About

Robert A. Weinberg is the Daniel K. Ludwig Professor for Cancer Research and a Core Member at the Whitehead Institute. His research focuses on understanding how cancer spreads, the molecular mechanisms involved in the formation of cancer stem cells, and the processes underlying metastasis. He investigates three broad questions: how cancer cells within a primary tumor acquire the ability to invade and metastasize, the interrelation between the stem-cell state and the epithelial-mesenchymal transition, and how regulators of this transition activate profound changes in cell phenotype. Weinberg's work has contributed significantly to the understanding of cancer biology, particularly in the context of metastasis and cancer stem cells.

Research topics

• Biology
• Cell biology
• Sociology
• Immunology
• Cancer research
• Medicine
• Computer Science
• Internal medicine
• Chemistry
• Computational biology
• History
• Biochemistry
• Data science
• Bioinformatics
• Genetics

Selected publications

• EMT-ciliary signaling in quasi-mesenchymal-stem-like cells drives therapeutic resistance and is a druggable vulnerability in triple-negative breast cancer

  EMBO Molecular Medicine · 2025-08-26 · 5 citations

  articleOpen access

  Cancer therapeutic resistance is mediated, in part, by phenotypic heterogeneity and the plasticity of tumor cells, the latter being enabled by epithelial-mesenchymal transition (EMT). However, EMT in human cancer therapeutic response remains poorly understood. We developed patient-derived organoids (PDOs) from human triple-negative breast cancer (TNBC) and investigated their response to chemotherapy. We found that chemotherapy treatment kills the bulk of tumor cells in PDOs, but there is selective survival of malignant cells that had activated an EMT program, entered a quasi-mesenchymal, stem cell-like state and display primary cilia. We developed a family of small-molecule inhibitors of ciliogenesis and show that treatment with these inhibitors, or genetic ablation of primary cilia, is sufficient to suppress this chemoresistance via NFκB-induced cell death. We conclude that an EMT-ciliary signaling axis induces chemoresistance in quasi-mesenchymal ciliated stem-like cells to help tumors evade chemotherapy and represents a druggable vulnerability in human TNBC.

  PublisherDOI

• Abstract 3826: Awakened dormant cancer cells undergo highly mesenchymal to quasi-mesenchymal transition and acquire stemness

  Cancer Research · 2025-04-21

  articleSenior author

  Abstract The awakening of dormant disseminated cancer cells is likely responsible for the clinical relapses of patients whose primary tumors have been successfully cured months and even years earlier. In the present study, we demonstrate that dormant breast cancer cells lodged in the lungs reside in a highly mesenchymal, non-proliferative phenotypic state. The awakening of these cells is not triggered by a cancer cell-autonomous process. Instead, inflammation of the surrounding tissue microenvironment causes them to shift from a highly mesenchymal to a quasi-mesenchymal phenotypic state in which they acquire stemness and proliferative ability. Once awakened, these cells can stably reside in this quasi-mesenchymal state and maintain their stemness, doing so without ongoing heterotypic signaling from the lung microenvironment. EGFR ligands released by the cells of the injured tissue microenvironment, including notably M2 type macrophages, promote dormant cancer cells to move toward this quasi-mesenchymal state, a transition that is critical for the awakening process. An understanding of the mechanisms of metastatic awakening may lead in the future to treatment strategies designed to prevent such awakening and resulting metastatic relapse. Citation Format: Jingwei Zhang, Robert Allan Weinberg. Awakened dormant cancer cells undergo highly mesenchymal to quasi-mesenchymal transition and acquire stemness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3826.

