About

Vera P. Krymskaya, PhD, MBA, FCPP, is a Professor of Medicine specializing in Pulmonary, Allergy, and Critical Care at the University of Pennsylvania's Perelman School of Medicine. She conducts basic and translational research focusing on the role of highly integrated signaling networks, particularly the PI3K-TSC2-mTOR pathway, in rare and common lung diseases. Her most recognized work includes the discovery of TSC2's function as a negative regulator of mTOR, which has significantly advanced understanding of diseases such as lymphangioleiomyomatosis (LAM). Her laboratory was the first to establish human LAM cell cultures for preclinical testing, demonstrating the efficacy of rapamycin in inhibiting mTOR and reducing LAM cell growth, leading to FDA approval of rapamycin analogs for LAM and TS-LAM in 2015. Dr. Krymskaya's research has also uncovered how TSC2 deregulates Rho GTPase and LAM cell survival through mTORC2 signaling, and she has developed novel mouse models of LAM. Her work includes preclinical studies of combination therapies, such as the phase 2 SOS clinical trial investigating the safety of combined simvastatin and sirolimus or everolimus treatments. Additionally, her investigation into immunity in LAM led to the identification of PD-L1 upregulation in LAM lungs and the development of immunocompetent mouse models, which facilitated preclinical testing of anti-PD1 antibodies. Her recent studies on LAM lung cell composition and genetic animal models aim to deepen mechanistic understanding of LAM pathobiology, especially involving mTORC1-WNT signaling crosstalk, and to expand therapeutic options for this devastating disease.

Research topics

• Cell biology
• Biology
• Medicine
• Cancer research
• Chemistry

Selected publications

• Fully Humanized Bispecific T Cell Engager Shows Potent Activity in Central Nervous System and Peripheral Tumors

  Advanced Science · 2026-04-30

  articleOpen access

  Bispecific T cell engagers (BTEs) induce MHC-independent cytotoxicity by bridging T cells to tumor cells via binding a T cell-activating receptor and a tumor-associated antigen. BTEs have proven effective in hematologic malignancies and some solid tumors, yet their potential in glioblastoma (GBM) is largely unexplored. We developed a fully humanized BTE (hBTE) targeting interleukin-13 receptor alpha 2 (IL13RA2), a tumor-associated antigen widely expressed in GBM and associated with poor prognosis. In vitro, hBTE activated T cells and induced antigen-dependent cytokine release and cytotoxicity against IL13RA2-positive GBM cells. In vivo, hBTE showed robust target-specific activity and markedly prolonged survival in primary and recurrent GBM xenograft models, without detectable off-target local or systemic toxicity. Beyond GBM, hBTE also exhibited antitumor activity in IL13RA2-expressing solid tumors, demonstrating selective tumor accumulation and therapeutic efficacy in models of breast cancer brain metastases and extracranial lung cancer. This work highlights the therapeutic potential of BTEs in IL13RA2-expressing tumors and establishes a strong preclinical rationale for advancing hBTE therapy toward clinical translation in GBM and other tumors.

  PublisherDOI

• Targeting fibroblast–endothelial cell interactions in LAM pathogenesis using 3D spheroid models and spatial transcriptomics

  JCI Insight · 2025-02-04 · 5 citations

  articleOpen access

  Lymphangioleiomyomatosis (LAM) is a progressive lung disease with limited treatments, largely because of an incomplete understanding of its pathogenesis. Lymphatic endothelial cells (LECs) invade LAM cell clusters, which include human melanoma black-45-positive epithelioid cells and smooth muscle α-actin-expressing LAM-associated fibroblasts (LAMFs). Recent evidence shows that LAMFs resemble cancer-associated fibroblasts, with LAMF-LEC interactions contributing to disease progression. To explore these mechanisms, we used spatial transcriptomics on LAM lung tissues and identified a gene cluster enriched in kinase signaling pathways linked to myofibroblasts and coexpressed with LEC markers. Kinase arrays revealed elevated PDGFR and FGFR in LAMFs. Using a 3D coculture spheroid model of primary LAMFs and LECs, we observed increased invasion in LAMF-LEC spheroids compared with non-LAM fibroblasts. Treatment with sorafenib, a multikinase inhibitor, significantly reduced invasion, outperforming rapamycin. We also verified tuberous sclerosis complex 2-deficient renal angiomyolipoma (TSC2-null AML) cells as key VEGF-A secretors; VEGF-A was suppressed by sorafenib in both TSC2-null AML cells and LAMFs. These findings highlight VEGF-A and basic FGF as potential therapeutic targets and suggest multikinase inhibition as a promising strategy for LAM.

