Mouse-Derived Isograft (MDI) In Vivo Tumor Models II. Carcinogen-Induced cMDI Models: Characterization and Cancer...

Area of Science:

• Oncology
• Immunology
• Cancer Models

Background:

• Developing reliable in vivo cancer models is crucial for understanding tumor biology and testing therapies.
• Previous models may not fully recapitulate the complexity of carcinogen-induced tumors and their immune microenvironments.
• Carcinogen induction offers a method to generate diverse tumor types for preclinical research.

Purpose of the Study:

• To establish and characterize novel syngeneic in vivo models, termed carcinogen-induced mouse-derived isografts (cMDIs).
• To evaluate the histological, immunological, and therapeutic response characteristics of these cMDI models.
• To compare carcinogen-induced models with previously described spontaneous models.

Main Methods:

• CBA/J mice were treated with carcinogens (3-methylcholanthrene or N-methyl-N-nitrosourea) to induce tumors.
• Primary tumors were re-transplanted into syngeneic mice (PDX-like manner).
• Characterization involved histology, growth curve analysis, flow cytometry, RNA sequencing, and efficacy studies with immune checkpoint inhibitors (anti-mPD-1, anti-mCTLA-4).

Main Results:

• Established cMDI models, predominantly differentiated sarcomas (7/8) and one spinocellular carcinoma (1/8).
• Observed significant heterogeneity in tumor growth, immune cell infiltration, and gene expression profiles (tyrosine kinase receptors, IFN-γ signature, immune markers).
• Demonstrated differential responses to immune checkpoint inhibitor treatments across various cMDI models.

Conclusions:

• Carcinogen-induced mouse-derived isografts (cMDIs) are low-passage, carcinogen-induced tumors propagated as tissue pieces, preserving tumor characteristics and immune cell populations.
• These cMDIs provide a valuable platform for studying tumor heterogeneity and immune responses.
• Carcinogen induction yields a greater number of individual, histologically related tumors, primarily sarcomas, offering a distinct advantage over spontaneous models for specific research questions.