Li Laboratory

Project 1:

Cell-specific roles of transforming growth factor (TGF)-β in bone metastases

Most people who die of cancer have metastases somewhere in their body, but metastases of certain cancers (such as breast, lung, and prostate) are more likely to be found in bone. Once in the bone, cancer cells induce either osteolytic (bone resorption) or osteoblastic (abnormal bone formation) lesions, which cause fractures, spinal cord compression, hypercalcemia, and extreme bone pain. Current treatments for bone metastasis reduce some symptoms such as pain but do not increase survival.

A better understanding of the mechanisms behind bone metastases is needed in order to develop early diagnostic and targeted therapeutic strategies. Bone lesion development is determined by the interactions between cancer cells and bone cells such as osteoblasts (mesenchymal lineage cells) and osteoclasts (myeloid lineage cells), and regulated by growth factors and cytokines embedded in the bone matrix such as TGF-β.

TGF-β plays crucial roles in both cancerous and healthy bone; the effects are highly context-dependent, spatially and temporally. We aim to delineate the cell-specific role of TGF-β in bone metastasis, and identify the downstream mediators that are targetable, so that it can be translated to benefit the patients. We have found that:

1.1. Basic fibroblast growth factor (bFGF) mediated by TGF-β signaling in cells of the myeloid lineage promotes breast cancer bone metastasis. Blocking bFGF reduces breast cancer bone lesion development. In bone metastatic tissues from breast cancer patients, TGF-β and bFGF signaling are likely to be activated in osteoclasts and cancer cells, but inactivated in osteoblasts (read more about this finding in Oncogene).

1.2. TGF-β signaling in cells of the myeloid lineage promotes bone metastases, while TGF-β signaling in cells of the mesenchymal lineage inhibits prostate cancer bone metastasis. bFGF is the functional mediator for TGF-β signaling effect in cells of the myeloid lineage, but not for the effect of the mesenchymal lineage.

1.3. The cell-specific roles of TGF-β signaling in bone are more complex in non-small cell lung cancer (NSCLC) bone metastasis. The effects are dependent on the types of bone lesion induced by different NSCLC.

Project 2:

TGF-β signaling in bone microenvironment effects tumor dormancy

Up to 70 percent of cancer patients have tumor cells in the bone marrow at the time of initial diagnosis. It is not known how cancer cells remain dormant and later reactivate in the bone microenvironment. Understanding tumor dormancy is important to eradicating metastatic recurrence that kills patients. Studies have shown that external cues from the bone microenvironment can determine tumor dormancy. We aim to create a growth-inhibitory (or dormancy-permissive) bone microenvironment, and determine the mechanism by which this bone microenvironment keeps cancer cell dormant. We have established a system in which loss of TGF-β signaling in myeloid lineage cells promotes prostate or NSCLC dormancy in the bone marrow.