Metastases are the leading cause of cancer-related death and frequently are widely disseminated, which has led to the prevailing view that metastases are always widespread and incurable. The oligometastasis hypothesis proposed by Hellman and Weichselbaum at the University of Chicago suggests that metastatic disease falls on a spectrum of virulence, where some metastases are limited both in number and organ involvement and are potentially curable with surgical resection or other loco-regional therapies. Patients with limited liver metastases from colorectal cancer (CRC) have been consistently demonstrated to achieve prolonged survival after surgical resection of liver metastases, and, therefore, they provide an opportunity to investigate the molecular basis for oligometastasis.

Recently, we studied independent clinical cohorts of CRC patients who underwent resection of limited de novo liver metastases and for the first time discovered integrated molecular patterns in liver metastases associated with long-term survival and cure. In particular, we determined that adaptive immune activation in concert with favorable clinical and pathological features predicted a 10-year survival of ~95% following surgical resection. By contrast, patients with metastases exhibiting poor adaptive immune responses were less likely to achieve long-term survival after surgical resection. The prestigious support of the Cancer Research Foundation has enabled the investigation into a novel mechanism by which CRC liver metastases evade the adaptive immune response through the action of oncogenic miRNAs that is associated with poor survival. Funding from the Cancer Research Foundation has been instrumental for my laboratory to pursue this high-risk, high-reward project, and has importantly provided a great source of initial funding to help establish my research program. These findings will ultimately have important implications in the selection of local therapy for those patients with potentially curable oligometastatic disease from those whose few metastases are a part of a large cascade of widespread disease, thereby changing the paradigm for the treatment of metastatic cancers.

The Cancer Research Foundation Young Investigator Award is allowing my lab to investigate a novel mechanism that colorectal cancer (CRC) liver metastases use to evade the body’s adaptive immune response through the action of MYC-dependent microRNAs (miRNAs) on tumor antigen presentation.  During the past year, my laboratory has completed Aim 1 of the proposed research and has confirmed that MYC drives the expression of oncogenic miRNAs in human colorectal cancer cell lines through direct promoter binding and transcriptional activation. Additionally, our work has demonstrated that these oncogenic miRNAs do suppress tumor antigen presentation.  Our next step is to use live mouse models to investigate the effects of these oncogenic miRNAs on immune evasion and liver metastasis. Taken together, these initial findings support an excellent foundation for the discovery of novel mechanisms that limit the potential curability of patients with limited metastatic disease.   These findings will ultimately have important implications in the selection of local therapy for those patients with potentially curable oligometastatic disease from those whose few metastases are a part of a large cascade of widespread disease, thereby changing the paradigm for the treatment of metastatic cancers.