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Sci Rep ; 10(1): 3156, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32081957


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.

Oncogene ; 38(26): 5142-5157, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30894682


The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transcriptional target of the lineage-survival oncogene NKX2-1/TTF-1 in lung adenocarcinomas. In addition to its kinase-dependent role, ROR1 functions as a scaffold protein to facilitate interaction between caveolin-1 (CAV1) and CAVIN1, and consequently maintains caveolae formation, which in turn sustains pro-survival signaling toward AKT from multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET (proto-oncogene, receptor tyrosine kinase), and IGF-IR (insulin-like growth factor receptor 1). Therefore, ROR1 is an attractive target for overcoming EGFR-TKI resistance due to various mechanisms such as EGFR T790M double mutation and bypass signaling from other RTKs. Here, we report that ROR1 possesses a novel scaffold function indispensable for efficient caveolae-dependent endocytosis. CAVIN3 was found to bind with ROR1 at a site distinct from sites for CAV1 and CAVIN1, a novel function required for proper CAVIN3 subcellular localization and caveolae-dependent endocytosis, but not caveolae formation itself. Furthermore, evidence of a mechanistic link between ROR1-CAVIN3 interaction and consequential caveolae trafficking, which was found to utilize a binding site distinct from those for ROR1 interactions with CAV1 and CAVIN1, with RTK-mediated pro-survival signaling towards AKT in early endosomes in lung adenocarcinoma cells was also obtained. The present findings warrant future study to enable development of novel therapeutic strategies for inhibiting the multifaceted scaffold functions of ROR1 in order to reduce the intolerable death toll from this devastating cancer.

Adenocarcinoma de Pulmão/patologia , Cavéolas/fisiologia , Endocitose , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/patologia , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Animais , Células COS , Cavéolas/metabolismo , Sobrevivência Celular/genética , Células Cultivadas , Endocitose/genética , Células HEK293 , Células HeLa , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ligação Proteica/fisiologia , Células Sf9 , Transdução de Sinais/genética , Spodoptera