Melanoma models for the next generation of therapies

Abstract

There is a lack of appropriate melanoma models that can be used to evaluate the efficacy of novel therapeutic modalities. Here, we discuss the current state of the art of melanoma models including genetically engineered mouse, patient-derived xenograft, zebrafish, and ex vivo and in vitro models. We also identify five major challenges that can be addressed using such models, including metastasis and tumor dormancy, drug resistance, the melanoma immune response, and the impact of aging and environmental exposures on melanoma progression and drug resistance. Additionally, we discuss the opportunity for building models for rare subtypes of melanomas, which represent an unmet critical need. Finally, we identify key recommendations for melanoma models that may improve accuracy of preclinical testing and predict efficacy in clinical trials, to help usher in the next generation of melanoma therapies.

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+T cells

“…In conclusion, by suppressing anti-tumor immunity while promoting metastasis via different LPA receptors, the ATX-LPAR signaling axis creates an T-cell excluding, protumorigenic microenvironment that is amenable to therapeutic intervention. Our findings pave the way for addressing major outstanding questions on ATX/LPA in other immunotherapeutic settings, such as genetically engineered melanoma models and/or patient-derived xenografts (PDX) engrafted in humanized mouse models (Patton et al, 2021;Rosato et al, 2018). Such clinically relevant models will provide further insight into the dual pro-tumor actions of ATX; furthermore, they will offer an opportunity to evaluate the anti-tumor benefits of pharmacological ATX inhibition, for example in combination with immune checkpoint inhibitors.…”

Mucosal Melanoma: Pathological Evolution, Pathway Dependency and Targeted Therapy

“…However, unlike CM, there is a lack of animal models that can recapitulate the oncogenesis process accompanied with the accumulation of genetic alterations in MM. By stepwise introduction of BRAF V600E mutation, CDKN2A loss, PTEN loss and mTOR activation, CM precursor lesions followed by CM formation was observed in mice ( 156 – 159 ). Likewise, decoding the accumulative mutation pattern based on MM patient samples will pave the path to the generation of MM transgenic mice model, which not only contribute to understanding the pathogenesis of MM but also serve as functional tools to evaluate the efficacy of novel therapeutic modalities.…”

Tfap2b specifies an embryonic melanocyte stem cell that retains adult multi-fate potential

“…As one of the most aggressive and heterogenous cancers, the melanoma transcriptional landscape spans developmental neural crest and melanocyte lineage signatures, stem cell signatures, and trans-differentiation signatures (Diener and Sommer, 2020;Marine et al, 2020;Patton et al, 2021). We propose that the molecular mechanisms that regulate MSC biology have direct relevance to melanoma pathogenesis.…”

“…In melanoma, a deadly cancer of the melanocyte, neural crest and melanocyte developmental mechanisms become reactivated in pathological processes driving melanoma initiation, metastasis, survival and drug resistance (Diener and Sommer, 2020;Johansson et al, 2020;Kaufman et al, 2016;Konieczkowski et al, 2014;Marie et al, 2020;Rambow et al, 2018;Shakhova et al, 2012;Travnickova et al, 2019;Varum et al, 2019;White et al, 2011). Therefore, while mechanisms that underpin neural crest and melanocyte development are important in understanding fundamental cell biology and pattern formation in the animal kingdom, in the disease context, understanding dysregulation and heterogeneity of developmental lineages in cancer provides a rich source of drug targets for the next generation of melanoma therapies (Patton et al, 2021). Zebrafish are uniquely amenable to advanced imaging of neural crest and pigment cell lineage pathways in vivo and have emerged as a powerful model system to study the melanocyte developmental lineage in pattern formation and in melanoma (Kelsh et al, 1996;Owen et al, 2020;Travnickova and Patton, 2021).…”