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Despite recent advances in cancer treatment, metastasis and therapy resistance remain among the major causes of cancer-related deaths worldwide. A recent pan-cancer study provides a comprehensive molecular profile of advanced and post-therapy tumors, integrating whole-genome and transcriptomic analysis with clinical outcomes.
Dysregulation of innate immune signaling in cancer can be pro-tumorigenic and can promote adaptive resistance to targeted therapies. Type I interferon signaling is now shown to promote survival following inhibition of the kinase EGFR, even in cells that are not ‘addicted’ to EGFR signaling.
Although many metabolic dependencies of cancer cells are well documented, altered cancer metabolism has not always been considered an active driver of tumorigenesis. Restrictive glutamine availability is now shown to promote colorectal cancer by lowering α-ketoglutarate levels and thereby promoting DNA hypermethylation, Wnt signaling and cellular de-differentiation.
To demonstrate the long-range effects of CD8+ T cell–secreted interferon-γ on bystander tumor cells, two studies now use mosaic models of antigen loss in tumors combined with intravital imaging. Factors that influence the length scale of diffusible signals could shape disease progression in cancer and autoimmunity.
Discerning and analyzing the mutational patterns that arise in the cancer genome can provide essential information on the process of tumorigenesis. An analytical framework and web-based tool now aim to aid in mutational signature assignment for improved tumor stratification.
Tumor heterogeneity remains an obstacle to effective clinical management of breast cancer. Two new studies use high-dimensional imaging of single-cell protein expression in situ in clinical samples to link genomic alterations to multi-cellular features of the tumor microenvironment and reveal breast-cancer phenotypes associated with clinical outcome.
Identifying indicators of response to immunotherapy is key for treatment decisions. Two studies now report that early changes in T cell repertoires and CD8+ memory effector cytotoxic T cells in peripheral blood correlate with response to immune-checkpoint inhibitors in metastatic melanoma and may serve as actionable biomarkers of immune activation.
Drug repurposing is an attractive strategy for extending the arsenal of oncology therapies. Screening of a large collection of existing non-oncology compounds against a panel of cancer cell lines now identifies several drugs capable of selectively inhibiting the growth of cancer cells.
Metastasis competence can be acquired early in tumorigenesis, although its underlying molecular intricacies remain unclear. A recent study provides key information about the function of L1CAM in conferring metastasis-initiation potential and chemoresistance in colorectal cancer by hijacking epithelial regenerative mechanisms.
Immunotherapy resistance is associated with poor T cell infiltration into tumors. Tumor-cell-intrinsic oncogenic events that contribute to this defect include Wnt–β-catenin activation. PAK4 is now identified as an upstream modulator of this pathway, thus suggesting the potential of enhancing the efficacy of immunotherapy by targeting this druggable kinase.
Identifying cancer driver mutations is essential to understand disease biology and devise effective therapies, but remains a complex endeavor. A focused analytical approach is now presented that defines driver mutations affecting ubiquitin-mediated proteolysis through machine learning and mining of cancer multi-omics data.
