| Summary: | Immunocompetent metastatic head and neck cancer (HNC) models, although scarce, can help understanding cancer progression and therapy responses in vivo. Their comprehensive genome characterizations are essential for translational research. We first exome-sequenced the two most widely used spontaneous metastatic immunocompetent models, namely AT-84 and SCC VII, followed by comprehensive genomic analyses with three prior-sequenced models (MOC2, MOC2-10, and 4MOSC2), together with patient tumors for utility assessment. AT-84 and SCC VII bear high HNC tumor resemblance regarding mutational signatures—<i>Trp53</i>, Fanconi anemia, and MAPK and PI3K pathway defects. Collectively, the five models harbor genetic aberrations across 10 cancer hallmarks and 14 signaling pathways and machineries (metabolic, epigenetic, immune evasion), to extents similar in patients. Immune defects in <i>HLA-A</i> (<i>H2-Q10</i>, <i>H2-Q4</i>, <i>H2-Q7</i>, and <i>H2-K1</i>), <i>Pdcd1</i>, <i>Tgfb1</i>, <i>Il2ra</i>, <i>Il12a</i>, <i>Cd40</i>, and <i>Tnfrsf14</i> are identified. Invasion/metastatic genome analyses first highlight potential druggable <i>ERBB4</i> and <i>KRAS</i> mutations, for advanced/metastatic oral cavity cancer, as well as known metastasis players (<i>Muc5ac</i>, <i>Trem3</i>, <i>Trp53</i>, and <i>Ttn</i>) frequently captured by all models. Notable immunotherapy and precision druggable targets (<i>Pdcd1</i>, <i>Erbb4</i>, <i>Fgfr1</i>, <i>H</i>/<i>Kras</i>, <i>Jak1</i>, and <i>Map2k2</i>) and three druggable hubs (RTK family, MAPK, and DNA repair pathways) are frequently represented by these models. Immunocompetent metastatic HNC models are worth developing to address therapy- and invasion/metastasis-related questions in host immunity contexts.
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