Abstract
Simple SummaryHead and neck cancer (HNC), once metastasized, is very difficult to treat as there are limited therapy options. Animal models of such can be very useful for preclinical drug development, including precision medicine and immunotherapy. By whole-exome analyses and functional annotation of five commonly used immune-intact metastatic models for HNC research, we aimed to fully annotate their genomic profiles on key cancer genes as well as signaling-, metastasis-, immune- and drug-related events, with direct comparisons with those of patient tumors. Our analyses revealed marked genomic similarities between these models and HNC patient tumors, and identified new potential drug targets for metastatic HNC. We suggest that more of such immune-relevant metastatic HNC models should be developed with full genomic annotations in order to enable preclinical research, and to accelerate precision medicine and immunotherapy development for this devastating cancer.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—Trp53, 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 HLA-A (H2-Q10, H2-Q4, H2-Q7, and H2-K1), Pdcd1, Tgfb1, Il2ra, Il12a, Cd40, and Tnfrsf14 are identified. Invasion/metastatic genome analyses first highlight potential druggable ERBB4 and KRAS mutations, for advanced/metastatic oral cavity cancer, as well as known metastasis players (Muc5ac, Trem3, Trp53, and Ttn) frequently captured by all models. Notable immunotherapy and precision druggable targets (Pdcd1, Erbb4, Fgfr1, H/Kras, Jak1, and Map2k2) 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.
Highlights
Head and neck cancer (HNC) is the sixth most common cancer worldwide, with nearly 0.83 million new incidences and 0.43 million deaths per year (2018, International Agency for Research on Cancer, IARC) [1]
Among pan-cancers characterized by The Cancer Genome Atlas (TCGA), HNC has been revealed as an immune-altered cancer [5,6]
TP53 is the most frequently mutated tumor suppressor gene in HNC, affecting 72% of HNC patients (365/510 cases) and 76% of HNC oral cancer ones (239/313). We found that both AT-84 and squamous cell carcinomas (SCCs) VII carried the Trp53 p.Arg270 hotspot mutation, while 4MOSC2 carried Trp53 p.Glu221 and p.Gly241 mutations, which are equivalent to human TP53 p.Glu224 and p.Gly244 hotspot mutations found in HNC patient tumors (Figure 2D)
Summary
Head and neck cancer (HNC) is the sixth most common cancer worldwide, with nearly 0.83 million new incidences and 0.43 million deaths per year (2018, International Agency for Research on Cancer, IARC) [1]. Studies in other cancers have begun to uncover intricate interplays between patient tumor genomic aberrations and the host immunity, such as cytokine-mediated cancer cell growth, invasion and metastasis, cancer drug-induced immunogenic cell death, and, recently, the ability of tumor-specific mutations and neo-antigens in the active shaping of tumor immune microenvironment, etc. In HNC, previous studies on immune regulators, for instance, the transforming growth factor-β (TGF-β) [15], interleukin-10 (IL-10) [16], and immune checkpoint molecules programmed cell death protein 1 (PD-1), and programmed death-ligand 1, known as PD-L1 [17], and to a lesser extent metastatic gene functions [18], have all utilized immunocompetent mouse models for detailed functional investigations and generated important knowledge, advancing our understanding of HNC tumorigenesis and progression in immune-related contexts. One immunogenomics bioinformatic study has taken the advantages of engineering immunocompetent HNC mouse models to prove a novel immunoactivating and CD8+
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