Background and Aims Vascular invasion (VI) is a critical risk factor for HCC recurrence and poor survival. The molecular drivers of vascular invasion in HCC are open for investigation. Deciphering the molecular landscape of invasive HCC will help identify therapeutic targets and noninvasive biomarkers. Approach and Results To this end, we undertook this study to evaluate the genomic, transcriptomic, and proteomic profile of tumors with VI using the multiplatform cancer genome atlas (The Cancer Genome Atlas; TCGA) data (n = 373). In the TCGA Liver Hepatocellular Carcinoma cohort, macrovascular invasion was present in 5% (n = 17) of tumors and microvascular invasion in 25% (n = 94) of tumors. Functional pathway analysis revealed that the MYC oncogene was a common upstream regulator of the mRNA, miRNA, and proteomic changes in VI. We performed comparative proteomic analyses of invasive human HCC and MYC‐driven murine HCC and identified fibronectin to be a proteomic biomarker of invasive HCC (mouse fibronectin 1 [Fn1], P = 1.7 × 10−11; human FN1, P = 1.5 × 10−4) conserved across the two species. Mechanistically, we show that FN1 promotes the migratory and invasive phenotype of HCC cancer cells. We demonstrate tissue overexpression of fibronectin in human HCC using a large independent cohort of human HCC tissue microarray (n = 153; P < 0.001). Lastly, we showed that plasma fibronectin levels were significantly elevated in patients with HCC (n = 35; mean = 307.7 μg/mL; SEM = 35.9) when compared to cirrhosis (n = 10; mean = 41.8 μg/mL; SEM = 13.3; P < 0.0001). Conclusions Our study evaluates the molecular landscape of tumors with VI, identifying distinct transcriptional, epigenetic, and proteomic changes driven by the MYC oncogene. We show that MYC up‐regulates fibronectin expression, which promotes HCC invasiveness. In addition, we identify fibronectin to be a promising noninvasive proteomic biomarker of VI in HCC.

The MYC oncogene is dysregulated in most human cancers and hence is an attractive target for cancer therapy. We and others have shown experimentally in conditional transgenic mouse models that suppression of the MYC oncogene is sufficient to induce rapid and sustained tumor regression, a phenomenon known as oncogene addiction. However, it is unclear whether a therapy that targets the MYC oncogene could similarly elicit oncogene addiction. In this study, we report that using antisense oligonucleotides (ASOs) to target and reduce the expression of MYC impedes tumor progression and phenotypically elicits oncogene addiction in transgenic mouse models of MYC-driven primary hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Quantitative image analysis of MRI was used to demonstrate the inhibition of HCC and RCC progression. After 4 weeks of drug treatment, tumors had regressed histologically. ASOs depleted MYC mRNA and protein expression in primary tumors in vivo, as demonstrated by real-time PCR and immunohistochemistry. Treatment with MYC ASO in vivo, but not with a control ASO, decreased proliferation, induced apoptosis, increased senescence, and remodeled the tumor microenvironment by recruitment of CD4 + T cells. Importantly, although MYC ASO reduced both mouse Myc and transgenic human MYC, the ASO was not associated with significant toxicity. Lastly, we demonstrate that MYC ASO inhibits the growth of human liver cancer xenografts in vivo. Our results illustrate that targeting MYC expression in vivo using ASO can suppress tumorigenesis by phenotypically eliciting both tumor-intrinsic and microenvironment hallmarks of oncogene addiction. Hence, MYC ASO therapy is a promising strategy to treat MYC-driven human cancers.