  PublisherDOI

• Unique Transcriptomic and Proteomic Signature of mTORC1 Hyperactivation in Lung Mesenchyme

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  articleSenior author

  Abstract RATIONALE: Uncontrolled activation of the mechanistic/mammalian target of rapamycin (mTOR) is a cause of pulmonary lymphangioleiomyomatosis (LAM), a predominantly female, rare genetic lung disease triggered by bi-allelic inactivating mutations in mTOR's upstream negative regulator the tuberous sclerosis complex (TSC1/TSC2) genes. The loss of TSC2 function and mTORC1 hyperactivation are associated with formation of microscopic smooth muscle (SM)-like LAM lesions and lung cysts – leading to spontaneous pneumothoraxes and progressive, accelerated loss of pulmonary function ultimately requiring a lung transplantation. RESULTS: We identified specific lung cells sustaining LAM cell growth and causing lung destruction using scRNA-seq of LAM lung. Additionally, transcriptomic and proteomic approaches were used to investigate the lung tissue from our mouse lung mesenchymal Tsc2-null model of LAM. We discovered: (1) a differential role of PDGFRα+ fibroblasts as collagen-producing cells within LAM lesions, and PDGFRβ+ fibroblasts characterized by upregulation of proteolytic and collagen remodeling enzymes (CTSK, MMP2, MMP14), (2) the rapamycin-insensitive 4E-BP1/eIF4E upregulation of collagen synthesis in PDGFRα+ cells in LAM lung, and upregulation of the rapamycin-insensitive 4E-BP1/eIF4E translation initiation pathway in LAM stem-like cells. By leveraging transcriptomic datasets from lung mesenchyme of 8-week-old (wo) and 1-year-old (yo) Tbx4LME-creTsc2KO and Tbx4LME-creTsc2WT mice, we identified differential gene expression with age-dependent molecular profiles. The mouse 8wo Tbx4LME-creTsc2KO lung mesenchyme transcriptome was characteristic of a lung injury response with upregulation of WNT signaling. This was reversed by genetic inhibition of the Wnt/β-Catenin pathway in vivo. In contrast, WNT pathway was decreased in 1yo KO lung mesenchyme. The pathways of collagen formation, collagen degradation, and extracellular matrix (ECM) organization including Ctsk, Mmp14, and Loxl2 were among the most upregulated in the 1yo pulmonary mesenchyme. Our data supports the hypothesis that mTORC1 hyperactivation in LAM causes chronic “frustrated” lung repair and progressive injury fueled by (a) rapamycin-insensitive 4E-BP1/eIF4E-dependent PDGFRα+ stem cell self-renewal and synthesis of ECM collagens sustaining LAM cell growth and survival, and (b) activated mTORC1 localization on lysosomes where CTSK and TFEB-dependent lysosomal proteases degrade proteins, ultimately destroying lung parenchyma. CONCLUSION: Our study provides new insights into the role of mTORC1 activation in a subset of lung mesenchymal cells affecting major changes in lung structure and function with specific focus on the rare, monogenic lung disease LAM.

  PublisherDOI

• Lymphangioleiomyomatosis Patient Research Priorities Survey (LAM-PREP)

  CHEST Pulmonary · 2025-05-24 · 2 citations

  articleOpen access

  <h3>Background</h3> Engaging patients in developing research agendas is recognized as critical in advancing scientific discovery and improving clinical care. There is a scarcity of such studies for respiratory diseases, particularly rare conditions like lymphangioleiomyomatosis (LAM). <h3>Research Question</h3> Can a comprehensive study inform and guide future LAM research for the benefit of patients, researchers, and clinical providers? <h3>Study Design and Methods</h3> We used a mixed-methods analysis consisting of focus groups of patients and caregivers. Participant responses were thematically analyzed and grouped into categories and subcategories using qualitative content analysis to generate a list of health needs, quality of life issues, and research areas. A survey to rank the priorities was then developed and administered electronically to patients with LAM, caregivers, scientists, and clinicians. <h3>Results</h3> The LAM Patient Research Priorities Survey (LAM-PREP) revealed a list of priorities centered on health, quality of life, and research needs. Areas of agreement among all respondents were prioritizing awareness of LAM among health care providers, access to comprehensive care, understanding and interpreting symptoms, mental health, managing supplemental oxygen, finding new treatments and a cure, and studying the role of hormones in LAM disease and treatment. Clinicians prioritized needs relating to travel, sexual and women's health, and childbearing and family planning. Patients prioritized questions regarding LAM and sleep quality, safe exercise, and the impact of diet. Both scientists and clinicians noted a priority in studying disease onset and progression. <h3>Interpretation</h3> LAM-PREP integrated diverse perspectives on LAM research and clinical priorities from LAM community stakeholders. These findings should serve as a roadmap for developing and implementing projects and interventions to improve the health outcomes of women living with LAM. Importantly, LAM-PREP can serve as a model for developing patient-focused research agendas for other rare diseases, particularly those affecting women.

