Cell Plasticity & Aging

Background

The concept of “cell plasticity” refers to the capacity of a cell to adopt different identities without any genetic mutations. A classic example of cell plasticity occurs during development, when embryonic stem cells differentiate into the immense diversity of cell types we see in the adult body. It is now appreciated that cell plasticity also plays an important role in adult tissues, particularly in the context of injury and regeneration, where it is indispensable for tissue repair. However, cell plasticity is also a salient feature of cancer and can contribute to tumorigenesis, resistance to therapy, and metastasis.
Our lab is interested in understanding and manipulating these dichotomous roles of cell plasticity. Our ultimate goal is to find ways to harness cell plasticity programs for enhanced tissue regeneration, and to control them in order to limit tumorigenesis, cancer progression, and relapse. To approach this, we use a combination of molecular and cell biology, and organoid models in vitro, in vivo mouse models, and next-generation sequencing technologies.

1. The relationship between reparative cell plasticity and tumorigenesis

We are interested in understanding whether the cell plasticity that is activated during tissue repair is similar, different, or related to the cell plasticity that occurs in tumorigenesis. We are using colorectal cancer and intestinal injury models combined with lineage tracing systems to temporally identify, isolate, and study these plastic cells and their progeny. We are particularly interested in using single cell omics to understand the epigenetic profiles that define healthy and diseased states, and in combining this with metabolic interventions to manipulate plasticity. We also aim to discover novel approaches to disrupt cell plasticity in cancer for improved disease control.

2. Cell plasticity during aging

As we age, our regenerative capacity declines, while our cancer risk significantly increases. We are investigating whether changes in cell plasticity contribute to these age-associated phenomena. We are also using in vivo models of Yamanaka factor reprogramming, combined with lineage tracing tools, to study whether artificially induced cell plasticity affects aging regeneration, and cancer.

3. The role of senescent cells in aging and disease

Senescent cells are stressed or damaged cells that accumulate within our tissues as we age. While senescence is an important tumor suppressor and can promote tissue repair, inappropriate accumulation of senescent cells is pathogenic and contributes to the development or exacerbation of many age-associated diseases. We are studying the role of senescent cells in cell plasticity in the context of transformation, therapy resistance, and tissue regeneration. We are also developing novel senolytics - drugs that specifically target senescent cells - for the therapeutic elimination of senescent cells.