pontaneous regression of cancer is rare and has been observed mostly in immunogenic cancers like melanoma. A few cases of spontaneous regression of hepatocellular carcinoma (HCC) have been reported, but the mechanisms of regression have not been elucidated. Here, we report a patient with advanced HCC who experienced spontaneous regression of her tumor and present evidence for a putative immune-mediated mechanism for tumor regression. Case SeriesThe index patient is a 65-year-old female patient with alcohol-associated cirrhosis diagnosed with infiltrative 17 cm HCC with occlusive portal vein tumor thrombus and serum alpha-fetoprotein (AFP) of 40,250 ng/mL (Fig. 1A). Before treatment was initiated, she showed a spontaneous decrease in serum AFP to 250 ng/mL, prompting repeat magnetic resonance imaging, which surprisingly showed complete involution of both the primary tumor and the portal vein tumor thrombus (Fig. 1A). The only (potentially related) intervening event was the receipt of pneumococcal vaccine. Eventually, 1 year after initial diagnosis, the patient received transarterial chemoembolization for a small area of suspected recurrence. The patient is currently asymptomatic with AFP <2 ng/mL (Fig. 1B). Furthermore, under institutional review board approval, we identified 5 other patients among 5,980 patients with HCC treated at our center between 2005 and 2020 (Table 1) who had experienced sustained spontaneous regression of very large HCC or even of metastatic HCC.

The incidence of hepatocellular carcinoma (HCC) is growing in the United States, especially among the elderly. Older patients are increasingly receiving transplants as a result of HCC, but the impact of advancing age on long-term posttransplant outcomes is not clear. To study this, we used data from the US Multicenter HCC Transplant Consortium of 4980 patients. We divided the patients into 4 groups by age at transplantation: 18 to 64 years (n = 4001), 65 to 69 years (n = 683), 70 to 74 years (n = 252), and ≥75 years (n = 44). There were no differences in HCC tumor stage, type of bridging locoregional therapy, or explant residual tumor between the groups. Older age was confirmed to be an independent and significant predictor of overall survival even after adjusting for demographic, etiologic, and cancer-related factors on multivariable analysis. A dose-response effect of age on survival was observed, with every 5-year increase in age older than 50 years resulting in an absolute increase of 8.3% in the mortality rate. Competing risk analysis revealed that older patients experienced higher rates of non-HCC-related mortality (P = 0.004), and not HCC-related death (P = 0.24). To delineate the precise cause of death, we further analyzed a single-center cohort of patients who received a transplant as a result of HCC (n = 302). Patients older than 65 years had a adeniji et al. liver transplantatiOn, vol. 27, no. 5, 2021 adeniji et al. Original article | 685higher incidence of de novo cancer (18.1% versus 7.6%; P = 0.006) after transplantation and higher overall cancer-related mortality (14.3% versus 6.6%; P = 0.03). Even carefully selected elderly patients with HCC have significantly worse posttransplant survival rates, which are mostly driven by non-HCC-related causes. Minimizing immunosuppression and closer surveillance for de novo cancers can potentially improve the outcomes in elderly patients who received a transplant as a result of HCC.

Long waiting times due to ongoing organ shortage have led to increased utilization of locoregional therapies (LRTs) to bridge patients with hepatocellular carcinoma (HCC) to liver transplantation (LT). We performed this study to evaluate the impact of LRTs on post-LT outcomes. We conducted a retrospective study of patients who were transplanted for HCC at Stanford University Hospital between 2008 and 2018 (n = 302). We found that receipt of ≥5 LRTs was an independent and significant predictor of poor overall 5-year survival (58.3% vs. 83.3%; HR 2.26, p = .03), poor recurrence-free 5-year survival (51.9% vs. 80.4%; HR 2.12, p = .03), and was associated with higher rates of recurrence (25.0% vs. 7.4%, p = .001). Moreover, recurrent HCC was more likely to be the cause of death (58.3% vs. 41.7%, p = .04) in patients who received ≥5 LRTs. Also, patients who required ≥5 LRTs showed an overall lower rate of radiological complete response (46.9% vs. 97.8%, p = .001) and were more likely to have more advanced pathological stage tumors in the explant (65.6% vs. 29.6%, p < .001). In conclusion, receipt of ≥5 bridging LRTs prior to LT is associated with worse post-transplant clinical outcomes.