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Super-enhancer receives signals from the extracellular matrix to induce PD-L1-mediated immune evasion via integrin/ braf/TAK1/ERK/ETV4 signaling

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Cancer Biology & Medicine 2022年第5期19卷 669-684页

作者： Panpan Ma Xinxin Jin Zhiwei Fan Zhou Wang Suhui Yue Changyue Wu Shiyin Chen Yuanyuan Wu Miaomiao Chen Donghua Gu Siliang Zhang Renfang Mao Yihui Fan Laboratory of Medical Science School of MedicineNantong UniversityNantong 226001China Department of Pathogenic Biology School of MedicineNantong UniversityNantong 226001China Department of Clinical Laboratory Yancheng No.1 People’s HospitalYancheng 224005China School of Life Sciences Nantong UniversityNantong 226001China Department of Dermatology Affiliated Hospital of Nantong UniversityNantong UniversityNantong 226001China The Department of Urology the Second Affiliated Hospital of Nantong UniversityNantong UniversityNantong 226001China The Department of Radiotherapy Oncology Harbin Medical University Cancer HospitalHarbin 150086China Department of Pathophysiology School of MedicineNantong UniversityNantong 226001China

Objective:PD-L1 and PD-L2 expression levels determine immune evasion and the therapeutic efficacy of immune checkpoint blockade.The factors that drive inducible PD-L1 expression have been extensively studied,but mechanisms that result in constitutive PD-L1 expression in cancer cells are largely unknown.Methods:DNA elements were deleted in cells by CRISPR/Cas9-mediated knockout.Protein function was inhibited by chemical inhibitors.Protein levels were examined by Western blot,mRNA levels were examined by real-time RT-PCR,and surface protein expression was determined by cellular immunofluorescence and flow cytometry.Immune evasion was examined by in vitro T cell-mediated killing.Results:We determined the core regions(chr9:5,496,378–5,499,663)of a previously identified PD-L1L2-super-enhancer(SE).Through systematic analysis,we found that the E26 transformation-specific(ETS)variant transcription factor(ETV4)bound to this core DNA region but not to DNA surrounding PD-L1L2SE.Genetic knockout of ETV4 dramatically reduced the expressions of both PD-L1 and PD-L2.ETV4 transcription was dependent on ERK activation,and braf/TAK1-induced ERK activation was dependent on extracellular signaling fromαvβ3 integrin,which profoundly affected ETV4 transcription and PD-L1/L2 expression.Genetic silencing or pharmacological inhibition of components of the PD-L1L2-SE-associated pathway rendered cancer cells susceptible to T cell-mediated killing.Conclusions:We identified a pathway originating from the extracellular matrix that signaled via integrin/braf/TAK1/ERK/ETV4 to PD-L1L2-SE to induce PD-L1-mediated immune evasion.These results provided new insights into PD-L1L2-SE activation and pathways associated with immune checkpoint regulation in cancer.

关键词： PD-L1 super-enhancer ETV4 ERK αvβ3 integrin braf TAK1

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Erianin suppresses constitutive activation of MAPK signaling pathway by inhibition of CRAF and MEK1/2

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Signal Transduction and Targeted Therapy 2023年第4期8卷 1874-1888页

作者： Penglei Wang Xuechao Jia Bingbing Lu Han Huang Jialin Liu Xuejiao Liu Qiong Wu Yamei Hu Pan Li Huifang Wei Tingting Liu Dengyun Zhao Lingwei Zhang Xueli Tian Yanan Jiang Yan Qiao Wenna Nie Xinli Ma Ruihua Bai Cong Peng Zigang Dong Kangdong Liu Department of Pathophysiology Basic Medicine Research CenterSchool of Basic Medical SciencesAMSZhengzhou University450000 ZhengzhouChina China-US(Henan)Hormel Cancer Institute 450000 ZhengzhouChina The Department of Pathology Affiliated Cancer Hospital of Zhengzhou University450000 ZhengzhouChina The Department of Dermatology Xiangya HospitalCentral South University410078 ChangshaChina The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention 450000 ZhengzhouChina State Key Laboratory of Esophageal Cancer Prevention and Treatment Zhengzhou University450000 ZhengzhouChina Provincial Cooperative Innovation Center for Cancer Chemoprevention Zhengzhou UniversityZhengzhouChina

