Lung Cancer

Current Projects
Saket Rahul Bagde, PhD

Most cancers develop in the epithelial tissue, which includes the skin and internal organ linings.  Hemidesmosomes (HDs) are adhesive structures that anchor epithelial cells to the underlying base layer and maintain tissue integrity. While HD disassembly occurs normally during wound healing, tumor cells can exploit this process to detach and spread to other parts of the body. Dr. Bagde is studying how HD components interlock like Lego blocks to form stable HDs in healthy tissues and how they disassemble in cancerous tissues. To investigate this phenomenon, Dr. Bagde plans to develop organoids—self-organizing mini-organs grown in a petri dish to study disease progression. By creating simple base layers that simulate the supportive properties of the native organ base layer, he plans to promote the growth of both normal and cancerous organoids. This work has the potential to support the development of personalized cancer therapies based on patient-derived tumor samples. Dr. Bagde received his PhD from Cornell University, Ithaca and his MS and BS from the Indian Institute of Science Education and Research, Pune.

Project title: "Integrin a6ß4 in hemidesmosome dynamics: structural and functional insights for tissue homeostasis, organoid growth, and cancer"
Institution: Boston Children's Hospital
Award Program: Fellow
Sponsor(s) / Mentor(s): Timothy A. Springer, PhD
Cancer Type: Head and Neck Cancer, Breast, Colorectal, Lung
Research Area: Aging
Debadrita Bhattacharya, PhD

Intra-tumoral heterogeneity (ITH), or the evolution of distinct cell types within a tumor, underlies most fatal features of cancer and presents a great therapeutic challenge. Using small cell lung cancer (SCLC), a highly heterogeneous and lethal form of lung cancer, as a model, Dr. Bhattacharya [Robert Black Fellow] will study how ITH arises during cancer progression. She will employ emerging genomics techniques to characterize the cellular subtypes that comprise SCLC tumors and identify “druggable” transcription factors which, if targeted, could reduce tumor heterogeneity in this cancer. By profiling thousands of cells from treatment-naïve and therapy-resistant tumors, Dr. Bhattacharya aims to identify the “master-regulators” of the cellular subtypes that expand upon treatment in SCLC. She will then evaluate the role of these factors in human patient-derived cell lines, with the goal of uncovering novel mechanisms underlying ITH in human cancers. Dr. Bhattacharya received her PhD from Cornell University and her BS from the University of Calcutta.

Project title: "Investigating molecular and cellular mechanisms of intra-tumoral heterogeneity in small-cell lung cancer"
Institution: Stanford University
Named Award: Robert Black Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Julien Sage, PhD
Cancer Type: Lung
Research Area: Epigenetics
Laura Crowley, PhD

Fibroblasts are one of the earliest known cell types and they contribute to many of the most burdensome lung diseases, including cancers, fibrosis, and emphysema; however, they are surprisingly poorly understood. Dr. Crowley [HHMI Fellow] will examine the different types of fibroblasts in the mouse lung to determine where they come from and how they function normally, as well as how they change with injury and disease. This will establish an important baseline for how these cells function in mice and also provide critical, long-term insights into how these cells may function in humans, where lung diseases are very difficult to treat and are among the leading causes of mortality worldwide. Though her work will directly analyze the fibroblasts and microenvironment around lung tumors, her findings could translate to many other solid tumor contexts. Dr. Crowley received her PhD from Columbia University, New York and her BA from Colby College, Waterville.

Project title: "Identifying fibroblast stem cells in organ maintenance, repair, and cancer"
Institution: Stanford University
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Mark A. Krasnow, MD, PhD
Cancer Type: Lung
Research Area: Stem Cell Biology
Phaedra C. Ghazi, PhD

An emerging hallmark of cancer is phenotypic plasticity, which enables cancer cells to change their traits throughout tumorigenesis and in response to targeted therapy treatment. While new targeted therapies are emerging for the treatment of lung cancers, it has been demonstrated that lung tumors with heterogeneous cell populations are especially resistant to current treatments. One reason that lung cancer cells with the same cancer-causing mutation but different cellular identities may have differential sensitivities to targeted therapies is altered gene expression. Dr. Ghazi aims to characterize how these hybrid lung tumors are innately resistant to treatment by determining differences in gene expression and regulation. She is engineering a novel mouse model that reports the cellular identity of lung tumors in live animals. Together these efforts aim to improve our ability to treat particularly aggressive lung tumors. Dr. Ghazi received her PhD and MS from the University of Utah, Salt Lake City, and her BS from the University of Massachusetts, Amherst. 

