Lewis Cantley

Mass spectrometry-based phosphoproteomics offers a comprehensive view of protein phosphorylation, but limited knowledge about the regulation and function of most phosphosites restricts our ability to extract meaningful biological insights from phosphoproteomics data. To address this, we combine machine learning and phosphoproteomic data from 1,195 tumor specimens spanning 11 cancer types to construct CoPheeMap, a network mapping the co-regulation of 26,280 phosphosites. Integrating network features from CoPheeMap into a machine learning model, CoPheeKSA, we achieve superior performance in predicting kinase-substrate associations. CoPheeKSA reveals 24,015 associations between 9,399 phosphosites and 104 serine/threonine kinases, including many unannotated phosphosites and under-studied kinases. We validate the accuracy of these predictions using experimentally determined kinase-substrate specificities. By applying CoPheeMap and CoPheeKSA to phosphosites with high computationally predicted functional significance and cancer-associated phosphosites, we demonstrate the effectiveness of these tools in systematically illuminating phosphosites of interest, revealing dysregulated signaling processes in human cancer, and identifying under-studied kinases as putative therapeutic targets.

Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved single cysteine compound N-acetylcysteine (NAC) reduced GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Normal brain cells and other cancer cells showed no response to NAC. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and …

2020-11-17 Assigned to CORNELL UNIVERSITY reassignment CORNELL UNIVERSITY CORRECTIVE ASSIGNMENT TO CORRECT THE CORRECT INVENTORSHIP FROM LEWIS C CANTLEY, BRYAN NGO AND SAMUEL F BAKHOUM TO LEWIS C CANTLEY AND BRYAN NGO PER ASSIGNMENT DIV PREVIOUSLY RECORDED AT REEL: 053412 FRAME: 0845. ASSIGNOR (S) HEREBY CONFIRMS THE ASSIGNMENT. Assignors: CANTLEY, LEWIS C., NGO, Bryan2020-11-17 Assigned to MEMORIAL SLOAN-KETTERING CANCER CENTER, CORNELL UNIVERSITY reassignment MEMORIAL SLOAN-KETTERING CANCER CENTER ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BAKHOUM, Samuel F.

Despite the successes of immunotherapy in cancer treatment over recent decades, less than <10%–20% cancer cases have demonstrated durable responses from immune checkpoint blockade. To enhance the efficacy of immunotherapies, combination therapies suppressing multiple immune evasion mechanisms are increasingly contemplated. To better understand immune cell surveillance and diverse immune evasion responses in tumor tissues, we comprehensively characterized the immune landscape of more than 1,000 tumors across ten different cancers using CPTAC pan-cancer proteogenomic data. We identified seven distinct immune subtypes based on integrative learning of cell type compositions and pathway activities. We then thoroughly categorized unique genomic, epigenetic, transcriptomic, and proteomic changes associated with each subtype. Further leveraging the deep phosphoproteomic data …

First, allow me to thank the editors for initiating this conversation-the first in International Studies Quarterly-about feminist perspectives on International Relations. I hope that these thoughtful critiques of my article and my response to them will be only the beginning of many such conversations. In the spirit of the constructive criticism evidenced in these responses, I will make three specific points about each and then draw some conclusions about the larger issues they both raise about conversations between IR scholars and feminists. For reasons I shall elaborate below, Marianne Marchand's European perspective is particularly welcome. I agree with several of her important claims. However, I do wish to challenge the assumptions she presumes underlie my argument, thereby elaborating on some of the broader issues that her criticisms raise. First, Marchand claims that I suggest that feminist scholars tend to work …

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. Histological transformations are frequently accompanied by activation of the Akt pathway. Manipulating this pathway permitted tolerance to Myc as an oncogenic driver, producing rare, stem-like cells that transcriptionally resemble the pulmonary basal lineage. These findings suggest that histological transformation may require the plasticity inherent to the basal stem cell, enabling tolerance to previously incompatible oncogenic driver …

To unravel the molecular mechanisms underlying high-grade glioma (HGG) in adolescent and young adult (AYA) patients, we conducted a comprehensive proteogenomic analysis for 34 AYA (age 15-40) and 59 pediatric (age 0-15) HGG cases. Our approach involved whole genome sequencing, methylation profiling, RNA sequencing, and a suite of mass spectrometry-based proteomic experiments, including global proteomic, phosphoproteomic, and glycoproteomic profiling. The proteomics study successfully identified and quantified approximately 11,000 proteins, 33,000 phosphosites, and 3000 glycopeptides with a 50% missing filtering threshold. To identify the unique characteristics of AYA HGG in contrast to both pediatric and adult HGG, we further integrated a proteogenomic dataset of 99 adult GBM tumors previously published by CPTAC and collaborators (PMID: 33577785). Our study unveiled a collection …

Subcellular location and activation of Tank Binding Kinase 1 (TBK1) govern precise progression through mitosis. Either loss of activated TBK1 or its sequestration from the centrosomes causes errors in mitosis and growth defects. Yet, what regulates its recruitment and activation on the centrosomes is unknown. We identified that NAK-associated protein 1 (NAP1) is essential for mitosis, binding to and activating TBK1, which both localize to centrosomes. Loss of NAP1 causes several mitotic and cytokinetic defects due to inactivation of TBK1. Our quantitative phosphoproteomics identified numerous TBK1 substrates that are not only confined to the centrosomes but are also associated with microtubules. Substrate motifs analysis indicates that TBK1 acts upstream of other essential cell cycle kinases like Aurora and PAK kinases. We also identified NAP1 as a TBK1 substrate phosphorylating NAP1 at S318 to promote its …