  PublisherDOI

• Inflammation awakens dormant cancer cells by modulating the epithelial–mesenchymal phenotypic state

  Proceedings of the National Academy of Sciences · 2025-09-03 · 4 citations

  articleOpen accessSenior authorCorresponding

  The awakening of dormant disseminated cancer cells appears to be responsible for the clinical relapses of patients whose primary tumors have been successfully cured months and even years earlier. In the present study, we demonstrate that dormant breast cancer cells lodged in the lungs reside in a highly mesenchymal, nonproliferative phenotypic state. The awakening of these cells is not triggered by a cancer cell-autonomous process. Instead, lung inflammation induced by the chemotherapeutic agent bleomycin effectively awakens dormant cancer cells, providing useful models for studying metastatic awakening. Mechanistically, the awakened cells shift from a highly mesenchymal to a quasi-mesenchymal phenotypic state in which they acquire tumorigenicity and proliferative ability. Once awakened, these cells can stably reside in this quasi-mesenchymal state and maintain their tumor-initiating ability, doing so without ongoing heterotypic signaling from the lung microenvironment. Epidermal growth factor receptor ligands released by the cells of the injured tissue microenvironment, including notably M2 type macrophages, promote dormant cancer cells to move toward this quasi-mesenchymal state, a transition that is critical for the awakening process. An understanding of the mechanisms of metastatic awakening may lead in the future to treatment strategies designed to prevent such awakening and resulting metastatic relapse.

  PublisherDOI

• Discovery of oncogenes

  ˜The œbiomedical & life sciences collection. · 2025-01-30

  articleOpen access1st authorCorresponding
  PublisherDOI

• CD47 predominates over CD24 as a macrophage immune checkpoint in cancer

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-11-26 · 2 citations

  preprintOpen access

  Macrophages hold tremendous promise as effectors of cancer immunotherapy, but the best strategies to provoke these cells to attack tumors remain unknown. Here, we evaluated the therapeutic potential of targeting two distinct macrophage immune checkpoints: CD47 and CD24. We found that antibodies targeting these antigens could elicit maximal levels of phagocytosis when combined together in vitro. However, to our surprise, via unbiased genome-wide CRISPR screens, we found that CD24 primarily acts as a target of opsonization rather than an immune checkpoint. In a series of in vitro and in vivo genetic validation studies, we found that CD24 was neither necessary nor sufficient to protect cancer cells from macrophage phagocytosis in most mouse and human tumor models. Instead, anti-CD24 antibodies exhibit robust Fc-dependent activity, and as a consequence, they cause significant on-target hematologic toxicity in mice. To overcome these challenges and leverage our findings for therapeutic purposes, we engineered a collection of 77 novel bispecific antibodies that bind to a tumor antigen with one arm and engage macrophages with the second arm. We discovered multiple novel bispecifics that maximally activate macrophage-mediated cytotoxicity and reduce binding to healthy blood cells, including bispecifics targeting macrophage immune checkpoint molecules in combination with EGFR, TROP2, and CD71. Overall, our findings indicate that CD47 predominates over CD24 as a macrophage immune checkpoint in cancer, and that the novel bispecifics we created may be optimal immunotherapies to direct myeloid cells to eradicate solid tumors.

  PublisherOA PDFDOI

• Primary cilia promote EMT-induced triple-negative breast tumor heterogeneity and resistance to therapy

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-09-14

  preprint

  Tumor heterogeneity and plasticity, driven by Epithelial-Mesenchymal Transition (EMT), enable cancer therapeutic resistance. We previously showed that EMT promotes primary cilia formation, which enables stemness and tumorigenesis in triple-negative breast cancer (TNBC). Here, we establish a role for primary cilia in human TNBC chemotherapeutic resistance. We developed patient-derived organoids, and showed that these recapitulated the cellular heterogeneity of TNBC biopsies. Notably, one of the identified cell states bore a quasi-mesenchymal phenotype, primary cilia, and stemness signatures. We treated our TNBC organoids with chemotherapeutics and observed partial killing. The surviving cells with organoid-reconstituting capacity showed selective enrichment for the quasi-mesenchymal ciliated cell subpopulation. Genomic analyses argue that this enrichment reflects a combination of pre-existing cells and ones that arose through drug-induced cellular plasticity. We developed a family of small-molecule inhibitors of ciliogenesis and show that these, or genetic ablation of primary cilia, suppress chemoresistance. We conclude that primary cilia help TNBC to evade chemotherapy.