  PublisherDOI

• Extracellular Matrix Proteins and Signaling in Lymphangioleiomyomatosis

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  articleSenior author

  Abstract Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease caused by hyperactivation of the mechanistic target of rapamycin 1 (mTORC1) growth pathway in a subset of lung mesenchymal cells. We demonstrate here that nests of extracellular matrix (ECM) collagens, including collagen 6A1 (COL6A1) and collagen 1A1 (COL1A1) surround fibrotically-activated LAM lesions. We showed that ECM genes COL6A1, COL1A1 and CTHRC1 are specifically expressed in the high cancer stem-like subset of LAM cells. We also observed that WNT/β-catenin signaling is upregulated in LAM tissue and LAM-associated fibroblasts (LAFs). β-Catenin was expressed on LAM alveolar epithelial cell membranes, cytoplasm and nuclei in LAM nodules. LAFs had increased gene expression of the WNT transcription target AXIN2 and the growth factor TGFβ3 compared to alveolar fibroblasts from normal human lung. In LAFs grown in vitro the ECM proteins COL6A1, COL1A1 and CTHRC1, and the mTORC1 activation proteins pS6 and p4E-BP1, were induced by each of the three TGFβ isoforms. The bisteric mTORC1-selective inhibitor RMC-5552 inhibited TGFβ increases in COL6A1, COL1A1 and CTHRC1, pS6 and p4E-BP1 whereas rapamycin only inhibited pS6. The WNT/β-catenin transcription inhibitor C82 prevented TGFβ induction of COL6A1, COL1A1 and CTHRC1. Our research highlights a protective role for ECM in LAM lesions and supports the hypothesis that the bisteric mTORC1-selective inhibitor RMC-5552 or inhibition of Wnt/β-catenin signaling may offer novel therapeutic benefits to LAM patients.

  PublisherDOI

• mTORC1 Activation in Lung Mesenchyme Drives Alveolar Epithelial Cell Fitness

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  articleSenior author

  Abstract Pulmonary lymphangioleiomyomatosis (LAM) is a cystic lung disease caused by the mutational inactivation of the tumor suppressor gene tuberous sclerosis complex 2 (TSC2) which results in constitutive activation of the mechanistic target of rapamycin (mTOR) pathway. Although this mutation only occurs in a subset of mesenchymal cells in patients with LAM, we found significant changes in the proportion of epithelial AT1 and AT2 cells in the LAM lungs. To test the hypothesis that the loss of mesenchymal Tsc2 causing mTOR hyperactivation may impact alveolar epithelial cell fitness, we looked for AT1/AT2 transition cells in a novel murine model (Tbx4LME_Cre Tsc2KO) and found age-dependent changes in vivo. To assess AT2 cell fitness, we utilized ex vivo 3D alveolosphere assay using mouse lung fibroblasts (MLFs) isolated from both Tbx4Tsc2WT and Tbx4Tsc2KO mice combined with AT2-GFP+ cells. We found that Tsc2KO MLF support cells accelerated growth and colony-forming efficiency of MLF-AT2 organoids, as well as enhanced the transdifferentiation from AT2 to AT1 cells, compared to Tsc2WT MLFs support cells. To investigate this phenomenon, we performed mass spectrometry-based proteomics of lung mesenchyme from 1yo Tbx4 Tsc2KO and Tbx4 Tsc2WT mice (n=5 in each group). Principal component analysis (PCA) demonstrated distinct clustering of female WT vs KO samples. Volcano plot was generated to illustrate the differentially expressed proteins and GO pathway highlighted differential abundance of proteins associated with lysosomal function and ATPase transporters. Among top upregulated proteins in lung mesenchyme from Tbx4 Tsc2KO compared to Tbx4 Tsc2WT mice, we identified upregulation of extracellular remodeling proteins including CTSK, MMP14, LOXL2, which were validated by qPCR. This highlights differential abundance of unique proteins in lung mesenchyme with mTOR hyperactivation that could modulate alveolar composition affecting AT1/AT2 cell fitness. To determine whether age-dependent ECM composition of lung mesenchyme with hyperactive mTORC1 sustains MLF growth, survival, and migration and modulate AT1/AT2 cell fitness we have established 3D decellularized lung scaffolds from 8wo and 1yo Tbx4Tsc2WT and Tbx4Tsc2KO mice repopulated with Pdgfra+tdTomatoTsc2WT and AT2-GFP+ cells. Taken together, our finding demonstrates that mesenchymal mTOR activation can alter alveolar epithelial cell fitness and enhance transdifferentiation.

