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.

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colorectal cancer demonstrates intra-tumour heterogeneity formed by a hierarchical structure comprised of cancer stem cells (CSCs) and their differentiated progenies. The mechanism by which CSCs are maintained and differentiated needs to be further elucidated, and there is evidence that the tumour microenvironment governs cancer stemness. Using PLR123, a colon cancer cell line with CSC properties, we determined the culture conditions necessary to establish a pair of three-dimensional (3D) culture models grown in Matrigel, designated stemCO and diffCO. The conditions were determined by comparing the phenotypes in the models with PLR123 mouse xenografts colonising lung and liver. StemCO resembled LGR5-positive undifferentiated tumours in the lung, and diffCO had lumen structures composed of polarised cells that were similar to the ductal structures found in differentiated tumours in the liver. In a case using the models for biomedical research, treatment with JAG-1 peptide or a γ-secretase inhibitor modified the Notch signaling and induced changes indicating that the signal participates in lumen formation in the models. Our results demonstrate that culture conditions affect the stemness of 3D culture models generated from CSCs and show that comparing models with different phenotypes is useful for studying how the tumour environment regulates cancer.Colorectal cancers, especially differentiated types that form ductal structures, are composed of a heterogeneous population of undifferentiated cancer stem cells (CSCs) and differentiated cells, constituting a hierarchical structure. The tumour microenvironment has an important effect on CSC maintenance and differentiation, which in turn affects the hierarchy of a cancer. CSCs reside in a tumour-host interface (the so-called stem-niche) in colorectal cancer, and their stemness is speculated to be maintained by host-derived factor(s) 1-3 . Therefore, reproducing a precise tumour microenvironment is crucial for modeling the cancer hierarchy in vitro.Three-dimensional (3D) cultures are frequently used for studying biology of epithelial tissues since they can reproduce the 3D organisation and function of cells within tissues 4 . They have been used to elucidate the contribution of microenvironmental factors to normal and disease processes and to advance therapeutic approaches 4-6 . One of the 3D culture techniques is the organoid culture, with which normal intestinal stem cells generate organoids with crypt-villus structures 4 . Organoid cultures are also used to culture cancer cells from patient tumour samples since they can recapitulate the structural and functional heterogeneity of the original tumour 7 . If the phenotypes of 3D cultures derived from colorectal CSCs can be controlled by adjusting culture conditions, then the cultures would be useful for analysing the relationship between CSC maintenance and differentiation induced by the tumour environment. To this end, the appropriate conditions should be tested using well-characterised CSCs.We established a colon cancer...

Brown adipose tissue plays a central role in the regulation of the energy balance by expending energy to produce heat. NAD+-dependent deacylase sirtuins have widely been recognized as positive regulators of brown adipose tissue thermogenesis. However, here we reveal that SIRT7, one of seven mammalian sirtuins, suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions. Whole-body and brown adipose tissue-specific Sirt7 knockout mice have higher body temperature and energy expenditure. SIRT7 deficiency increases the protein level of UCP1, a key regulator of brown adipose tissue thermogenesis. Mechanistically, we found that SIRT7 deacetylates insulin-like growth factor 2 mRNA-binding protein 2, an RNA-binding protein that inhibits the translation of Ucp1 mRNA, thereby enhancing its inhibitory action on Ucp1. Furthermore, SIRT7 attenuates the expression of batokine genes, such as fibroblast growth factor 21. In conclusion, we propose that SIRT7 serves as an energy-saving factor by suppressing brown adipose tissue functions.

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