Research – Ellisen Lab

We address these questions through basic research studies of key cancer drivers including DNA repair defects through BRCA1/2 and related pathways, and transcriptional reprogramming through the p53 gene family. Supporting and complementing these studies are leading-edge analyses of patient-derived precancerous and cancerous tissues. Recent innovative tissue-based studies have led to our discovery of novel cancer drivers, and have provided a unique window on early cancer pathogenesis, intratumoral heterogeneity and tumor progression. Our discoveries in the basic laboratory and through human tumor analysis are being applied in ongoing clinical trials that seek to identify predictive markers of response to specific therapeutics for breast and other cancers. Our ability to work at the interface of basic tumor biology and therapeutic application is strongly supported by our network of collaborators and by the research and clinical infrastructure of the Mass General Cancer Center.

Our recent work employing advanced tumor molecular diagnostics has revealed gene fusions as novel drivers of an aggressive breast cancer subset. In a distinct aggressive breast cancer, triple-negative breast cancer (TNBC), extensive intratumoral heterogeneity is itself a driver that we have characterized through single-cell genomic and transcriptomic analysis. Our longstanding work on the biology of TNBC is supported by the institution-wide Triple-Negative Breast Cancer Program, which integrates basic research, translational and clinical studies together with human tumor propagation and high-throughput drug screening, all focused on overcoming drug resistance and improving outcomes for patients with TNBC.

Germline mutations in the DNA repair genes BRCA1 and BRCA2 confer dramatically elevated risk of cancers of the breast, ovary, and pancreas, yet the precise pathogenesis of BRCA1/2-associated cancer remains to be elucidated. Together with an international team of collaborators we are carrying out systematic studies of early events that give rise to these cancers, in part through detailed molecular analysis of normal and pre-cancerous tissues from BRCA1/2 mutation carriers. Defining the altered signaling and early cooperating events in this context is likely to reveal new markers of breast cancer predisposition and new targets for prevention. For example, our recently-published single-cell genome analysis has revealed extensive chromosomal damage in BRCA1/2-mutant breast tissues that precedes any histological abnormalities. This seminal finding implies the existence of early cellular defects and associated vulnerabilities that could be exploited for cancer prevention in this setting.

The p53 tumor suppressor is inactivated in more than 50% of sporadic human cancers, and patients carrying heterozygous germline p53 mutations show striking tumor predisposition. As a transcription factor and key nodal point for integrating cellular responses to DNA damage, p53 regulates genes involved in diverse cellular processes including cell cycle progression, apoptosis and angiogenesis. Through analysis of two p53-related genes, p63 and p73, we and others have defined a functional network through which these factors interact in human tumorigenesis. We have further defined a tissue-specific role for p63 as the enforcer of an epigenetically-controlled stem/progenitor state. Tumor-selective deregulation of p63 and its associated chromatin remodeling factors reprograms the transcriptome and thereby promotes proliferation, inhibits differentiation, and contributes to immune evasion. These findings are likely to explain the observation that p63 is over-expressed in a broad variety of epithelial tumors, particularly squamous cell and breast carcinomas. Collectively, this work serves as a paradigm for analysis of transcriptional reprogramming in cancer, while potentially providing new therapeutic possibilities for multiple treatment-refractory malignancies.

Our efforts to identify new pathways regulated by p53 family members have yielded surprising insights into the re-wiring of cellular metabolism that drives carcinogenesis. One central player in this effect is REDD1, a p53-regulated gene we identified that functions as a critical negative regulator of redox status and the mammalian mechanistic Target of Rapamycin (mTOR) kinase. Most human tumors exhibit abnormalities of p53 and/or mTOR signaling, and our recent studies have demonstrated the contribution of REDD1 to autophagy and metabolic homeostasis during tumorigenesis. We are currently using animal models, in vitro studies, and biochemical approaches to understand key metabolic dependencies of tumors that can be exploited to therapeutic advantage.