Constitutive activation of RAS-RAF-MEK-ERK signaling pathway(MAPK pathway)frequently occurs in many cancers harboring RAS or RAF oncogenic mutations.Because of the paradoxical activation induced by a single use of braf or MEK inhibitors,dual-target RAF and MEK treatment is thought to be a promising strategy.In this work,we evaluated erianin is a novel inhibitor of CRAF and MEK1/2 kinases,thus suppressing constitutive activation of the MAPK signaling pathway induced by braf V600E or RAS mutations.KinaseProfiler enzyme profiling,surface plasmon resonance(SPR),isothermal titration calorimetry(ITC),cellular thermal shift assay,computational docking,and molecular dynamics simulations were utilized to screen and identify erianin binding to CRAF and MEK1/2.Kinase assay,luminescent ADP detection assay,and enzyme kinetics assay were investigated to identify the efficiency of erianin in CRAF and MEK1/2 kinase activity.Notably,erianin suppressed braf V600E or RAS mutant melanoma and colorectal cancer cell by inhibiting MEK1/2 and CRAF but not braf kinase activity.Moreover,erianin attenuated melanoma and colorectal cancer in vivo.Overall,we provide a promising leading compound for braf V600E or RAS mutant melanoma and colorectal cancer through dual targeting of CRAF and MEK1/2.

关键词： MEK1/2 braf activation

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Remarkable response of braf^(V600E)-mutated metastatic pancreatic cancer to braf/MEK inhibition:a case report

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Gastroenterology Report 2022年第1期10卷 615-617页

作者： Hong-Shuai Li Ke Yang Yan Wang Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP.R.China Department of Medical Oncology Cancer Hospital of HuanXingChaoyang DistrictBeijingP.R.China

Introduction Advanced pancreatic ductal adenocarcinoma(PDAC)has very limited treatment options due to few targetable mutations,and chemotherapeutic treatment is currently the mainstay of palliative therapy for PDAC pa... 详细信息

关键词： V600E braf adenocarcinoma

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Effect of braf mutation on the prognosis for patients with colorectal cancer undergoing cytoreductive surgery for synchronous peritoneal metastasis

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Gastroenterology Report 2023年第1期11卷 492-499页

作者： Zhijie Wu Xiusen Qin Yuanxin Zhang Jian Luo Rui Luo Zonglu Cai Hui Wang Department of General Surgery(Colorectal Surgery) The Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdongP.R.China Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases The Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdongP.R.China Biomedical Innovation Center The Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdongP.R.China

Background:KRAS/braf mutations(mutKRAS/mutbraf)are unfavorable prognostic factors for colorectal cancer(CRC)metastases to the liver and lungs.However,their effects on the prognosis for patients with synchronous peritoneal metastasis(S-PM)of CRC after cytoreductive surgery(CRS)and hyperthermic intraperitoneal chemotherapy(HIPEC)are controversial.In the study,we aimed to determine the effects of mutKRAS/mutbraf on the prognosis for patients with S-PM who received CRS.Methods:A total of 142 patients diagnosed with S-PM between July 2007 and July 2019 were included in this study.The demographics,mutKRAS/mutbraf status,overall survival(OS),and progression-free survival(PFS)of the patients were evaluated.The Kaplan–Meier method and log-rank test were used to estimate the difference in survival between groups.Results:Among 142 patients,68(47.9%)showed mutKRAS and 42(29.5%)showed mutbraf.The median OS values were 8.4 and 34.3 months for patients with mutbraf and braf wild-type,respectively(Pbraf as independent predictors for OS.Based on these findings,a nomogram was constructed.The C-index was 0.789(95%confidence interval,0.742–0.836),indicating good predictive ability of the model.Furthermore,the 1-and 2-year survival calibration plots showed good agreement between the predicted and actual OS rates.The area under curves of the 1-and 2-year survival predictions based on the nomogram were 0.807 and 0.682,respectively.Additionally,mutbraf was significantly associated with lower PFS(Pbraf is an independent prognostic risk factor for S-PM.The established nomogram predicted the OS of patients with CRC having S-PM with high accuracy,indicating its usefulness as a valuable prognostic tool for the designated patient cohort.

关键词： colorectal cancer peritoneal metastasis braf prognosis

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World Journal of Clinical Cases 2022年第19期10卷 6722-6727页

作者： Aysegul Gencer Gizem Ozcibik Fatma Gulsum Karakas Ismail Sarbay Sebnem Batur Sermin Borekci Akif Turna Department of Pulmonary Diseases Istanbul University-CerrahpasaCerrahpasa Medical Faculty CampusIstanbul 34098Turkey Department of Thoracic Surgery Istanbul University-CerrahpasaCerrahpasa Medical FacultyIstanbul 34098Turkey Department of Pathology Istanbul University-CerrahpasaCerrahpasa Medical FacultyIstanbul 34098Turkey

BACKGROUND Pulmonary Langerhans cell histiocytosis(PLCH)is a rare cystic lung disease usually affecting young adults.It is predicted that PLCH is a lung tumor precursor associated with dysfunction of the myeloid dendritic cells in the lung.CASE SUMMARY A 70-year-old male patient presented with chronic cough and sputum.He had symptoms for 5 years and described shortness of breath on exertion for the previous 3 years.He had a 60 packs/year smoking history.Computerized tomography of the thorax revealed an 11-mm nodule in the right lung lower lobe superior segment and a 7-mm nodule in the right lung lower lobe poster basal segment.Those two nodules were resected by means of right thoracoscopic surgery.Pathological evaluation revealed a squamous cell carcinoma and PLCH.CONCLUSION Coexistent squamous cell carcinoma and PLCH suggest possible association between PLCH and lung cancer.

关键词： Pulmonary Langerhans cell histiocytosis Lung cancer Squamous cell carcinoma braf Mitogen-activated protein kinase Case report

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Ovarian mucinous tumor with mural nodules of anaplastic carcinoma:Three case reports

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World Journal of Clinical Cases 2022年第21期10卷 7459-7466页

作者： Xiao-Juan Wang Chun-Yan Wang Yan-Feng Xi Peng Bu Pei Wang Department of Pathology Shanxi Cancer Hospital and InstituteTaiyuan 030013Shanxi ProvinceChina Department of Molecular Biology Department of Blood TransfusionShanxi Cancer Hospital and InstituteTaiyuan 030013Shanxi ProvinceChina Department of Gynecology Shanxi Cancer Hospital and InstituteTaiyuan 030013Shanxi ProvinceChina

BACKGROUND Anaplastic carcinoma mural nodules in ovarian mucinous tumors are very rare.This study aimed to report the morphological characteristics,molecular detection results,clinical treatment and prognosis of three ovarian mucinous tumors with mural nodules of anaplastic carcinoma.CASE SUMMARY The pathomorphological features,molecular detection results,clinical treatment and prognosis of anaplastic carcinoma mural nodules were described in three cases.In case 1,sarcoma-like mural nodules(SLMNs)coexisted with anaplastic carcinoma mural nodules.No mutation was found in mucinous tumors.KRAS mutation was found in anaplastic carcinoma nodules and heterotypic cells were found in SLMNs.In case 2,KRAS mutation occurred in the mucinous epithelium and braf mutation occurred in mural nodules.In case 3,both mural nodules and mucinous tumors had the same KRAS mutation and a morphological transition between them was observed.All three patients died within 2 years,whether receiving chemotherapy or not.CONCLUSION Anaplastic carcinoma mural nodules may develop from dedifferentiation of mucinous tumors or are unrelated to mucinous tumors.

关键词： Anaplastic carcinoma braf KRAS Mucinous tumor Mural nodules Case report

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Papillary thyroid carcinoma occurring with undifferentiated pleomorphic sarcoma: A case report

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World Journal of Clinical Cases 2022年第23期10卷 8336-8343页

作者： Yu-Li Lee Ya-Qiong Cheng Chen-Fang Zhu Hai-Zhong Huo Department of General Surgery Shanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineDiscipline Construction Research Center of China Hospital Development InstituteShanghai Jiao Tong UniversityShanghai 200011China

BACKGROUND Papillary thyroid cancer(PTC)is the most common malignant tumor of the thyroid.However,the coexistence of PTC and sarcoma in one patient is rare.In this article,we report the case of a patient who presented with both PTC and undifferentiated pleomorphic sarcoma(UPS),which has not been previously reported in the online Medline database(PubMed).CASE SUMMARY A 71-year-old man was admitted to our hospital for a mass on the right side of his neck for one month,which rapidly enlarged within 2 wk with distending pain.The patient was diagnosed with a thyroid malignancy by fine-needle aspiration and underwent total thyroidectomy and bilateral central lymph node dissection.Histology and immunohistochemistry revealed features of both PTC and UPS.The thyroid cancer 8 gene detection kit results showed braf and telomerase reverse transcriptase mutations.The disease progressed rapidly,and the patient died four months after surgery from extensive lung metastasis.CONCLUSION Our report highlights the patient’s pathological characteristics and related genetic mutations.Due to the rapid development and poor prognosis of cooccurring PTC and sarcoma,it is important for clinical physicians and pathologists to raise awareness of this type of tumor.

关键词： Thyroid tumor Papillary thyroid carcinoma Undifferentiated pleomorphic sarcoma braf TERT Case report

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Colorectal cancer carcinogenesis:From bench to bedside

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World Journal of Gastrointestinal Oncology 2022年第3期14卷 654-663页

作者： Pedro Currais Isadora Rosa Isabel Claro Department of Gastroenterology Instituto Portugues de Oncologia de Lisboa Francisco GentilLisboa 1099-023Portugal

Colorectal cancer(CRC)remains one of the main causes of cancer death in developed countries.Yet,it is potentially preventable,by removing the precursor lesions-adenomas or serrated lesions.Several studies proved that this intervention reduces CRC mortality and that the first colonoscopy’s results can guide surveillance strategies.More recently,it became clear that several carcinogenesis pathways may lead to sporadic CRC.CRC is a heterogeneous disease,characterized by multiple molecular subtypes.Three main pathways have been implicated in the development of CRC:Chromosomal instability,microsatellite instability,and the“serrated”pathways,with overlapping features between them.This and other molecular and genetic based CRC classifications are known to have clinical implications,spanning from familial risk assessment to therapy choices.The authors review basic science data and provide insight on current implications for the management of patients with CRC.

关键词： Colorectal cancer Carcinogenesis pathways Microsatellite instability APC KRAS braf

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Can dietary flavonoids be useful in the personalized treatment of colorectal cancer?

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World Journal of Gastrointestinal Oncology 2022年第6期14卷 1115-1123页

作者： Cristina Pereira-Wilson Department of Biology Centre of Biological EngineeringLABBELS Associate LaboratoryUniversity of MinhoBraga 4710-057Portugal

Activating mutations in the oncogenes KRAS,braf and PI3K define molecular colorectal cancer(CRC)subtypes because they play key roles in promoting CRC development and in determining the efficacy of chemotherapeutic agents such as 5-fluorouracil and anti-epidermal growth factor receptor monoclonal antibodies.Survival of patients with cancers displaying these molecular profiles is low.Given the limited efficacy of therapeutic strategies for CRC presenting mutational activations in mitogen-activated protein kinase and/or PI3K pathways,developing combination therapies with natural flavonoids or other phytochemicals with demonstrated effects on these pathways(and little or no toxic effects)may constitute a valuable path forward.Much has been published on the anticancer effects of dietary phytochemicals.However,even an exhaustive characterization of potential beneficial effects produced by in vitro studies cannot be extrapolated to effects in humans.So far,the available data constitute a good starting point.Published results show quercetin and curcumin as possibly the best candidates to be further explored in the context of adjuvant CRC therapy either as part of dietary prescriptions or as purified compounds in combination regimens with the drugs currently used in CRC treatment.Clinical trial data is still largely missing and is urgently needed to verify relevant effects and for the development of more personalized treatment approaches.

关键词： Colorectal cancer Personalized treatment Quercetin Curcumin KRAS braf

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Emerging actionable targets to treat therapyresistant colorectal cancers

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Cancer Drug Resistance 2022年第1期5卷 36-63页

作者： Emanuela Grassilli Maria Grazia Cerrito Department of Medicine and Surgery University of Milano-BicoccaMonza 20900Italy

In the last two decades major improvements have been reached in the early diagnosis of colorectal cancer(CRC)and,besides chemotherapy,an ampler choice of therapeutic approaches is now available,including targeted and immunotherapy.Despite that,CRC remains a“big killer”mainly due to the development of resistance to therapies,especially when the disease is diagnosed after it is already metastatic.At the same time,our knowledge of the mechanisms underlying resistance has been rapidly expanding which allows the development of novel therapeutic options in order to overcome it.As far as resistance to chemotherapy is concerned,several contributors have been identified such as:intake/efflux systems upregulation;alterations in the DNA damage response,due to defect in the DNA checkpoint and repair systems;dysregulation of the expression of apoptotic/anti-apoptotic members of the BCL2 family;overexpression of oncogenic kinases;the presence of cancer stem cells;and the composition of the tumoral microenvironment and that of the gut microbiota.Interestingly,several mechanisms are also involved in the resistance to targeted and/or immunotherapy.For example,overexpression and/or hyperactivation and/or amplification of oncogenic kinases can sustain resistance to targeted therapy whereas the composition of the gut microbiota,as well as that of the tumoral niche,and defects in DNA repair systems are crucial for determining the response to immunotherapy.In this review we will make an overview of the main resistance mechanisms identified so far and of the new therapeutic approaches to overcome it.

关键词： Colorectal cancer resistance chemotherapy target therapy EGFR ERBB2 MET braf kinase inhibitors immune checkpoint inhibitors gut microbiota

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