Significant advances have been made in developing novel therapeutics for cancer treatment, and targeted therapies have revolutionized the treatment of some cancers. Despite the promise, only about ...five percent of new cancer drugs are approved, and most fail due to lack of efficacy. The indication is that current preclinical methods are limited in predicting successful outcomes. Such failure exacts enormous cost, both financial and in the quality of human life. This Primer explores the current status, promise, and challenges of preclinical evaluation in advanced mouse cancer models and briefly addresses emerging models for early-stage preclinical development.
Significant advances have been made in developing novel therapeutics for cancer treatment, and targeted therapies have revolutionized the treatment of some cancers. Despite the promise, only about five percent of new cancer drugs are approved, and most fail due to lack of efficacy. The indication is that current preclinical methods are limited in predicting successful outcomes. Such failure exacts enormous cost, both financial and in the quality of human life. This Primer explores the current status, promise, and challenges of preclinical evaluation in advanced mouse cancer models and briefly addresses emerging models for early-stage preclinical development.
Individual MHC genotype constrains the mutational landscape during tumorigenesis. Immune checkpoint inhibition reactivates immunity against tumors that escaped immune surveillance in approximately ...30% of cases. Recent studies demonstrated poorer response rates in female and younger patients. Although immune responses differ with sex and age, the role of MHC-based immune selection in this context is unknown. We find that tumors in younger and female individuals accumulate more poorly presented driver mutations than those in older and male patients, despite no differences in MHC genotype. Younger patients show the strongest effects of MHC-based driver mutation selection, with younger females showing compounded effects and nearly twice as much MHC-II based selection. This study presents evidence that strength of immune selection during tumor development varies with sex and age, and may influence the availability of mutant peptides capable of driving effective response to immune checkpoint inhibitor therapy.
Somatic gene mutations can alter the vulnerability of cancer cells to T-cell-based immunotherapies. Here we perturbed genes in human melanoma cells to mimic loss-of-function mutations involved in ...resistance to these therapies, by using a genome-scale CRISPR-Cas9 library that consisted of around 123,000 single-guide RNAs, and profiled genes whose loss in tumour cells impaired the effector function of CD8
T cells. The genes that were most enriched in the screen have key roles in antigen presentation and interferon-γ signalling, and correlate with cytolytic activity in patient tumours from The Cancer Genome Atlas. Among the genes validated using different cancer cell lines and antigens, we identified multiple loss-of-function mutations in APLNR, encoding the apelin receptor, in patient tumours that were refractory to immunotherapy. We show that APLNR interacts with JAK1, modulating interferon-γ responses in tumours, and that its functional loss reduces the efficacy of adoptive cell transfer and checkpoint blockade immunotherapies in mouse models. Our results link the loss of essential genes for the effector function of CD8
T cells with the resistance or non-responsiveness of cancer to immunotherapies.
Melanoma evolution may recapitulate the embryonic development of its progenitor tissue, neural crest (NC), but the exact process is unclear. In a recent issue of Nature, Karras et al. (2022) ...demonstrate that melanoma expansion mirrors the hierarchic process of NC differentiation, generating cell subpopulations, each with distinct function, including growth and metastasis.
Melanoma evolution may recapitulate the embryonic development of its progenitor tissue, neural crest (NC), but the exact process is unclear. In a recent issue of Nature, Karras et al. (2022) demonstrate that melanoma expansion mirrors the hierarchic process of NC differentiation, generating cell subpopulations, each with distinct function, including growth and metastasis.
Cutaneous malignant melanoma is an aggressive cancer of melanocytes with a strong propensity to metastasize. We posit that melanoma cells acquire metastatic capability by adopting an embryonic-like ...phenotype, and that a lineage approach would uncover metastatic melanoma biology. Using a genetically engineered mouse model to generate a rich melanoblast transcriptome dataset, we identify melanoblast-specific genes whose expression contribute to metastatic competence and derive a 43-gene signature that predicts patient survival. We identify a melanoblast gene, KDELR3, whose loss impairs experimental metastasis. In contrast, KDELR1 deficiency enhances metastasis, providing the first example of different disease etiologies within the KDELR-family of retrograde transporters. We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation. Our work demonstrates that the melanoblast transcriptome can be mined to uncover targetable pathways for melanoma therapy.
