Kornelia Polyak, M.D., Ph.D.
Research in the Polyak laboratory is dedicated to the study of human breast cancer with the goal of dissecting tumor evolution and use this information to improve the clinical management of breast cancer patients.
Main areas of interests are: (1) breast cancer risk prediction and prevention, (2) drivers of tumor evolution from the earliest pre-invasive to metastatic treatment-resistant disease, and (3) novel therapeutic targets and rational combination therapies. Highlights from some of our recent studies:
Breast cancer risk prediction and prevention. Cancer prevention plays a crucial role in reducing both mortality and morbidity associated with the disease. We previously identified TGFβ signaling as a potential regulator of mammary epithelial cells linked to cancer risk. More recently, we demonstrated that short-term treatment with a TGFBR inhibitor (TGFBRi) in peripubertal ACI inbred, and Sprague Dawley outbred rats induces enduring changes that effectively prevent the development of estrogen- and carcinogen-induced mammary tumors. Utilizing single-cell RNA sequencing, we identified TGFBRi-responsive cell populations, including a distinct epithelial subpopulation we designated as secretory basal cells (SBCs), which exhibit progenitor-like characteristics. Notably, we have detected SBCs in normal human tissues, where they appear to be associated with an increased risk of cancer. Our interactome analysis reveals that SBCs represent the most interactive cell population and serve as a primary source of insulin-IGF signaling. Consequently, the inhibition of both TGFBR and IGF1R leads to a reduction in the proliferation of organoid cultures. These findings underscore the critical role of TGFβ in regulating mammary epithelial cells in the context of cancer and provide a compelling proof-of-principle for a novel cancer prevention strategy.
Tumor evolution. Immune escape is a critical factor in tumor growth and progression. Our research focuses on the mechanisms of immune evasion during the transition from ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC), a critical step that influences tumor evolution. In previous studies, we observed a significant decline in the frequency of activated CD8+ T cells and T cell receptor (TCR) clonotype diversity in IBC compared to DCIS. This decline suggests that reduced T cell activity and TCR diversity may play a pivotal role in tumor progression. To further investigate these dynamics, we conducted a comprehensive analysis of the immune landscapes in normal tissue, DCIS, and IBC across all three major tumor subtypes. Utilizing large-scale single-cell RNA sequencing (scRNA-seq) profiling of clinical samples in combination with functional validation in a rat model of breast cancer, we defined T cell populations that appear to be key drivers of immune suppression during invasive progression.
Novel therapeutic targets. Epigenetic regulators are commonly mutated in cancer and represent novel therapeutic targets. KMT2C and KMT2D, which encode histone H3 lysine 4 methyltransferases, are among the most frequently mutated genes in triple-negative breast cancer (TNBC). However, the mechanisms by which these mutations influence the epigenomic and transcriptomic landscapes to facilitate tumorigenesis remain largely unexplored. We determined that the deletion of Kmt2c or Kmt2d in non-metastatic murine models of TNBC significantly promotes metastasis, particularly to the brain. Through comprehensive global chromatin profiling and chromatin immunoprecipitation followed by sequencing, we observed alterations in key chromatin marks, including H3K4me1, H3K27ac, and H3K27me3, in knockout cells. Notably, we identified an enhanced binding of the H3K27me3 lysine demethylase KDM6A, which exhibited a significant correlation with gene expression changes. Our analysis revealed that Mmp3 is commonly upregulated through epigenetic mechanisms in both knockout models. Consistent with these findings, patient samples harboring KMT2C mutations in TNBC exhibited elevated levels of MMP3. Furthermore, the downregulation or pharmacological inhibition of KDM6A effectively reduced the upregulation of Mmp3 induced by the loss of histone-lysine N-methyltransferase 2 (KMT2) and prevented brain metastasis, akin to the effects observed with direct downregulation of Mmp3. Collectively, our findings highlight the KDM6A-MMP3 axis as a critical mediator of metastasis driven by the loss of KMT2C/D in TNBC, providing valuable insights into potential therapeutic targets for this aggressive cancer subtype.
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