"What you leave behind is not what is engraved in stone monuments, but what is woven into the lives of others."

- Pericles

Creating New Models for Multiple Myeloma

Our lab has a longstanding focus on generating models for multiple myeloma, the second most common blood cancer. Whereas great strides have been made in treating myeloma and prolonging patient survival, cures are rare.

 

Once diagnosed with myeloma, most patients will succumb to their disease at some point, even if many patients enjoy prolonged survival. We believe that better, more accurate models for the disease are needed. However historically, myeloma has been a tough cancer to model in the mouse. This is because of several complex conundrums is myeloma biology that have been difficult to accurate replicate; for example, the cell-of-origin, the number/sequence of causative mutations and the complex clonal architecture of myeloma have posed important conceptual and technical barriers.

Asimakopoulos and Zhang Labs

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Our lab recently co-developed (in collaboration with Jing Zhang's group) the first Ras-driven model for myeloma, a cancer driven by RAS mutations in a large proportion of patients (Wen et al., 2020). Moreover, we have developed a system to introduce sequential mutations in plasma cells in vivo through avian leukosis virus-mediated gene transfer (Asimakopoulos and Varmus, 2009).

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Understanding How Matrix Remodeling Shapes Anti-Tumor Immunity

Our lab has been interested in the elucidation of factors that balance immunogenic versus tolerogenic inflammation in tumors and ways to redress this balance, as a means to potentiate modern immunotherapies. In particular, we have focused on the mechanisms by which the tumor matrix models the behavior of immune cells infiltrating tumors. The tumor matrix is not inert “goo” or scaffold but rather, a living organ that responds to, and often drives, tumor development and tumor-immune system interactions. We have been studying a component of the matrix, a proteoglycan called versican, that possesses dual functions.

In its intact form, versican neuters tumor-sensing immune cells (dendritic cells) thus helping shield a tumor from immune attack. However, bits of broken versican (called versican-matrikines) can often act in opposing ways to the “mother” macromolecule: a case of a daughter antagonizing the mother. In particular, a versican-matrikine called versikine, promotes tumor-sensing dendritic cells and lowers the threshold for immune attack. Versikine could help make tumors exquisitely sensitive to immunotherapies and also be part of novel vaccination strategies utilizing different dendritic cell platforms.

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Dissecting Mechanisms that Promote the Persistence of Residual Cancer Cells After Therapy

Cures in myeloma are rare because even the best of therapies do not clear tumors completely. A few cells remain and they form the seed for the cancer to regrow (“relapse”). Eradicating this “minimal residual disease” is the key to cures.

 

 

Our lab is working to understand the characteristics of the residual cells that enable them to persist and thrive. Once we know what keeps these residual tumor cells in business (Their own special attributes? Help from other cells in the microenvironment?) we can begin to design therapies to rationally target every single remaining cell and thus clear the cancer.