spontaneous-murine-model-of-anaplastic-thyroid-cancer

Spontaneous Murine Model of Anaplastic Thyroid Cancer

Anaplastic thyroid cancer (ATC) is a rare but lethal malignancy with a dismal prognosis. There is an urgent need for more in-depth research on the ...

University of Arizona

Alterations in the epidermal growth factor receptor and PI3K pathways in head and neck squamous cell carcinomas (HNSCCs) are frequent events that promote tumor progression. Ectopic expression of the epidermal growth factor receptor-targeting microRNA (miR), miR-27a* (miR-27a-5p), inhibits tumor growth. We sought to identify mechanisms mediating repression of miR-27a* in HNSCC, which have not been previously identified.

Disruption of TP63-miR-27a* Feedback Loop by Mutant TP53 in Head and Neck Cancer.

Skin homeostasis is controlled by a complex interplay between tightly regulated transcription factors and signaling pathways. MYB is a transcription factor expressed in hair follicle progenitor cells and found overexpressed in adnexal skin tumors. However, the biological consequences of deregulated MYB expression in the skin remain poorly understood. To address this, we generated transgenic mice that overexpress MYB in epidermal and follicular keratinocytes. These mice exhibited a normal hair coat after birth but gradually developed alopecia, accompanied by altered follicular differentiation, disrupted hair cycle, and a marked depletion of hair follicle stem cells. Additionally, transgenic mice developed massive epidermal hyperplasia and hyperkeratosis. Global expression profiling not only confirmed that the skin of these mice exhibited transcriptomic features of alopecia and epidermal differentiation, but also revealed features of psoriasis and the inflammatory response. The latter was further confirmed by the increased T-cell infiltration found in the skin of transgenic mice. Overall, these results suggest that tight regulation of MYB expression in the skin is critical to maintain skin homeostasis.

Overexpression of MYB in the Skin Induces Alopecia and Epidermal Hyperplasia.

The solid tumour microenvironment includes nerve fibres that arise from the peripheral nervous system. Recent work indicates that newly formed adrenergic nerve fibres promote tumour growth, but the origin of these nerves and the mechanism of their inception are unknown. Here, by comparing the transcriptomes of cancer-associated trigeminal sensory neurons with those of endogenous neurons in mouse models of oral cancer, we identified an adrenergic differentiation signature. We show that loss of TP53 leads to adrenergic transdifferentiation of tumour-associated sensory nerves through loss of the microRNA miR-34a. Tumour growth was inhibited by sensory denervation or pharmacological blockade of adrenergic receptors, but not by chemical sympathectomy of pre-existing adrenergic nerves. A retrospective analysis of samples from oral cancer revealed that p53 status was associated with nerve density, which was in turn associated with poor clinical outcomes. This crosstalk between cancer cells and neurons represents mechanism by which tumour-associated neurons are reprogrammed towards an adrenergic phenotype that can stimulate tumour progression, and is a potential target for anticancer therapy.

Loss of p53 drives neuron reprogramming in head and neck cancer.

Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women present with less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation.

Female Immunity Protects from Cutaneous Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) develops through the multistep malignant progression of squamous epithelium. This process can be prevented by PD-1 blockade in a mouse model for oral carcinogenesis. OSCCs exhibit a high incidence of  mutations that confer oncogenic gain-of-function (GOF) activities that promote resistance to standard therapies and poor clinical outcomes. To determine whether epithelial  mutations modulate anti-PD-1-mediated oral cancer immunoprevention, we generated mouse models for oral carcinogenesis by exposing mice carrying epithelial-specific  mutations to the carcinogen 4NQO. Consistent with the oncogenic functions of mutant , mice with OSCCs expressing the  GOF mutation developed higher metastasis rates than mice with loss-of-function (LOF)  deletion or with wild-type . Throughout oral cancer progression, pre-invasive and invasive lesions showed a gradual increase in T-cell infiltration, recruitment of immunosuppressive regulatory T-cells (Tregs), and induction of PD-1/PD-L1 immune checkpoint proteins. Notably, while PD-1 blockade prevented the development of OSCCs in mice with wild-type  or  deletion, GOF  abrogated the immunopreventive effects of anti-PD-1, associated with upregulation of IL17 signaling and depletion of exhausted CD8 cells in the microenvironment of the  tumors. These findings sustain a potential role for  profiling in personalized oral cancer immunoprevention.

