A5009118439- Cancer Genomics and Diagnostics
- Cancer Cells and Metastasis
- Mathematical Biology Tumor Growth
- Lung Cancer Treatments and Mutations
- Brain Metastases and Treatment
- Evolution and Genetic Dynamics
- Microtubule and mitosis dynamics
- Single-cell and spatial transcriptomics
- Advanced Breast Cancer Therapies
- Cancer, Hypoxia, and Metabolism
- Acute Lymphoblastic Leukemia research
- HER2/EGFR in Cancer Research
- Cancer-related Molecular Pathways
- Bioinformatics and Genomic Networks
- Acute Myeloid Leukemia Research
- Breast Cancer Treatment Studies
- Chronic Lymphocytic Leukemia Research
- Epigenetics and DNA Methylation
- Monoclonal and Polyclonal Antibodies Research
- Computational Drug Discovery Methods
- RNA modifications and cancer
- PI3K/AKT/mTOR signaling in cancer
- Peptidase Inhibition and Analysis
- Lung Cancer Research Studies
- Cancer therapeutics and mechanisms
Moffitt Cancer Center
2016-2025
Brigham and Women's Hospital
2009-2024
University of South Florida
2017-2024
Dana-Farber Cancer Institute
2011-2019
Harvard University
2011-2019
University of Colorado Anschutz Medical Campus
2007-2013
Beth Israel Deaconess Medical Center
2013
University of Colorado Denver
2006-2012
Harvard University Press
2011
Laboratory of Molecular Genetics
2009
Intratumor heterogeneity is a major clinical problem because tumor cell subtypes display variable sensitivity to therapeutics and may play different roles in progression. We previously characterized 2 populations human breast tumors with distinct properties: CD44+CD24- cells that have stem cell-like characteristics, CD44-CD24+ resemble more differentiated cancer cells. Here we identified 15 genes required for growth or proliferation large-scale loss-of-function screen found inhibition of...
Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis cellular heterogeneity for genetic and phenotypic features their spatial distribution in breast pre- post-neoadjuvant chemotherapy. We found intratumor diversity was tumor-subtype specific, it did not with partial or no response. However, lower pretreatment significantly associated pathologic complete In contrast,...
The molecular mechanisms of clathrin-dependent internalization epidermal growth factor receptor (EGFR) are not well understood and, in particular, the sequence motifs that mediate EGFR interactions with coated pits have been mapped. We generated a panel mutants and stably expressed these porcine aortic endothelial (PAE) cells. Interestingly, mutations tyrosine phosphorylation sites 1068 1086 interact growth-factor-receptor-binding protein Grb2 completely abolished PAE Quantitative analysis...
Triple-negative breast cancer (TNBC) is currently the only major tumor subtype without effective targeted therapy and, as a consequence, in general has poor outcome. To identify new therapeutic targets TNBC, we performed short hairpin RNA (shRNA) screen for protein kinases commonly amplified and overexpressed cancer. Using this approach, identified AKT3 gene preferentially required growth of TNBCs. Downregulation Akt3 significantly inhibits TNBC lines three-dimensional (3D) spheroid cultures...
While disruption of p53 is selectively neutral within non-stressed hematopoiesis, it confers a strong selective advantage upon irradiation, leading to expansion mutant clones and lymphoma development.
Abstract Using a three-dimensional coculture model, we identified significant subtype-specific changes in gene expression, metabolic, and therapeutic sensitivity profiles of breast cancer cells contact with cancer-associated fibroblasts (CAF). CAF-induced expression signatures predicted clinical outcome immune-related differences the microenvironment. We found that strongly protect carcinoma from lapatinib, attributable to its reduced accumulation an elevated apoptotic threshold. Fibroblasts...
Women in North America have a one eight lifetime risk of developing breast cancer (BC), and significant proportion these individuals will develop recurrent BC eventually succumb to the disease. Metastatic, therapy-resistant cells are refractory cell death induced by multiple stresses. Here, we document that vitamin D receptor (VDR) acts as master transcriptional regulator autophagy. Activation VDR induces autophagy an autophagic signature correlates with increased survival patients;...
ABSTRACT Despite high initial efficacy, targeted therapies eventually fail in advanced cancers, as tumors develop resistance and relapse. In contrast to the substantial body of research on molecular mechanisms resistance, understanding how evolves remains limited. Using an experimental model ALK positive NSCLC, we explored evolution different clinical inhibitors. We found that can originate from heterogeneous, weakly resistant subpopulations with variable sensitivity Instead commonly assumed...
Drug resistance remains an elusive problem in cancer therapy, particularly for novel targeted therapies. Much work is focused upon the development of arsenal therapies, towards oncogenic driver genes such as ALK-EML4, to overcome inevitable that develops over time. Currently, after failure first line ALK TKI another administered, though collateral sensitivity not considered. To address this, we evolved rearranged non-small cell lung (H3122) a panel 4 TKIs, and performed analysis. All...
Abstract The application of evolutionary and ecological principles to cancer prevention treatment, as well recognizing a selection force in nature, has gained impetus over the last 50 years. Following initial theoretical approaches that combined knowledge from interdisciplinary fields, it became clear using eco‐evolutionary framework is key importance understand cancer. We are now at pivotal point where accumulating evidence starts steer future directions discipline allows us underpin...
Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are often linked to drug resistance. Here, we found that coculture with CAFs or culture CAF-conditioned medium unexpectedly induced sensitivity certain lung cancer cell lines. Gene expression and secretome analyses of normal lung–associated (NAFs) revealed differential abundance insulin-like growth factors (IGFs) IGF-binding proteins (IGFBPs), which promoted inhibited, respectively, signaling by receptor IGF1R kinase FAK....
In this study, we experimentally measure the frequency-dependent interactions between a gefitinib-resistant non–small cell lung cancer population and its sensitive ancestor via evolutionary game assay. We show that cost of resistance is insufficient to accurately predict competitive exclusion growth rate measurements are required. Using data, then gefitinib treatment results in ancestor, while absence likely, but not guaranteed, resistant strain. Then, using simulations, demonstrate...