Microenvironmental interactions in mantle cell lymphoma and multiple myeloma

Tumors, such as mantle cell lymphoma (MCL) and multiple myeloma (MM), arise at distinct anatomical sites within the human body. Interaction between malignant cells and their tumor microenvironment (TME) is crucial for the growth, survival and drug-resistance of malignancies. Improving our understanding of these interactions is therefore crucial to comprehend the underlying pathogenesis. Furthermore, disrupting the interactions between malignant cells and the TME can provide clinical benefit, as exemplified by the mode of action of clinically applied BTK inhibitors.
In this thesis we studied the kinase HCK in mantle cell lymphoma. We showed that HCK is aberrantly expressed in MCL, that high expression correlates with patient prognosis and that genetic and pharmacological disruption of HCK reduces MCL proliferation and adhesion to extracellular matrix components and stromal cells present in the TME. Next, we showed that a dual HCK/BTK inhibitor, KIN-8194, inhibits the proliferation and adhesion of MCL cells with and without primary or secondary resistance to BTK inhibitors. Furthermore, we demonstrated that the gamma isoform of CXCL12 is expressed in bone marrow stromal cells (BMSC) and retained on the cell surface by heparan sulfate proteoglycans. We showed that CXCL12γ is critical for the adhesion of MM cells to BMSCs and regulates cell adhesion-mediated drug-resistance in MM. Lastly, we revealed that HSPG-bound CXCL12γ, in comparison to the CXCL12α, activates its cognate receptor CXCR4 but does not desensitize it.
Our findings provide novel insights in overcoming therapy resistance in MCL and MM and crucial interactions between MCL and MM and their TME.