RESEARCH

Parallels between healing and cancer formation

Healthy individuals have a remarkable inherent ability to heal after injury. Wound healing involves complex and coordinated actions of dozens of cell populations and hundreds of their molecular products. They collectively act across three distinct and partially overlapping healing phases: inflammation, proliferation and resolution. Critical spatial and temporal processes occur during in each phase of repair, and they result in the restoration of tissue homeostasis. These same healing processes become dysregulated in major chronic diseases, especially during cancer formation. In fact, cancer encapsulates the entire wound healing process run amok, and it has been described as a “wound that fails to heal”. 

In healthy tissues like skin and oral mucosa, epithelial cells maintain a barrier against the outside world. In the underlying stromal layer, resident cells like fibroblasts maintain a stable microenvironment composed of extra-cellular matrix (ECM) components, including collagen and elastin, that collectively imbue tissues with their unique mechanical properties. Blood vessels help to maintain the environment by supplying the tissue with stable supplies of oxygen. This stable state that defines tissue health is therefore actively maintained by cells in a fine-tuned balancing act called homeostasis. 

When the tissue barrier is broken during injury, epithelial cells become activated and release signals into the immediate microenvironment in the form of cytokines and growth factors. These signals in turn recruit and activate immune cells to initiate inflammation, a critical yet self-limiting first phase of healing. The signals stimulate nearby blood vessels to sprout in a process called angiogenesis. Fibroblasts also become activated to produce ECM components in order to recapitulate the damaged connective tissue. These processes naturally resolve as the tissue is repaired and eventually returns to homeostasis.

When epithelial cells mutate into cancer cells, they become chronically activated, proliferate uncontrollably and release excessive amounts of cytokines and growth factors into their immediate tumor microenvironment. These signals in turn hyper-activate immune cells and cause long lasting, chronic inflammation. The signals stimulate blood vessels to continually sprout into an aberrant and leaky vasculature that feeds the growing tumor. Fibroblasts also hyper-activate into cancer-associated fibroblasts, producing excessive amounts of ECM components that lead to localized fibrosis and tissue stiffness. 

Our research motivation is to use the wound healing spectrum as a quantitative bio-marker for cancer progression. 

Using healing as a template allows for the identification of novel spatial and temporal diagnostic and prognostic signatures for cancer. 

It also allows for the development of targeted cancer therapies that either activate or inhibit dysregulated wound-associated pathways to promote a return to tissue homeostasis.

Connection between oral healing and oral cancer

ORAL vs SKIN 

WOUND HEALING


Compared to skin, oral mucosa has greater regenerative potential


Oral wounds heal faster, with reduced inflammation, reduced vascularization, and reduced scar formation

ORAL vs SKIN 

CANCER FORMATION


Skin cancers are diagnosed twenty times more often than oral cancers


However, oral cancers lead to three times as many deaths as skin cancers

Since cancer is a “wound that fails to heal”, 

why is the dysfunctional oral wound so much more aggressive 

than the dysfunctional skin wound?

Our hypothesis is that the superior healing potential of oral mucosa plays a critical role.

TOOLSET: the multi-omics approach

We leverage powerful new technologies, such as single-cell and spatial transcriptomics, with high-content microscopy and comparative bioinformatics approaches to study complex systems such as wounds and tumors at multiple levels: from cell to tissue. Such tools allow us to more fully appreciate the symphony of coordination between hundreds of cells and thousands molecules in healing tissues. Comparative bioinformatics allow us to learn from the optimized healing response and identify healing pathways that become dysregulated in cancer, to more effectively diagnose tumors, to better predict tumor severity, and even to combat cancer with novel drugs that target these dysregulated healing pathways. Finally, we use cell and animal models of healing and carcinogenesis and traditional molecular biology methods to validate our discoveries in vitro and in vivo, pushing our findings forward in the translational pathway from bench to clinic.

Single-cell Transcriptomics

Spatial Transcriptomics

High-content Microscopy

Comparative Bioinformatics

Cell and Animal Models

Molecular Biology

Inter-disciplinary collaborations