  PublisherDOI

• It took a long, long time: Ras and the race to cure cancer

  Cell · 2024-03-01 · 15 citations

  articleOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Publisher Correction: Cell-intrinsic and microenvironmental determinants of metastatic colonization

  Nature Cell Biology · 2024-06-26 · 1 citations

  erratumOpen accessSenior author
  PublisherOA PDFDOI

• Ether lipids influence cancer cell fate by modulating iron uptake

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-03-21 · 8 citations

  preprintOpen accessCorresponding

  Cancer cell fate has been widely ascribed to mutational changes within protein-coding genes associated with tumor suppressors and oncogenes. In contrast, the mechanisms through which the biophysical properties of membrane lipids influence cancer cell survival, dedifferentiation and metastasis have received little scrutiny. Here, we report that cancer cells endowed with high metastatic ability and cancer stem cell-like traits employ ether lipids to maintain low membrane tension and high membrane fluidity. Using genetic approaches and lipid reconstitution assays, we show that these ether lipid-regulated biophysical properties permit non-clathrin-mediated iron endocytosis via CD44, resulting in significant increases in intracellular redox-active iron and enhanced ferroptosis susceptibility. Using a combination of in vitro three-dimensional microvascular network systems and in vivo animal models, we show that loss of ether lipids from plasma membranes also strongly attenuates extravasation, metastatic burden and cancer stemness. These findings illuminate a mechanism whereby ether lipids in carcinoma cells serve as key regulators of malignant progression while conferring a unique vulnerability that can be exploited for therapeutic intervention.

  PublisherOA PDFDOI

• Abstract C018: Awakened dormant cancer cells undergo highly mesenchymal to quasi- mesenchymal transition and acquire stemness

  Cancer Research · 2024-11-17

  articleSenior author

  Abstract The awakening of dormant disseminated cancer cells is likely responsible for the clinical relapses of patients whose primary tumors have been cured months and even years earlier. In the present study, we demonstrate that dormant breast cancer cells lodged in the lungs reside in a highly mesenchymal, non-proliferative phenotypic state. The awakening of these cells does not occur by a cancer cell-autonomous process. Instead, inflammation and wound healing of the surrounding tissue microenvironment causes them to shift from a highly mesenchymal to a quasi-mesenchymal phenotypic state in which they acquire stemness and proliferative ability. Once awakened, these cells can stably reside in this quasi-mesenchymal state and maintain their stemness, doing so without ongoing heterotypic signaling from the lung microenvironment. EGFR ligands released by the cells of the injured tissue microenvironment, including notably M2 type macrophages, promote dormant cancer cells to move toward this quasi-mesenchymal state, a transition that is essential for the awakening process. An understanding of the mechanisms of metastatic awakening may lead in the future to treatment strategies designed to prevent such awakening and resulting metastatic relapse. Citation Format: Jingwei Zhang, Robert Weinberg. Awakened dormant cancer cells undergo highly mesenchymal to quasi- mesenchymal transition and acquire stemness [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C018.

  PublisherDOI

Recent grants

• NIH Grant U54CA163109

  NIH · $4.3M · 2016

• NIH Grant R21CA096689

  NIH · $262k · 2004

• NIH Grant R01NS029879

  NIH · $1.5M · 2001

• Epi-genetic Programs in Cancer Progression

  NIH · $7.3M · 2017–2024

• NIH Grant R01CA078461

  NIH · $8.9M · 2019

Frequent coauthors

• Ferenc Reinhardt

  Whitehead Institute for Biomedical Research

  281 shared

• William C. Hahn

  Dana-Farber Cancer Institute

  121 shared

• Mary W. Brooks

  98 shared

• Tsukasa Shibue

  Broad Institute

  83 shared

• Eric S. Lander

  Broad Institute

  74 shared

• Scott Valastyan

  73 shared

• Elinor Ng Eaton

  Whitehead Institute for Biomedical Research

  68 shared

• Anushka Dongre

  Ithaca College

  67 shared

Labs

• Robert A. Weinberg LabPI

Awards & honors

• Japan Prize, Japan Prize Foundation, 2021
• Salk Institute Medal for Research Excellence, 2016
• Breakthrough Prize in Life Sciences, 2013
• Wolf Foundation Prize, 2004
• Institute of Medicine, Member, 2000