Project title: "Investigating therapeutic vulnerabilities of lung cancer by tracking cellular identity"
Institution: Massachusetts Institute of Technology
Award Program: Fellow
Sponsor(s) / Mentor(s): Tyler Jacks, PhD
Cancer Type: Lung
Research Area: Cancer Genetics
Rodrigo Gier, PhD

Drug therapies that selectively target proteins that drive the growth of tumor cells are rapidly becoming the standard of care for many cancers. However, tumors are often able to evade inhibition by targeted anti-cancer drugs by activating other proteins, leading to drug resistance. Dr. Gier [HHMI Fellow] is developing a new therapeutic approach that repurposes existing drugs to release highly toxic cargoes, known as payloads, that aggregate in drug-resistant cancer cells and kill them. As a general platform, it is applicable to a wide range of solid and liquid cancers. Dr. Gier received his PhD from University of Pennsylvania, Philadelphia and his BA from Swarthmore College, Swarthmore. 

Project title: "Targeted chemical aggregation as a general strategy to overcome cancer drug resistance"
Institution: University of California, San Francisco
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Kevan M. Shokat, PhD
Cancer Type: Blood, Other Cancer, Lung
Research Area: Chemical Biology
Alex M. Jaeger, PhD

Recent advances in genomic and proteomic technologies have ushered in a new era of antigen-specific immunotherapies, including cancer vaccines. Such therapies depend upon immune system recognition and processing of antigens-proteins or fragments of proteins displayed on the cancer cell surface. However, our understanding of the principles that govern antigen presentation across cell types throughout the tumor microenvironment (TME) remains limited. Dr. Jaeger's [William Raveis Charitable Fund Innovator] research uses sophisticated mouse models to understand how cells present and process antigens in healthy lung tissue and the lung cancer TME. These studies will advance our understanding of how different patterns of antigen presentation activate different T cell pathways and identify opportunities to engineer next-generation immunotherapies. The fundamental insights gained from these studies will be broadly applicable to multiple cancer types.

Project title: "Engineering approaches to exploit MHC-II antigen presentation in cancer"
Institution: H. Lee Moffitt Cancer Center
Named Award: William Raveis Charitable Fund Innovator
Award Program: Innovator
Cancer Type: Lung
Research Area: Tumor Immunology
Tadashi Manabe, MD, PhD

Lung cancer remains the leading cause of cancer mortality. Substantial breakthrough discoveries, including the identification of lung cancer-specific genetic drivers (e.g., EGFR mutations, EML4-ALK fusion genes) and the development of molecular inhibitors of these pathogenic factors, have improved outcomes for patients with advanced-stage lung cancer. However, lung cancer cells eventually acquire resistance to these molecular inhibitors, resulting in progressive disease. Dr. Manabe’s [Connie and Bob Lurie Fellow] research focuses on protein compounds formed by the self-assembly of oncogenic fusion proteins such as EML4-ALK. These compounds initiate a signaling pathway that causes abnormal cell proliferation in cancer. Dr. Manabe will explore the newly discovered structures of signaling proteins with the goal of developing molecular therapies that enhance precision medicine strategies and improve the control of lung cancer. Dr. Manabe received both his MD and PhD from Keio University School of Medicine.

