Research
Tumor recurrence following therapy is a leading cause of death in patients with cancer. In many instances, tumor recurrence is caused by dormant residual tumor cells that can survive for many years prior to re-emerging as a recurrent tumor. Our laboratory is focused on understanding the biological properties of these residual tumor cells. Our goal is to ultimately develop strategies aimed at specifically killing these residual cells in order to prevent cancer recurrence and improve patient survival.
Our specific interests are centered around the following themes:
Dormant Residual Cell Metabolism
How do cancer cells rewire their metabolism during transitions between proliferation and dormancy? How do molecularly targeted therapies alter cancer cell metabolism? Do dormant tumors have unique metabolic properties that can be therapeutically targeted? We are using in vivo and in vitro approaches to dissect these question and gain insight into dormant cell metabolism.
Recurrent tumors (right) upregulate macropinocytosis as compared to primary tumors (left). Dextran uptake is shown in red.
Doug FoxPublications
Fox et al., Nature Metabolism 2020
Fox et al., bioRxiv 2020
Lin et al., Oncogene 2021
Lin et al., Cell Death & Differentiation 2020
Genomic Instability and Heterogeneity during Tumor Recurrence
Genetic instability and intratumor heterogeneity are hallmarks of human cancer, but their contribution to dormant residual disease and recurrence are understudied. We are building improved mouse models of cancer to address the functional contribution of genome instability and intratumor heterogeneity to dormancy and recurrence. Particular interests include the role of APOBEC mutagenesis and whole-genome duplications in tumor progression.
Publications
Newcomb et al., Scientific Reports 2021
DiMarco et al., bioRxiv 2021
CldU and IdU labeling to detect replication fork stalling in recurrent tumor cells.
Nina Marie GarciaNongenetic Mechanisms of Recurrence
Emerging evidence indicates that, in many cases, recurrent tumors do not have distinct genetic mutations as compared to their antecedent primary tumors. This suggests that nongenetic factors may play important roles in driving recurrence. We are exploring how two types of nongenetic mechanisms – epigenetic alterations and the tumor microenvironment – contribute to tumor dormancy and recurrence, with the goal of identifying pathways that may be therapeutically targeted.
Publications
Mabe et al., Journal of Clinical Investigation 2018
Mabe et al., Cell Reports 2020
Walens et al., eLife 2019
Masson’s Trichrome staining showing abundant collagen deposition in a residual tumor in the mammary gland.
Andrea WalensDevelopment of New Approaches to Study Residual Tumor Cells
We are developing and deploying new models and technologies – including tumor organoids, cellular barcoding, single-cell genomics and functional genomic screening – to uncover new aspects of residual cancer cell biology.
DNA barcoding reveals changes in the clonal architecture of tumors during residual disease and recurrence.
Walens et al., Nature Communications, 2020Publications
Walens et al., Nature Communications 2020
Madonna et al., Molecular Cancer Research 2019
Mouse mammary tumor organoid stained to show F-actin (green), hoechst (blue), and Ki-67 (red).
Kelley McCutcheon
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