A niche-dependent myeloid transcriptome signature defines dormant myeloma cells

Abstract

The era of targeted therapies has seen significant improvements in depth of response, progression-free survival, and overall survival for patients with multiple myeloma. Despite these improvements in clinical outcome, patients inevitably relapse and require further treatment. Drug-resistant dormant myeloma cells that reside in specific niches within the skeleton are considered a basis of disease relapse but remain elusive and difficult to study. Here, we developed a method to sequence the transcriptome of individual dormant myeloma cells from the bones of tumor-bearing mice. Our analyses show that dormant myeloma cells express a distinct transcriptome signature enriched for immune genes and, unexpectedly, genes associated with myeloid cell differentiation. These genes were switched on by coculture with osteoblastic cells. Targeting AXL, a gene highly expressed by dormant cells, using small-molecule inhibitors released cells from dormancy and promoted their proliferation. Analysis of the expression of AXL and coregulated genes in human cohorts showed that healthy human controls and patients with monoclonal gammopathy of uncertain significance expressed higher levels of the dormancy signature genes than patients with multiple myeloma. Furthermore, in patients with multiple myeloma, the expression of this myeloid transcriptome signature translated into a twofold increase in overall survival, indicating that this dormancy signature may be a marker of disease progression. Thus, engagement of myeloma cells with the osteoblastic niche induces expression of a suite of myeloid genes that predicts disease progression and that comprises potential drug targets to eradicate dormant myeloma cells.

Cancer Cell Dormancy in Metastasis

“…Notably, AXL and nearest-neighbor genes were able to distinguish patients with myeloma from normal subjects, and those with the premalignant monoclonal gammopathy of undetermined significance. This dormant cell myeloid signature was also able to predict survival, pointing to an important functional role (Khoo et al 2019).…”

“…Nevertheless, some aspects of the cell-extrinsic and molecular control of tumor cell dormancy are likely to be organ specific, particularly those involving tissue-restricted cell types such as osteoblasts in bone (Croucher et al 2016). Indeed, tumor cell dormancy in models of multiple myeloma has been shown to be osteoblastic niche specific (Chen et al 2014;Lawson et al 2015), with pathway targeted interventions affecting skeletal but not spleen resident dormant cell numbers (Khoo et al 2019). Understanding and distinguishing organ-specific from organ-independent mechanisms of dormancy is an important and ongoing research goal.…”

“…Similarly, lymphoblastic leukaemia cells are induced into a state of dormancy by binding of GAS6 to MER, conferring extended survival and chemotherapeutic resistance via a MAPK-dependant mechanism (Shiozawa et al 2010b). When multiple myeloma cells interact with osteoblastic cells in vivo, they enter a state of dormancy, mediated by the induction of a suite of myeloid lineage related genes in the tumor cells (Khoo et al 2019). AXL is a key induced gene in this context and blocking AXL was associated with release of cells from dormancy (Khoo et al 2019).…”

“…When multiple myeloma cells interact with osteoblastic cells in vivo, they enter a state of dormancy, mediated by the induction of a suite of myeloid lineage related genes in the tumor cells (Khoo et al 2019). AXL is a key induced gene in this context and blocking AXL was associated with release of cells from dormancy (Khoo et al 2019). Notably, AXL and nearest-neighbor genes were able to distinguish patients with myeloma from normal subjects, and those with the premalignant monoclonal gammopathy of undetermined significance.…”

“…An alternative approach to maintaining cells in a dormant state is to liberate dormant cells from niche-dependent control, thereby making cells more susceptible to conventional chemotherapeutic approaches. Reactivation could be achieved by targeting dormancy pathwayspecific mechanisms, including AXL, p38, or TGF-β2 inhibition (Bragado et al 2013;Khoo et al 2019), or niche-dependent mechanisms of control. In the case of bone, this could include osteoclast activators such as RANK-ligand (Lawson et al 2015).…”