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Significance There is a pressing need for new approaches to combat metastatic disease. We demonstrate, here, a strategy that targets and activates the molecular machines that control cell shape in cell division, wound healing, immune surveillance, embryonic development, and cancer metastasis. Cells control their shape by remodeling their cytoskeletal actin filaments, microtubules, and intermediate filaments, while cytoskeletal motor proteins, such as the myosins generate forces that can produce local contractions. By targeting and activating NM2C directly, we interfere with cytoskeletal plasticity. We demonstrate the effectiveness of this activation strategy in vitro and in vivo and provide a molecular mechanism for our measured increase in cell stiffness. Our strategy can be integrated readily with existing approaches to combat aggressive cancers.

The oligometastasis hypothesis suggests a spectrum of metastatic virulence where some metastases are limited in extent and curable with focal therapies. A subset of patients with metastatic colorectal cancer achieves prolonged survival after resection of liver metastases consistent with oligometastasis. Here we define three robust subtypes of de novo colorectal liver metastasis through integrative molecular analysis. Patients with metastases exhibiting MSI-independent immune activation experience the most favorable survival. Subtypes with adverse outcomes demonstrate VEGFA amplification in concert with (i) stromal, mesenchymal, and angiogenic signatures, or (ii) exclusive NOTCH1 and PIK3C2B mutations with E2F/MYC activation. Molecular subtypes complement clinical risk stratification to distinguish low-risk, intermediate-risk, and high-risk patients with 10-year overall survivals of 94%, 45%, and 19%, respectively. Our findings provide a framework for integrated classification and treatment of metastasis and support the biological basis of curable oligometastatic colorectal cancer. These concepts may be applicable to many patients with metastatic cancer., The oligometastasis hypothesis suggests certain metastases are limited in extent and curable with focal therapies. Here they identify three integrated molecular subtypes of colorectal cancer liver metastasis, which complement clinical risk stratification to distinguish the subset of oligometastatic patients.

Background: The CXCL10/CXCR3 signalling mediates paracrine interactions between tumour and stromal cells that govern leukocyte trafficking and angiogenesis. Emerging data implicate noncanonical CXCL10/CXCR3 signalling in tumourigenesis and metastasis. However, little is known regarding the role for autocrine CXCL10/CXCR3 signalling in regulating the metastatic potential of individual tumour clones. Methods: We performed transcriptomic and cytokine profiling to characterise the functions of CXCL10 and CXCR3 in tumour cells with different metastatic abilities. We modulated the expression of the CXCL10/CXCR3 pathway using shRNA-mediated silencing in both in vitro and in vivo models of B16F1 melanoma. In addition, we examined the expression of CXCL10 and CXCR3 and their associations with clinical outcomes in clinical data sets derived from over 670 patients with melanoma and colon and renal cell carcinomas. Results: We identified a critical role for autocrine CXCL10/CXCR3 signalling in promoting tumour cell growth, motility and metastasis. Analysis of publicly available clinical data sets demonstrated that coexpression of CXCL10 and CXCR3 predicted an increased metastatic potential and was associated with early metastatic disease progression and poor overall survival. Conclusion: These findings support the potential for CXCL10/CXCR3 coexpression as a predictor of metastatic recurrence and point towards a role for targeting of this oncogenic axis in the treatment of metastatic disease.

Multiple therapeutic agents are typically used in concert to effectively control metastatic tumors. Recently, we described microRNAs that are associated with the oligometastatic state, in which a limited number of metastatic tumors progress to more favorable outcomes. Here, we report the effective delivery of an oligometastatic microRNA (miR-655-3p) to colorectal liver metastases using nanoscale coordination polymers (NCPs). The NCPs demonstrated a targeted and prolonged distribution of microRNAs to metastatic liver tumors. Tumor-targeted microRNA miR-655-3p suppressed tumor growth when co-delivered with oxaliplatin, suggesting additive or synergistic interactions between microRNAs and platinum drugs. This is the first known example of systemically administered nanoparticles delivering an oligometastatic microRNA to advanced metastatic liver tumors and demonstrating tumor-suppressive effects. Our results suggest a potential therapeutic strategy for metastatic liver disease by the co-delivery of microRNAs and conventional cytotoxic agents using tumor-specific NCPs.