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Shengyu Zhou,1,2,* Jiawei Xu,1,* Wenqing Sun,3 Jintao Zhang,1 Fayan Zhang,4 Xuesong Zhao,5 Ximing Wang,6 Wei Zhang,7 Yu Li,1 Kang Ning,8 Yun Pan,1 Tian Liu,1 Jiping Zhao,1 Jiguang Yu,9 Yunbo Sun,10 Feng Gao,11 Rumin Zhang,12 Chunsheng Fu,13 Yu Sun,14 Xiuhe Ouyang,15 Fusen Zhang,16 Qing Hu,17 Haifeng Teng,18 Yun Li,19 Chunke Zhang,20 Wei Tan,21 Jinlai Li,22 Lixia Yin,23 Liang Dong,1 Chunting Wang5 1Department of Respiratory and Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Clinical Nursing Department, School of Nursing, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 3Intensive Care Unit, Shandong Provincial Chest Hospital, Jinan, People’s Republic of China; 4College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 5Department of Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China; 6Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong University, Jinan, People’s Republic of China; 7Department of Lung Disease, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 8The First Affiliated Hospital of Shandong First Medical University Shandong Provincial Qianfoshan Hospital, Jinan, People’s Republic of China; 9Department of Infectious Diseases, Qishan Hospital, Yantai, People’s Republic of China; 10Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 11Department of Infectious Disease, Linyi People’s Hospital, Linyi, People’s Republic of China; 12Department of Critical Care Medicine, Zibo Central Hospital, Zibo, People’s Republic of China

Aberrant Shh signaling promotes tumor growth in diverse cancers. The importance of Shh signaling is particularly evident in medulloblastoma and basal cell carcinoma (BCC), where inhibitors targeting the Shh pathway component Smoothened (Smo) show great therapeutic promise. However, the emergence of drug resistance limits long-term efficacy, and the mechanisms of resistance remain poorly understood. Using new medulloblastoma models, we identify two distinct paradigms of resistance to Smo inhibition. Sufu mutations lead to maintenance of the Shh pathway in the presence of Smo inhibitors. Alternatively activation of the RAS-MAPK pathway circumvents Shh pathway dependency, drives tumor growth, and enhances metastatic behavior. Strikingly, in BCC patients treated with Smo inhibitor, squamous cell cancers with RAS/MAPK activation emerged from the antecedent BCC tumors. Together, these findings reveal a critical role of the RAS-MAPK pathway in drug resistance and tumor evolution of Shh pathway-dependent tumors.

We demonstrate self-similar evolution of fundamental and higher-order dark soliton stripes on a paraboloidal background in a bulk graded-index waveguide with self-defocusing nonlinearity. The results show that the dark soliton stripes can self-similarly evolve on the paraboloidal background when they pass through the nonlinear well or barrier, and their evolutions may lead to the generation of the optical vortex when the initial dark soliton stripes deviate from the central position of the paraboloidal background. In addition, the interactions between neighboring dark soliton stripes on the paraboloidal background are investigated, which exhibits some complicated vortex patterns.