The Charlotte Kuperwasser Lab
The Kuperwasser Laboratory studies breast cancer biology through the lens of developmental biology and molecular biology. As such, we examine the genetic and molecular etiology, progression and metastasis of breast cancer by investigating stem cells, differentiation, and stromal-epithelial interactions during normal mammary gland development and how these events are co-opted under pathologic conditions such as cancer. The laboratory has several areas of focus.
Epigenetic Drivers of Breast Cancer Development
Epigenetic abnormalities are becoming more appreciated as drivers of malignancy. An active area of research in the Kuperwasser lab is illuminating the potential link between mRNA processing, epitranscriptomic modification, and malignant growth. One understudied epigenetic mechanism that can modulate protein expression and function is switching polyadenylation (pA) sites. Choice of pA sites (PAS) determines the location at which a pre-mRNA is cleaved and polyadenylated in a process called alternative or premature polyadenylation (PPA). We found that premature cleavage and pA can occur in the intron of a gene despite the absence of mutations causing gene-truncating alterations. This PPA of transcripts can lead to constitutively active or dominant-negative proteins that promote transformation. We are working towards developing new bioinformatics pipelines to identify global genome-wide PPA events to generate a transcriptome-wide catalog of recurrent PPA events specific to cancer. We are also seeking to elucidate the mechanisms controlling PPA selection and establishing whether such mechanisms are drivers of human breast cancer development. Moreover, as epigenetic abnormalities are reversible, we are trying to establish whether the use of PPA manipulation is a viable strategy as a cancer therapy.
Stroma and Cancer Immunology
The breast tumor microenvironment (TME) is characterized by a robust stromal reaction even at the earliest stages of invasive progression. This stromal reaction is a prominent pathological feature of early tumors marked by a dramatic increase in the proliferation of activated contractile fibroblasts (myofibroblasts), increased deposition of many extracellular matrix components, and a dramatic increase in tissue rigidity. The stromal response causes production of inflammatory and angiogenic growth factors that aid in the growth of cancer cells, as well as eventual progression and metastasis. These changes presumably have important functions during immuosurveillance and therefore, understanding how the TME imprints and sculpts tumor immunogenicity could provide new actionable targets for new immunotherapies, or combinations that improve the efficacy of existing immunotherapies.
The Kuperwasser lab has a longstanding focus on investigating the role of the tissue stromal microenvironment in controlling breast tumor development and progression. Currently the lab is defining how stromal rigidity affects the recruitment and stimulation of immune cells, which likely participates in cancer development and progression. In addition, we are seeking to define how the tissue microenvironment controls immune responses during breast tumor initiation, development, and progression with the goal of identifying new immune targets that enable early tumors to escape immune surveillance. We have developed several novel histocompatible transplantable tumor cell line models as well as transgenic mouse models to study these areas of cancer immunology.
Figure 1. Genetically labeled mouse mammary gland tissue
Understanding The Diversity of Slug Function: Moving Beyond EMT
E-cadherin suppression has been considered the principal action of the transcriptional repressor Slug/SNAI2. Beyond its importance in the epithelial-to-mesenchymal transition (EMT), we have found that Slug represents a master transcription factor that regulates a broad spectrum of biological processes relevant in tissue maintenance and tumorigenesis. A major focus of the Kuperwasser lab has been elucidating the role, regulation and function of Slug in tissue homeostasis, differentiation and stem cell biology. Our current efforts are in investigating the role of Slug in aging, as well as its critical role in DNA damage response (DDR). In addition, we are interested in understanding how Slug couples DDR to replicative or oncogenic stress thereby acting as either an enabler or inhibitor of neoplastic transformation.
Figure 2. The diversity of Slug function in development and tumorigenesis.