Fudan University Cancer HospitalTodayAccording to the news, the team of Professor Yu Xianjun, President of the hospital, together with Peking University Cancer Hospital, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai Changhai Hospital, and the Center for Excellence in Molecular and Cell Science of the Chinese Academy of Sciences, successfully drew the world's first multi-omics panorama of non-functional pancreatic neuroendocrine tumors after five years of research, and proposed a breakthrough molecular typing framework, prognostic model and target-immunity of this "silent tumor" according to the mapThe new treatment strategy provides an important basis for clinical precision diagnosis and treatment. Cancer, the top international oncology journalCancer Cell published this important research result on the same day, with an impact factor of 8.0 points.

Neuroendocrine tumors originate from neuroendocrine cells, which are found all over the human body, and are most common in the digestive system such as stomach, intestines, and pancreas, and occur most in the pancreas in Chinese patients. Pancreatic neuroendocrine tumors are the second most common tumors of the pancreas, occurring in about 90%It is non-functional.This type of non-functioning pancreatic NET has no symptoms in the early stages, so it is also called a "silent tumor". thatAbout half of the patients were diagnosed with metastases, particularly liver metastases, and had undergone radical surgeryMany patients are prone to recurrence, and there is a lack of molecular markers that can effectively predict prognosis in clinical practice, and the efficacy of comprehensive treatment needs to be improved.

Pancreatic neuroendocrine tumors are complex, such as:The same encrypted "book from heaven", its high heterogeneity and treatment dilemma have long plagued the medical community. Existing drug regimensMost patients only improved progression-free survival and limited improvement in overall survival.

Professor Yu Xianjun's team, together with a multi-center research team, integrated four omics data: genome, transcriptome, proteome and phosphorylation modification genomics, and drew the world's first panoramic molecular map of non-functional pancreatic neuroendocrine tumor protein genomics. The team conducted multi-dimensional integrated analysis of whole exome, transcriptome, proteome and phosphorylation modification group in 108 Chinese patients with non-functional pancreatic NET to draw a panoramic molecular map and revealedMEN1、ATRX、DAXXGene mutations are stained by interfering with themQuality structureStability and mechanisms by which the mTOR pathway is activated to drive tumor malignancy.

The research team also passedMEN1A genetic knockout mouse model was validatedMEN1Deletion triggers a vicious cycle of metabolic reprogramming and proliferative signal cross-priming, resulting in:Chromosome separationCrucialCENPVproteinBottom tone,It fills the gap in mechanism research in this field. In addition, copy number amplification of genes such as CDK5 and WASL was found to be non-functional pancreatic neuroendocrine tumorgrowis expected to be a potential "target" for targeted therapies.

The research team found that:In the clinical diagnosis and treatment of patients with non-functional pancreatic NET, the traditional tumor staging and pathological grading are difficult to meet the needs of individualized treatment.forTo solve this clinical dilemma, the research team based on massive proteomic data and used the previous research and developmentReProMSigThe platform is based on:The artificial intelligence algorithm screened out the three proteins of GNAO1, INA and VCAN, and constructed the characteristic spectrum of prognostic markers and the prognostic model, which provided an important tool for the prognosis judgment of non-functional pancreatic NET.

According to reports, the model is incontain345例患者的四組獨立佇列中均展現出優良的預測效能和區分效果：高危患者五年生存率僅為51.4%，而低危組則高達97.8%。更具臨床意義的是，研究團隊還證實分泌蛋白VCAN在患者血漿中的濃度與腫瘤進展顯著相關，這一發現有望推動診療模式從“有創組織活檢”向“無創血液檢測”跨越。

The research team further divided the patients with non-functional pancreatic NET into four molecular subtypes through proteomic feature cluster analysis, providing a precise route for clinical treatment. Among them, the C1 subtype tumor is characterized by the activation of the immunosuppressive microenvironment and the EMT pathway, and the prognosis of patients is the worst, and there is an urgent need to explore immunocombination therapy.C2Subtypeexhibits abnormally active oxidative phosphorylation activity; The C3 subtype consists of MYCAberrant activation and out-of-control cell cycle signaling dominance; The C4 isoform is inVHLDriven by mutations, a unique hypoxic ecology is formed.

Follow-up drug studies confirmed the accuracy of the "quadrangle". Protein kinases and expression based on subtype-specific initiation/activityUp-regulated proteins, the team used patient-derived organoids (PDOs) to carry out drug screening and patient-derived tumor xenograft models (PDX) for validation, confirming that CDK5 inhibitors can inhibit tumor growth of four molecular subtypes;Calcium channelsBlockers (egCardiovascular diseaseClassic medicinesAmiodarone hydrochloride) with CDK5Two inhibitorsJointIn C2SubtypeExpressionBetter tumor suppression;currently in clinical usemTORInhibitors are good at inhibiting C4 subtype tumors。 These evidences show that the "treatment by type" strategy based on "quartile type" provides a scientific basis for individualized precision treatment.

This study is the first large-scale clinical trial of pancreatic NET in the worldtargetThe comprehensive analysis of multi-omics results provides a solid theoretical basis for the pathogenesis, prognosis prediction, molecular typing and individualized treatment of non-functional pancreatic NET, which is expected to promote the rapid development of pancreatic NET research.

In recent years, Professor Yu Xianjun has led the team continuouslyExploration and technological innovation, starting from the selection of surgical methods, lymph node dissection and recurrence and metastasis prediction of pancreatic neuroendocrine tumors, a complete new individualized treatment strategy for pancreatic neuroendocrine tumors has been formed, which has achieved accurate prediction of lymph node metastasis risk before surgery, minimally invasive and precise resection of tumors during surgery, standardized lymph node dissection, maximum preservation of pancreatic function, postoperative screening of high-risk recurrence and metastasis population, and individualized follow-up treatment. A series of research results have been obtainedCome onThe first "Clinical Innovation Award of Shanghai Municipal Hospital"and many other honors。