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Genome-wide CRISPR screens in spheroid culture reveal that the tumor suppressor LKB1 inhibits growth via the PIKFYVE lipid kinase.
Proc Natl Acad Sci U S A
May 2024
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021.
Article Synopsis
- * To better understand how LKB1 suppresses cell growth, researchers created a specific cell culture model and conducted genome-wide CRISPR screenings, discovering that LKB1 partially achieves this by activating the PIKFYVE lipid kinase.
- * The study also revealed that LKB1 inhibits growth by promoting the internalization of the EGFR protein in a way that depends on PIKFYVE, using both chemical inhibitors and a special reporter to observe these effects.
Lineage-specific intolerance to oncogenic drivers restricts histological transformation.
Science
February 2024
Meyer Cancer Center, Weill Cornell Medicine, New York, NY.
Lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC) are thought to originate from different epithelial cell types in the lung. Intriguingly, LUAD can histologically transform into SCLC after treatment with targeted therapies. In this study, we designed models to follow the conversion of LUAD to SCLC and found that the barrier to histological transformation converges on tolerance to Myc, which we implicate as a lineage-specific driver of the pulmonary neuroendocrine cell.
View Article and Find Full Text PDFThe tumor suppressor LKB1 is a serine/threonine protein kinase that is frequently mutated in human lung adenocarcinoma (LUAD). LKB1 regulates a complex signaling network that is known to control cell polarity and metabolism; however, the pathways that mediate the tumor suppressive activity of LKB1 are incompletely defined. To identify mechanisms of LKB1- mediated growth suppression we developed a spheroid-based cell culture assay to study LKB1- dependent growth.
View Article and Find Full Text PDFFORMATION OF MALIGNANT, METASTATIC SMALL CELL LUNG CANCERS THROUGH OVERPRODUCTION OF cMYC PROTEIN IN TP53 AND RB1 DEPLETED PULMONARY NEUROENDOCRINE CELLS DERIVED FROM HUMAN EMBRYONIC STEM CELLS.
bioRxiv
October 2024
Meyer Cancer Center, Weill Cornell Medicine, New York, NY.
We recently described our initial efforts to develop a model for small cell lung cancer (SCLC) derived from human embryonic stem cells (hESCs) that were differentiated to form pulmonary neuroendocrine cells (PNECs), a putative cell of origin for neuroendocrine-positive SCLC. Although reduced expression of the tumor suppressor genes and allowed the induced PNECs to form subcutaneous growths in immune-deficient mice, the tumors did not display the aggressive characteristics of SCLC seen in human patients. Here we report that the additional, doxycycline-regulated expression of a transgene encoding wild-type or mutant cMYC protein promotes rapid growth, invasion, and metastasis of these hESC-derived cells after injection into the renal capsule.
View Article and Find Full Text PDFThreatening the Global AIDS Response - Obstacles to PEPFAR's Reauthorization.
N Engl J Med
September 2023
From the Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban (S.S.A.K.); the Department of Epidemiology, Mailman School of Public Health, Columbia University (S.S.A.K.), and Weill Cornell Medicine (H.E.V., J.W.P.) - both in New York; Paris (F.B.-S.); Makerere University School of Public Health, Kampala, and Rakai Health Sciences Program, Kalisizo - both in Uganda (D.S.); the Centre for Microbiology Research, Kenya Medical Research Institute, Nairobi (E.B.); the Departments of Global Health and Obstetrics and Gynecology, University of Washington, Seattle (E.B.); the Institut de Recherche en Santé, de Surveillance Epidémiologique et de Formation, and the School of Medicine and Pharmacy, Université Cheikh Anta Diop - both in Dakar, Senegal (S.M.); Monash University Malaysia, Selangor, and the Faculty of Medicine, University of Malaya, Kuala Lumpur - both in Malaysia (A.K.); the M.S. Swaminathan Research Foundation, Chennai, India (S.S.); and Les Centres GHESKIO, Port-au-Prince, Haiti (J.W.P.).
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