Project title: "Characterization of oncogenic kinase signaling by membraneless cytoplasmic protein granules"
Institution: University of California, San Francisco
Named Award: Connie and Bob Lurie Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Trever G. Bivona, MD, PhD
Cancer Type: Lung
Research Area: Signal Transduction
Léa Montégut, PhD

Early detection of lung cancer is associated with significantly better clinical outcomes. For this reason, CT-scan-based screenings in at-risk populations have been widely adopted, notably in people over 50 with a history of smoking. Still, other contributing factors include chronic exposure to environmental carcinogens, advanced age, and preexisting lung conditions. Compounding this complexity, not all precancerous lesions will evolve into invasive tumors, emphasizing the need to understand the mechanisms that govern the shift from benign to malignant states. To address this gap, Dr. Montégut [National Mah Jongg League Fellow] will focus on decoding the early immune system alterations that occur within the lung microenvironment during the pre-cancer-to-cancer transition. By doing so, she aims to identify molecular markers that indicate high-risk patients and pinpoint potential molecular targets, with the goal of intercepting tumors at a non-invasive stage. Dr. Montégut received her PhD from Paris-Saclay University, Paris, her MS from Polytechnique Montréal, Montréal, and her MEng from Ecole Polytechnique, Palaiseau.

Project title: "Targeting age-driven myeloid dysfunction in cancer: unraveling the immunomodulatory and metabolic contributions of GLP-1R agonists"
Institution: Icahn School of Medicine at Mount Sinai
Named Award: National Mah Jongg League Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Miriam Merad, MD, PhD
Cancer Type: Lung
Research Area: Tumor Immunology
Anna Karen Orta, PhD

Mitochondria are best known as the cell’s power plants, but they also help cells respond to stress and repair their own DNA. A mitochondrial protein called ATAD3A plays a key role in these processes and is found at abnormally high levels in many aggressive cancers such as glioblastoma, breast cancer, and colorectal cancer, where it contributes to tumor growth and resistance to treatment. Dr. Orta studies how ATAD3A acts as a sensor of mitochondrial DNA damage—detecting trouble inside the mitochondria and helping signal to other parts of the cell, like the endoplasmic reticulum, that stress responses are needed. Using cryo-electron microscopy along with biochemical and cell-based approaches, she aims to uncover how ATAD3A is regulated and how its function supports cancer cell survival. Ultimately, she hopes to expose new ways to target mitochondrial stress pathways in cancer. Dr. Orta received her PhD from California Institute of Technology, Pasadena, and her BS from the University of Texas at El Paso, El Paso.

Project title: "Structural and functional studies of ATAD3A: implications for mitochondrial maintenance and cancer progression"
Institution: Scripps Research Institute
Award Program: Fellow
Sponsor(s) / Mentor(s): Gabriel C. Lander, PhD, and Danielle A. Grotjahn, PhD
Cancer Type: Breast, Colorectal, Lung
Research Area: Structural Biology
Manuel Osorio Valeriano, PhD

Human cells compact their vast genomes into the small confines of the nucleus by wrapping their DNA into a highly complex structure called chromatin. Packaging DNA into chromatin, however, affects all nucleic acid-transacting machines (e.g., transcription factors) that need to access the genomic information stored in the DNA. NuRD is a large multi-subunit protein complex that plays a major role in making chromatin either accessible or inaccessible. Dysregulation of NuRD and aberrant targeting of the complex can result in the emergence of several types of cancers, including breast, liver, lung, blood, and prostate cancers. Dr. Osorio Valeriano’s [Philip O'Bryan Montgomery, Jr., MD, Fellow] work will reveal mechanistic aspects of NuRD-mediated chromatin regulation and pave the way for the development of novel therapeutic approaches that target cancers more effectively. Dr. Osorio Valeriano received his PhD from Philipps University and his MSc and BSc from the National Autonomous University of Mexico.

Project title: "Molecular and structural basis of gene expression regulation by the nucleosome remodeling and deacetylase (NuRD) complex in human cancer"
Institution: Harvard Medical School
Named Award: Philip O’Bryan Montgomery Jr. MD Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Lucas Farnung, PhD, and Danesh Moazed, PhD
Cancer Type: Blood, Gastric, Breast, Lung, Prostate
Research Area: Structural Biology
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