis upon EGFR withdrawal. These findings identify the PRC2 complex as a key epigenetic enforcer of SCLC neuroendocrine identity and nominate EED inhibition as a potential strategy to block SCLC transformation in high-risk LUAD. bioRxiv [Preprint]. 2025 Jul 10:2025.07.07.663486. PMID 40672300. 

Contribution of the Core: Provided tissue processing, H&E staining and slide review services.

Organoid modeling reveals the tumorigenic potential of the alveolar progenitor cell state.

Principal Investigator: Carla Kim (BCH)

Description of the Project: Cancers display cellular, genetic and epigenetic heterogeneity, complicating disease modeling. Multiple cell states defined by gene expression have been described in lung adenocarcinoma (LUAD). However, the functional contributions of cell state and the regulatory programs that control chromatin and gene expression in the early stages of tumor initiation are not well understood. Using single-cell RNA and ATAC sequencing in Kras/p53-driven tumor organoids, we identified two major cellular states: one more closely resembling alveolar type 2 (AT2) cells (SPC-high), and the other with epithelial-mesenchymal-transition (EMT)-associated gene expression (Hmga2-high). Each state exhibited distinct transcription factor networks, with SPC-high cells associated with TFs regulating AT2 fate and Hmga2-high cells enriched in Wnt- and NFκB-related TFs. CD44 was identified as a marker for the Hmga2-high state, enabling functional comparison of the two populations. Organoid assays and orthotopic transplantation revealed that SPC-high, CD44-negative cells exhibited higher tumorigenic potential within the lung microenvironment. These findings highlight the utility of organoids in understanding chromatin regulation in early tumorigenesis and identifying novel early-stage therapeutic targets in Kras-driven LUAD. EMBO J. 2025 Feb 10;44(6):1804–1828., PMID 39930268. 

Contribution of the Core: For tumor organoid staining, transwells were fixed with 10% neutral-buffered formalin overnight at room temperature, followed by dehydration by 70% ethanol overnight at room temperature. The Matrigel plugs with organoids were immobilized with Histogel (Thermo Scientific) and embedded in paraffin, sectioned, hematoxylin and eosin (HE) stained and slide was reviewed by Core pathologist.

General Contact:
(617) 432-2409
(617) 432-2942 Fax

Technical Questions/Project Status:
Li Zhang, Senior Histologist
(617) 432-2409
(617) 432-2942 Fax
Li_zhang@hms.harvard.edu

Professional Support:
Amanda J. Martinot DVM, MPH, PhD
Co-Director Comparative Pathology and Genomics Shared Resource
Cummings School of Veterinary Medicine at Tufts University

Administrative/Billing Concerns:
Lauri Wyner, Research Cores Director of Administration
lauri_wyner@hms.harvard.edu