  PublisherDOI

• mTOR dysregulation induces IL-6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis

  Nature Communications · 2025-10-09 · 4 citations

  articleOpen access

  Lymphangioleiomyomatosis (LAM) is a rare disease of women in which TSC2 deficient 'LAM cells' with dysregulated mTOR signalling and recruited fibroblasts form nodules causing lung cysts and respiratory failure. We examine if mTOR dysregulation can induce senescence and impair the response to lung injury in LAM. The senescence markers p21, p16 and the SenMayo gene set are increased in LAM lungs and colocalise with alveolar type 2 cells. LAM models induce mTOR dependent senescence in alveolar type 2 cell organoids in vitro and in vivo. IL-6 produced by LAM cells, induces p16 and p21 in alveolar type 2 cells, inhibits epithelial wound resolution and is related to lung function in LAM patients. Rapamycin and the IL-6 receptor antagonist Tocilizumab reduce alveolar type 2 cell organoid p21 accumulation and Tocilizumab enhances epithelial wound repair. Targeting IL-6 signalling in parallel with mTOR inhibition, may reduce lung damage in LAM.

  PublisherOA PDFDOI

• Lymphangioleiomyomatosis Patient Research Priorities Survey: Developing Patient-centered Research Agenda

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  article

  Abstract RATIONALE. The LAM Foundation (TLF) is a nonprofit dedicated to lymphangioleiomyomatosis (LAM) – a rare lung disease primarily affecting women. TLF provides patient, family, and LAM clinic support, and funds a diverse range of research projects spanning basic, translational, and patient-centered studies, yielding an expansive body of knowledge. To continue supporting high-impact work, strategic planning and prioritization of LAM research goals are crucial. To this end, we conducted the LAM Patient Needs Assessment and Research Priorities Survey (LAM-PREP) – a comprehensive study with the goal of intentionally guiding future directions in LAM research for the benefit of patients and the scientific community. METHODS. We employed a Mixed-Methods analysis consisting of focus groups of patients and caregivers followed by a survey administered to a broad community of LAM stakeholders. To gather diverse perspectives, three in-person and two virtual focus groups were conducted in the summer and fall of 2023, with a total of 88 participants. Participant responses were thematically analyzed and grouped into categories and subcategories using qualitative content analysis to generate a list of health needs, quality of life issues, and research areas. Focus groups informed the development of the priority ranking survey, which was administered electronically for three months in the spring of 2024, generating 754 responses, of which 82.5% were LAM patients. RESULTS. LAM-PREP identified key priorities across three domains: health management, quality of life, and research needs, and revealed consistent themes across stakeholder groups (Table 1). High-priority areas across all stakeholder groups in health management included: understanding LAM symptoms, healthcare provider awareness, and access to comprehensive care. In the quality-of-life domain, stakeholders prioritized mental health and managing supplemental oxygen. Top-ranked research priorities included finding new treatments and a cure, and studying the role of hormones in LAM. Notable differences emerged between stakeholder groups: clinicians prioritized travel considerations and reproductive health, while patients emphasized sleep quality and lifestyle modifications. Scientists and clinicians uniquely prioritized studying disease progression mechanisms. CONCLUSION. LAM-PREP integrated diverse perspectives on LAM research and clinical priorities from LAM community stakeholders. These findings will serve as a roadmap for developing and implementing a strategic research plan to inform the allocation of TLF resources and improve the health outcomes of women living with LAM. Importantly, LAM-PREP can serve as a model for developing patient-focused research agendas for other rare and chronic pulmonary diseases, particularly those affecting women.