Epithelial Mutant p53 Promotes Resistance to Anti-PD-1-Mediated Oral Cancer Immunoprevention in Carcinogen-Induced Mouse Models.

To date, there is no FDA-approved chemoprevention approach for tobacco-related HNSCC. Effective chemoprevention approaches validated in sufficiently powered randomized trials are needed to reduce the incidence and improve survival. In this review, we recap the challenges encountered in past chemoprevention trials and discuss emerging approaches, with major focus on green chemoprevention, precision prevention, and immunoprevention. As our current depth of knowledge expands in the arena of cancer immunotherapy, the field of immunoprevention is primed for new discoveries and successes in cancer prevention.

Precision and Immunoprevention Strategies for Tobacco-Related Head and Neck Cancer Chemoprevention.

Understanding of dedifferentiation, an indicator of poo prognosis for patients with thyroid cancer, has been hampered by imprecise and incomplete characterization of its heterogeneity and its attributes. Using single-cell RNA sequencing, we explored the landscape of thyroid cancer at single-cell resolution with 46,205 cells and delineated its dedifferentiation process and suppressive immune microenvironment. The developmental trajectory indicated that anaplastic thyroid cancer (ATC) cells were derived from a small subset of papillary thyroid cancer (PTC) cells. Moreover, a potential functional role of  on ATC development was revealed by integrated analyses of copy number alteration and transcriptional regulatory network. Multiple genes in differentiation-related pathways (e.g., EMT) were involved as the downstream targets of CREB3L1, increased expression of which can thus predict higher relapse risk of PTC. Collectively, our study provided insights into the heterogeneity and molecular evolution of thyroid cancer and highlighted the potential driver role of  in its dedifferentiation process.

Characterizing dedifferentiation of thyroid cancer by integrated analysis.

Cancer-associated fibroblasts (CAFs) are the predominant components of the tumor microenvironment (TME) and influence cancer hallmarks, but without systematic investigation on their ubiquitous characteristics across different cancer types. Here, we perform pan-cancer analysis on 226 samples across 10 solid cancer types to profile the TME at single-cell resolution, illustrating the commonalities/plasticity of heterogenous CAFs. Activation trajectory of the major CAF types is divided into three states, exhibiting distinct interactions with other cell components, and relating to prognosis of immunotherapy. Moreover, minor CAF components represent the alternative origin from other TME components (e.g., endothelia and macrophages). Particularly, the ubiquitous presentation of endothelial-to-mesenchymal transition CAF, which may interact with proximal SPP1 tumor-associated macrophages, is implicated in endothelial-to-mesenchymal transition and survival stratifications. Our study comprehensively profiles the shared characteristics and dynamics of CAFs, and highlight their heterogeneity and plasticity across different cancer types. Browser of integrated pan-cancer single-cell information is available at https://gist-fgl.github.io/sc-caf-atlas/ .

Article	Year
Disruption of TP63-miR-27a* Feedback Loop by Mutant TP53 in Head and Neck Cancer. Journal of the National Cancer Institute\| PubMed ID: 31124563	2020
Overexpression of MYB in the Skin Induces Alopecia and Epidermal Hyperplasia. The Journal of investigative dermatology\| PubMed ID: 31758945	2020
Loss of p53 drives neuron reprogramming in head and neck cancer. Nature\| PubMed ID: 32051587	2020
Female Immunity Protects from Cutaneous Squamous Cell Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 33795258	2021
Epithelial Mutant p53 Promotes Resistance to Anti-PD-1-Mediated Oral Cancer Immunoprevention in Carcinogen-Induced Mouse Models. Cancers\| PubMed ID: 33806894	2021
Precision and Immunoprevention Strategies for Tobacco-Related Head and Neck Cancer Chemoprevention. Current treatment options in oncology\| PubMed ID: 33991232	2021
Characterizing dedifferentiation of thyroid cancer by integrated analysis. Science advances\| PubMed ID: 34321197	2021
Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment. Nature communications\| PubMed ID: 36333338	2022

Carlos Caulin

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