A stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia

Abstract

Intratumoral heterogeneity is a common feature of many myeloid leukemias and a significant reason for treatment failure and relapse. Thus, identifying the cells responsible for residual disease and leukemia re-growth is critical to better understanding how they are regulated. Here, we show that a knock-in reporter mouse for the stem cell gene Musashi 2 (Msi2) allows identification of leukemia stem cells in aggressive myeloid malignancies, and provides a strategy for defining their core dependencies. Specifically, we carry out a high throughput screen using Msi2-reporter blast crisis chronic myeloid leukemia (bcCML) and identify several adhesion molecules that are preferentially expressed in therapy resistant bcCML cells and play a key role in bcCML. In particular, we focus on syndecan-1, whose deletion triggers defects in bcCML growth and propagation and markedly improves survival of transplanted mice. Further, live imaging reveals that the spatiotemporal dynamics of leukemia cells are critically dependent on syndecan signaling, as loss of this signal impairs their localization, migration and dissemination to distant sites. Finally, at a molecular level, syndecan loss directly impairs integrin β7 function, suggesting that syndecan exerts its influence, at least in part, by coordinating integrin activity in bcCML. These data present a platform for delineating the biological underpinnings of leukemia stem cell function, and highlight the Sdc1-Itgβ7 signaling axis as a key regulatory control point for bcCML growth and dissemination.

The Role of the Microenvironment and Immune System in Regulating Stem Cell Fate in Cancer

“…Nevertheless, given the complexity of the TME, delineating microenvironmental crosstalk in vivo will likely prove more useful in identifying novel signaling axes that drive stem cell fate in cancer. Intravital imaging presents an emergent strategy for interrogating interactions between microenvironmental cells and heterogeneous cancer cells in their native niche [92].…”

“…Similarly, we have shown that the adhesive signal syndecan-1 can support therapy resistance in aggressive leukemias. Syndecan-1 inhibition led to sensitization of blast crisis chronic myeloid leukemia to tyrosine kinase inhibitor therapy [ 92 ]. Endothelium derived miRNA has also been shown to support leukemia stem cell resistance to tyrosine kinase inhibitor therapy in chronic myeloid leukemia.…”

“…Nevertheless, given the complexity of the TME, delineating microenvironmental crosstalk in vivo will likely prove more useful in identifying novel signaling axes that drive stem cell fate in cancer. Intravital imaging presents an emergent strategy for interrogating interactions between microenvironmental cells and heterogeneous cancer cells in their native niche [ 92 ]. Live imaging is also extraordinarily powerful in delineating in high resolution both the spatial and temporal nature of cellular interactions and behavior [ 36 , 92 , 93 ], shedding light on dynamic processes such as development, tumor growth, metastasis, and immune infiltration [ 94 ].…”

“…Intravital imaging presents an emergent strategy for interrogating interactions between microenvironmental cells and heterogeneous cancer cells in their native niche [ 92 ]. Live imaging is also extraordinarily powerful in delineating in high resolution both the spatial and temporal nature of cellular interactions and behavior [ 36 , 92 , 93 ], shedding light on dynamic processes such as development, tumor growth, metastasis, and immune infiltration [ 94 ]. Ultimately, our ability to successfully integrate the molecular and cellular understanding of oncogenesis with a systems view of the dynamics of cancer growth, will be essential for fundamentally changing our ability to effectively treat and manage this disease.…”

Development and Validation of a Prognostic Classifier Based on Metabolism-Related Genes for Breast Cancer

“…However, the exact role and diagnostic significance of SORBS1 in BRCA are not yet clear. Syndecan-1 (SDC1, also known as CD138) is a key regulator of fatty acid synthesis and catalyzes the formation of mono-unsaturated fatty acids (MUFA) from saturated fatty acids (SFA) [87][88][89][90] .SDC1 has been implicated in various cancers, including BRCA [91][92][93][94] . The inactivation of SDC1 can lead to the consumption of unsaturated fatty acids, thereby inhibiting cancer cells 90,95,96 .…”