  PublisherDOI

• Extracellular Matrix and Fibroblast Activation in Lymphangioleiomyomatosis

  American Journal of Respiratory Cell and Molecular Biology · 2025-09-08

  articleSenior author

  Lymphangioleiomyomatosis (LAM) is a rare lung disease caused by hyperactivation of the mTORC1 (mechanistic/mammalian target of rapamycin 1) growth pathway in a subset of mesenchymal lung cells. Histopathologically, LAM lesions have been described as immature smooth muscle-like cells that are positive for the immature melanocytic marker HMB45/PMEL/gp100 and phosphorylated ribosomal protein S6 (pS6). Advances in single-cell sequencing technology allowed us to group LAM cells according to their expression of cancer stem cell (CSC) genes and identify three clusters: a high CSC-like state (i.e., stem-like state), an intermediate state, and a low CSC-like inflammatory state. We show here that, in unique LAM cells, many extracellular matrix (ECM) genes, including collagens and CTHRC1 (collagen triple helix repeat-containing 1), are expressed in the high and intermediate CSC-like LAM clusters and suggest that, as is observed in CSCs, the ECM may provide a shield for LAM lesions against immunosurveillance. In LAM-associated fibroblasts, the bisteric mTORC1-selective inhibitor RMC-5552 blocked translation of TGF-β (transforming growth factor-β)-induced COL1A1, COL6A1, and phosphorylation of the mTORC1 substrates ribosomal protein S6K1/S6 (S6K1/ribosomal protein S6) and 4E-BP1/eIF4E (eukaryotic initiation factor 4E-binding protein/translation initiation factor 4E), whereas rapamycin, the U.S. Food and Drug Administration-approved therapy for LAM disease, inhibited only the S6K1/S6 axis. C82, a Wnt/β-catenin transcription inhibitor, prevented TGF-β-induced collagens but not pS6 or p4E-BP1. This demonstrates that mTORC1-driven 4E-BP1/eIF4E rapamycin-insensitive translational control overrides transcriptional control of ECM genes. Inhibition by RMC-5552 of ECM and fibroblast activation may result in destruction of CSC-like LAM cells and provide more enduring therapy for LAM.

  PublisherDOI

• Addressing Sex as a Biological Variable in Preclinical Models of Lung Disease: An Official American Thoracic Society Research Statement

  American Journal of Respiratory and Critical Care Medicine · 2025-08-01 · 5 citations

  articleOpen access

  Abstract Background Pulmonary diseases have sex-specific predilections across the lifespan. The rigor of preclinical research is paramount to ensure the reproducibility and applicability of findings to clinical studies. The overarching goal was to identify current research gaps and the need for consideration of sex as a biological variable (SABV) in preclinical pulmonary research. The objective was to provide a roadmap and the best standards to incorporate and investigate the role of biological sex in preclinical models of lung diseases. Methods A multidisciplinary working group of 17 international investigators from the American Thoracic Society Assembly on Allergy, Immunology, and Inflammation, external content experts, and researchers engaged in lung basic and translational research. They reviewed the literature, identified critical knowledge gaps, and provided recommendations. Results The research statement provides an updated summary of the currently available evidence on the standards of SABV research in preclinical models and then offers specific research recommendations focused on the needs of researchers in the pulmonary field. The statement identifies knowledge gaps and develops guidance for experimental design and key considerations for incorporating SABV in two major topic areas: 1) in vivo; and 2) in vitro models. Furthermore, the group developed a checklist to guide researchers in including SABV in preclinical studies. Conclusions This statement provides a roadmap for the investigation of SABV in preclinical models. This will increase the applicability of findings to both sexes, uncover sex-biased mechanisms in lung diseases, and identify novel therapeutic targets.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01HL090829

  NIH · $1.6M · 2014

• NIH Grant R01HL071106

  NIH · $2.5M · 2012

• NIH Grant R01HL114085

  NIH · $1.9M · 2017

• Urokinase-type plasminogen activator (uPA) in pathogenesis of lymphangioleiomyomatosis (LAM)

  NIH · $1.8M · 2019–2024

• mTOR signaling in lung homeostasis, aging and disease

  NIH · $2.0M · 2020–2025

Frequent coauthors

• Elena A. Goncharova

  University of California, Davis

  87 shared

• Dmitry A. Goncharov

  University of California, Davis

  60 shared

• Reynold A. Panettieri

  Rutgers, The State University of New Jersey

  56 shared

• Ryan W. Rue

  Hospital of the University of Pennsylvania

  40 shared

• Alexander R. Mukhitov

  Hospital of the University of Pennsylvania

  29 shared

• Raymond B. Penn

  Thomas Jefferson University

  27 shared

• Kseniya Obraztsova

  University of Pennsylvania

  26 shared

• Andrew Eszterhas

  24 shared

Awards & honors

• FCPP Fellow
• Phase II clinical trial of the Safety Of Simvastatin (SOS) i…
• NIHMSID: 889033