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Rodent Histopathology Core

Murine models of cancer have provided investigators with a unique opportunity to understand tumor cell biology in the setting of complex and dynamic physiological systems. This genetic model system has not only yielded insight into the role of oncogenes and tumor suppressor genes in specific tumors, but also created the opportunity to investigate the role of the microenvironment in tumor development and maintenance. Vital to these investigations has been the ability to fully scrutinize the pathologic consequences of the genetic changes that are being studied.

The Rodent Histopathology Core provides high quality professional, technical, and educational pathology services. The goal of the core is to support investigator research that leads to the identification of pathologic processes in mice and can be directly translatable to human disease.

The facility provides complete histopathologic services that include:

  • Whole mouse necropsies, tissue processing, and histological slide preparation from both fixed paraffin-embedded and frozen tissues. 
  • Histopathological interpretation of slides. Comprehensive expertise is available in: tumor diagnosis, diagnoses of inflammatory, degenerative and proliferative diseases in embryonic, neonatal, juvenile and adult mice. The pathologist documents findings using digital photo-microscopy for use in laboratory presentations and publications. 
  • One-on-one discussions regarding slides, using a multi-headed microscope. In-depth discussions on interpretations of slides and experimental design are undertaken with users and other laboratory personnel who often have little knowledge of histopathology and pathology. In addition, the Core participates in educational community programs and Core professional staff members publish educational material.

 

Below are abstracts of publications that resulted from select scientific projects in which the Rodent Core has contributed.

Using combination therapy to override stromal-mediated chemoresistance in mutant FLT3-positive AML: synergism between FLT3 inhibitors, dasatinib/multi-targeted inhibitors, and JAK inhibitors.

Principal Investigator: JD Griffin (DFCI) (Leukemia Program)

Description of Project: Acute myeloid leukemia (AML) progenitors are frequently characterized by activating mutations in the receptor tyrosine kinase FLT3. Protein tyrosine kinases are integral components of signaling cascades that play a role in both FLT3-mediated transformation as well as viability pathways that are advantageous to leukemic cell survival. The bone marrow microenvironment can diminish AML sensitivity to tyrosine kinase inhibitors (TKIs). We hypothesized that inhibition of protein kinases in addition to FLT3 may be effective in overriding drug resistance in AML. We used a cell-based model mimicking stromal protection as part of an unbiased high-throughput chemical screen to identify kinase inhibitors with the potential to override microenvironment-mediated drug resistance in mutant FLT3-positive AML. Several related multi-targeted kinase inhibitors, including dasatinib, with the capability of reversing microenvironment-induced resistance to FLT3 inhibition were identified and validated. We validated synergy in vitro and demonstrated effective combination potential in vivo. In particular Janus kinase (JAK) inhibitors were effective in overriding stromal protection and potentiating FLT3 inhibition in primary AML and cell lines. These results hint at a novel concept of using combination therapy to override drug resistance in mutant FLT3-positive AML in the bone marrow niche and suppress or eradicate residual disease.

Contribution of Core: Slide interpretation and histopathological interpretation

Publication: Weisberg E, Liu Q, Nelson E, Kung AL, Christie AL, Bronson RT, Sattler M, Sanda T, Zhao Z, Hur W, Mitsiades C, Smith R, Daley JF, Stone R, Galinsky I, Griffin JD, Gray N. Leukemia. 2012 Apr 3. doi: 10.1038/leu.2012.96. PMID: 22469781

Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice.

Principal Investigator: BD Manning (HSPH) (Cancer Cell Biology Program, Kidney Cancer Program)
Description of Project: The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a nutrient-sensitive protein kinase that is aberrantly activated in many human cancers. Whether dysregulation of mTORC1 signaling in normal tissues increases the risk for cancer, however, is unknown. We focused on hepatocellular carcinoma, which has been linked to environmental factors that affect mTORC1 activity, including diet. Ablation of the gene encoding TSC1 (tuberous sclerosis complex 1), which as part of the TSC1-TSC2 complex is an upstream inhibitor of mTORC1, results in constitutively increased mTORC1 signaling, an effect on this pathway similar to that of obesity. We found that mice with liver-specific knockout of Tsc1 developed sporadic hepatocellular carcinoma with heterogeneous histological and biochemical features. The spontaneous development of hepatocellular carcinoma in this mouse model was preceded by a series of pathological changes that accompany the primary etiologies of this cancer in humans, including liver damage, inflammation, necrosis, and regeneration. Chronic mTORC1 signaling led to unresolved endoplasmic reticulum stress and defects in autophagy, factors that contributed to hepatocyte damage and hepatocellular carcinoma development. Therefore, we conclude that increased activation of mTORC1 can promote carcinogenesis and may thus represent a key molecular link between cancer risk and environmental factors, such as diet.

Contribution of Core: Slide interpretation and histopathological interpretation

Publication: Menon S, Yecies JL, Zhang HH, Howell JJ, Nicholatos J, Harputlugil E, Bronson RT, Kwiatkowski DJ, Manning BD. Sci Signal. 2012 Mar 27;5(217):ra24. doi: 10.1126. PMID: 22457330: