Investigating L1CAM-dependent stem cell regeneration in metastasis

研究转移中 L1CAM 依赖性干细胞再生

• 批准号: 10452652
• 负责人: Karuna Ganesh
• 金额: $ 25.68万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-13 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452652
• 关键词: Advisory Committees; Alleles; Anoikis; Antibodies; Award; Biochemical; Biochemistry; Cancer Etiology; Cancer Patient; Carcinoma; Cell Adhesion Molecules; Cell Cycle; Cell Differentiation process; Cells; Cessation of life; Chromatin; Clinical; Colitis; Colon; Colorectal; Colorectal Cancer; Data; Dependence; Development; Development Plans; Disease Outbreaks; Disseminated Malignant Neoplasm; Dissociation; Distant; Distant Metastasis; Drug Targeting; E-Cadherin; Educational workshop; Enhancers; Environment; Epithelial; Epithelial Attachment; Epithelial Cells; Foundations; Funding; Gene Expression; Genetic Engineering; Genetic Transcription; Genetically Engineered Mouse; Gland; Goals; Grant; Homeostasis; Human; In Vitro; Injections; Injury; International; Intestinal Mucosa; Intestinal Neoplasms; Investigation; KRAS2 gene; Knock-out; LGR5 gene; Laboratories; Liver; Maintenance; Medical Oncologist; Medical Oncology; Membrane; Memorial Sloan-Kettering Cancer Center; Mentors; Metastatic Neoplasm to the Liver; Modeling; Molecular; Molecular Target; Mus; Mutation; NRCAM gene; Natural regeneration; Neoplasm Metastasis; Neural Cell Adhesion Molecule L1; Oncogenic; Organ; Organoids; Patient-Focused Outcomes; Patients; Phenotype; Physicians; Positioning Attribute; Process; Relapse; Research; Research Personnel; Research Project Grants; Resistance; Role; Sampling; Scientist; Signal Pathway; Structure; Structure of splenic vein; TP53 gene; Tail; Therapeutic; Time; Tissues; Training; Transcription Repressor; Transcriptional Regulation; Transplantation; Tumor Cell Invasion; Work; adenoma; base; cancer cell; career; career development; clinically relevant; effective therapy; epigenetic regulation; experience; gastrointestinal; improved; in vivo; in vivo Model; inhibitor; innovation; instructor; knock-down; lung metastatic; mRNA Expression; metastatic colorectal; mouse model; murine colitis; mutant; neoplastic; novel; novel strategies; oncology service; predicting response; prevent; public health relevance; rectal; regenerative; restoration; self-renewal; stem cell self renewal; stem cells; stem-like cell; targeted biomarker; therapeutic development; therapy outcome; therapy resistant; tissue repair; trait; transcriptomics; translational cancer research; transplant model; tumor; tumor initiation; tumor progression

PROJECT SUMMARY Metastatic cancers invariably relapse due to the emergence of resistant subclones that are capable of self- renewal, slow cell-cycling, tumor re-initiation and therapy resistance, termed metastasis stem cells (MetSCs). Yet the molecular mechanisms MetSCs employ for survival and regrowth are poorly understood. Preliminary data described in this proposal identify the cell-adhesion molecule cell adhesion molecule L1 (L1CAM) as a critical target for suppressing metastatic relapse. Employing novel patient-derived organoid models of therapy- resistant colorectal cancer (CRC) liver metastases, L1CAM+ cells in patient tumors are shown to selectively regenerate organoids ex vivo. L1CAM is required for the regeneration of organoids in vitro, and the mouse colon epithelium after colitis injury in vivo. Disruption of cell-cell contact in intact epithelial structures is necessary and sufficient for L1CAM induction, with expression diminishing over time as the epithelium is regenerated. We hypothesize that epithelial disintegrity induces L1CAM expression, which is required for the survival and regrowth of cancer cells during invasion, metastasis and following therapy. The mechanisms that induce L1CAM dependency during tumor progression will be defined (1) using patient-derived organoid models of metastatic CRC to define the transcriptional regulation of L1CAM downstream of epithelial junction dissociation and (2) using genetically engineered mouse models, cutting-edge organoid-derived orthotopic rectal transplantation, and orthotopic liver and lung metastatic models in vivo to determine the role of L1CAM in tumor initiation, local invasion, metastatic colonization and maintenance. The proposed investigations will delineate signaling pathways by which tumor dissemination induces phenotypic plasticity and the emergence of metastatic traits, and will pave the way for L1CAM-targeting drugs that inhibit metastasis regeneration. The applicant, Dr. Karuna Ganesh, an Instructor in the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center (MSKCC), has delineated a 5-year career plan that builds upon her research background in biochemistry and clinical training in medical oncology. This project will provide the ideal training for Dr. Ganesh in using clinically representative, state-of-the-art patient-derived organoid and mouse models to dissect the transcriptional and epigenetic regulation of metastasis. Dr. Ganesh will be mentored by Dr. Joan Massagué, an internationally renowned expert in metastasis with a strong track record of training successful independent physician scientists. The candidate's career development plan includes coursework, workshops, mentoring from an interdisciplinary advisory committee comprising distinguished basic scientists and medical oncologists, and research experience in the outstanding institutional environment of MSKCC, a center of excellence in translational cancer research. Successful completion of the research project will lead to new approaches for treating patients with metastatic cancer and will provide the foundation for Dr. Ganesh to transition to a position as an independent investigator with her own laboratory and R01 funding.

项目总结

项目成果

Characterization and Clinical Outcomes of DNA Mismatch Repair-deficient Small Bowel Adenocarcinoma.

• DOI: 10.1158/1078-0432.ccr-20-2892
• 发表时间: 2021-03-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Latham A;Shia J;Patel Z;Reidy-Lagunes DL;Segal NH;Yaeger R;Ganesh K;Connell L;Kemeny NE;Kelsen DP;Hechtman JF;Nash GM;Paty PB;Zehir A;Tkachuk KA;Sheikh R;Markowitz AJ;Mandelker D;Offit K;Berger MF;Cercek A;Garcia-Aguilar J;Saltz LB;Weiser MR;Stadler ZK
• 通讯作者: Stadler ZK

Breaking up MTDH-SND1 to break down metastasis.

破坏 MTDH-SND1 以破坏转移。

• DOI: 10.1038/s43018-021-00320-7
• 发表时间: 2022
• 期刊: Nature cancer
• 影响因子: 22.7
• 作者: Jiang,Qingwen;Ganesh,Karuna
• 通讯作者: Ganesh,Karuna

The joys and challenges of being a physician-scientist.

• DOI: 10.1038/s41575-021-00443-3
• 发表时间: 2021-06
• 期刊: Nature reviews. Gastroenterology & hepatology
• 作者: Ganesh K

Phase II Single-arm Study of Durvalumab and Tremelimumab with Concurrent Radiotherapy in Patients with Mismatch Repair-proficient Metastatic Colorectal Cancer.

• DOI: 10.1158/1078-0432.ccr-20-2474
• 发表时间: 2021-04-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Segal NH;Cercek A;Ku G;Wu AJ;Rimner A;Khalil DN;Reidy-Lagunes D;Cuaron J;Yang TJ;Weiser MR;Romesser PB;Stadler ZK;Varghese AM;Ganesh K;Yaeger R;Connell LC;Faleck D;Abou-Alfa GK;Mcauliffe KC;Vaiskauskas P;Solter ML;Ogle M;Adamow MJ;Holland A;Vedantam P;Wong P;Merghoub T;Vakiani E;Hollmann TJ;Juluru K;Chou JF;Capanu M;Erinjeri J;Solomon S;Yamada Y;Kemeny N;Crane CH;Saltz LB
• 通讯作者: Saltz LB

Initial evaluation of dual-energy computed tomography as an imaging biomarker for hepatic metastases from neuroendocrine tumor of the gastrointestinal tract.

• DOI: 10.21037/qims-20-917
• 发表时间: 2021-05
• 期刊: Quantitative imaging in medicine and surgery
• 影响因子: 2.8
• 作者: Eddiel Cruz-Hernández;U. Mahmood;J. G. Golia Pernicka;V. Paroder;I. Petkovska;M. Gollub;J. Shia;K. Ganesh;D. Bates