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Tumor‐initiating cells are major drivers of chemoresistance and attractive targets for cancer therapy, however, their identity in human pancreatic ductal adenocarcinoma (PDAC) and the key molecules underlying their traits remain poorly understood. Here, we show that a cellular subpopulation with partial epithelial‐mesenchymal transition (EMT)‐like signature marked by high expression of receptor tyrosine kinase‐like orphan receptor 1 (ROR1) is the origin of heterogeneous tumor cells in PDAC. We demonstrate that ROR1 depletion suppresses tumor growth, recurrence after chemotherapy, and metastasis. Mechanistically, ROR1 induces the expression of Aurora kinase B (AURKB) by activating E2F through c‐Myc to enhance PDAC proliferation. Furthermore, epigenomic analyses reveal that ROR1 is transcriptionally dependent on YAP/BRD4 binding at the enhancer region, and targeting this pathway reduces ROR1 expression and prevents PDAC growth. Collectively, our findings reveal a critical role for ROR1high cells as tumor‐initiating cells and the functional importance of ROR1 in PDAC progression, thereby highlighting its therapeutic targetability. Synopsis: Cancer cell diversity and contribution of tumor‐initiating cells to pancreatic ductal adenocarcinoma (PDAC) progression remain poorly defined. In this work, single‐cell RNA sequencing and functional analyses uncovered targetable tumor‐initiating cells in PDAC. Heterogeneous tumor cells in PDAC arise from a subpopulation with partial EMT signature characterized by high expression of ROR1.Intratumoral ROR1high cells are tumor‐initiating cells with increased tumorigenic capacity.ROR1 functionally promotes PDAC tumor growth, relapse after chemotherapy, and metastasis.ROR1 induces the expression of AURKB via activation of AKT/c‐Myc/E2F signaling, thereby enhancing PDAC proliferation.ROR1 transcription is dependent on the YAP/BRD4 axis. [ABSTRACT FROM AUTHOR]

Aim: The appropriate extent of lymphadenectomy for pancreatic cancer of the body/tail has not been standardized worldwide. The present study evaluated the optimal extent of harvesting lymph nodes. Methods: Patients who underwent distal pancreatectomy for invasive ductal carcinoma of the pancreas between 2007 and 2018 were retrospectively reviewed. Patients were subclassified into three groups depending on the tumor location: pancreatic body (Pb), proximal pancreatic tail (Ptp), and distal pancreatic tail (Ptd). The pancreatic tail was further divided into even sections of Ptp and Ptd. Patterns of lymph node metastasis and the impact of lymph node metastasis on the prognosis were examined. Results: A total of 120 patients were evaluated. Fifty‐eight patients had a tumor in the Pb, 38 in the Ptp, and 24 in the Ptd. No patients with a Ptd tumor had metastasis beyond the peripancreatic and splenic hilar lymph nodes (LN‐PSH). All patients with metastasis to the lymph nodes along the common hepatic artery (LN‐CHA) or along the left lateral superior mesenteric artery (LN‐SMA) also had metastasis to the LN‐PSH. Recurrence after surgery occurred significantly earlier in this population. In a multivariate analysis, metastasis to the LN‐CHA or LN‐SMA (hazard ratio [HR] 3.3; P =.04) was an independent risk factor for overall survival. Furthermore, high levels of preoperative serum CA19‐9 (HR 10.9; P =.013) were a predictive factor for metastasis to the LN‐CHA or LN‐SMA. Conclusions: Metastasis to the LN‐CHA or LN‐SMA was rare but a significant prognostic factor in patients with pancreatic body/tail cancer. [ABSTRACT FROM AUTHOR]

Introduction: The genomic characteristics of hepatocellular carcinoma (HCC) after a sustained virological response (SVR) and its differences according to whether an SVR was achieved by treatment with direct‐acting antivirals (DAA) or interferon (IFN) are still not fully understood. Methods: Sixty‐nine surgically resected HCCs from patients with hepatitis C virus infection were analyzed by gene expression profiling and whole‐exome sequencing. Results: Among the 69 HCC patients, 34 HCCs in which an SVR was not achieved at the time of surgery were classified as HCV‐positive, and 35 HCCs in which an SVR was achieved at the time of surgery were classified as HCV‐SVR. According to the HCV treatment, 35 HCV‐SVR HCCs were classified into two groups: eight tumors with DAA (HCV‐SVR‐DAA) and 24 tumors with interferon (HCV‐SVR‐IFN). The frequency of samples with ARID2 mutations was significantly lower in HCV‐SVR than in HCV‐positive tumors (p = 0.048). In contrast, the frequency of samples with PREX2 mutations was significantly higher in HCV‐SVR samples than in HCV‐positive samples (p = 0.048). Among the patients with HCV‐SVR, the frequency of samples with TP53 mutations was significantly higher in HCV‐SVR‐DAA tumors than in HCV‐SVR‐IFN tumors (p = 0.030). TP53 inactivation scores in HCV‐SVR‐DAA tumors were found to be significantly enhanced in comparison to HCV‐SVR‐IFN tumors (p = 0.022). In addition, chromosomal instability and PI3K/AKT/mTOR pathway signatures were enhanced in HCV‐SVR‐DAA tumors. HCV‐SVR‐DAA was significantly associated with portal vein invasion (p = 0.003) in comparison to HCV‐SVR‐IFN. Conclusion: Our dataset potentially serves as a fundamental resource for the genomic characteristics of HCV‐SVR‐DAA tumors. Our comprehensive genetic profiling by WES revealed significant differences in the mutation rate of several driver genes between HCV‐positive tumors and HCV‐SVR tumors. Furthermore, it was revealed that the frequency of samples with mutations in TP53 was significantly higher in HCV‐SVR‐DAA tumors than in HCV‐SVR‐IFN tumors. [ABSTRACT FROM AUTHOR]