Melanocytes, a neural crest cell derivative, produce pigment to protect keratinocytes from ultraviolet radiation (UVR). Although melanocytic lesions such as nevi and cutaneous malignant melanomas are ...known to be associated with sun exposure, the role of UVR in oncogenesis is complex and has yet to be clearly elucidated. UVR appears to have a direct mutational role in inducing or promoting melanoma formation as well as an indirect role through microenvironmental changes. Recent advances in the modeling of human melanoma in animals have built platforms upon which prospective studies can begin to investigate these questions. This review will focus exclusively on genetically engineered mouse models of UVR-induced melanoma. The role that UVR has in mouse models depends on multiple factors, including the waveband, timing, and dose of UVR, as well as the nature of the oncogenic agent(s) driving melanomagenesis in the model. Work in the field has examined the role of neonatal and adult UVR, interactions between UVR and common melanoma oncogenes, the role of sunscreen in preventing melanoma, and the effect of UVR on immune function within the skin. Here we describe relevant mouse models and discuss how these models can best be translated to the study of human skin and cutaneous melanoma.
Accumulating evidence points to an important role for the gut microbiome in anti-tumor immunity. Here, we show that altered intestinal microbiota contributes to anti-tumor immunity, limiting tumor ...expansion. Mice lacking the ubiquitin ligase RNF5 exhibit attenuated activation of the unfolded protein response (UPR) components, which coincides with increased expression of inflammasome components, recruitment and activation of dendritic cells and reduced expression of antimicrobial peptides in intestinal epithelial cells. Reduced UPR expression is also seen in murine and human melanoma tumor specimens that responded to immune checkpoint therapy. Co-housing of Rnf5
and WT mice abolishes the anti-tumor immunity and tumor inhibition phenotype, whereas transfer of 11 bacterial strains, including B. rodentium, enriched in Rnf5
mice, establishes anti-tumor immunity and restricts melanoma growth in germ-free WT mice. Altered UPR signaling, exemplified in Rnf5
mice, coincides with altered gut microbiota composition and anti-tumor immunity to control melanoma growth.
There is a growing awareness that tumor-adjacent normal tissues used as control samples in cancer studies do not represent fully healthy tissues. Instead, they are intermediates between healthy ...tissues and tumors. The factors that contribute to the deviation of such control samples from healthy state include exposure to the tumor-promoting factors, tumor-related immune response, and other aspects of tumor microenvironment. Characterizing the relation between gene expression of tumor-adjacent control samples and tumors is fundamental for understanding roles of microenvironment in tumor initiation and progression, as well as for identification of diagnostic and prognostic biomarkers for cancers.
Oncogenesis mimics key aspects of embryonic development. However, the underlying mechanisms are incompletely understood. Here, we demonstrate that the splicing events specifically active during human ...organogenesis, are broadly reactivated in the organ-specific tumor. Such events are associated with key oncogenic processes and predict proliferation rates in cancer cell lines as well as patient survival. Such events preferentially target nitrosylation and transmembrane-region domains, whose coordinated splicing in multiple genes respectively affect intracellular transport and N-linked glycosylation. We infer critical splicing factors potentially regulating embryonic splicing events and show that such factors are potential oncogenic drivers and are upregulated specifically in malignant cells. Multiple complementary analyses point to MYC and FOXM1 as potential transcriptional regulators of critical splicing factors in brain and liver. Our study provides a comprehensive demonstration of a splicing-mediated link between development and cancer, and suggest anti-cancer targets including splicing events, and their upstream splicing and transcriptional regulators.
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