Targeting the biophysical properties of the myeloma initiating cell niches: a pharmaceutical synergism analysis using multi-scale agent-based modeling.

Multiple myeloma, the second most common hematological cancer, is currently incurable due to refractory disease relapse and development of multiple drug resistance. We and others recently established the biophysical model that myeloma initiating (stem) cells (MICs) trigger the stiffening of their niches via SDF-1/CXCR4 paracrine; The stiffened niches then promote the colonogenesis of MICs and protect them from drug treatment. In this work we examined in silico the pharmaceutical potential of targeting MIC niche stiffness to facilitate cytotoxic chemotherapies. We first established a multi-scale agent-based model using the Markov Chain Monte Carlo approach to recapitulate the niche stiffness centric, pro-oncogenetic positive feedback loop between MICs and myeloma-associated bone marrow stromal cells (MBMSCs), and investigated the effects of such intercellular chemo-physical communications on myeloma development. Then we used AMD3100 (to interrupt the interactions between MICs and their stroma) and Bortezomib (a recently developed novel therapeutic agent) as representative drugs to examine if the biophysical properties of myeloma niches are drugable. Results showed that our model recaptured the key experimental observation that the MBMSCs were more sensitive to SDF-1 secreted by MICs, and provided stiffer niches for these initiating cells and promoted their proliferation and drug resistance. Drug synergism analysis suggested that AMD3100 treatment undermined the capability of MICs to modulate the bone marrow microenvironment, and thus re-sensitized myeloma to Bortezomib treatments. This work is also the first attempt to virtually visualize in 3D the dynamics of the bone marrow stiffness during myeloma development. In summary, we established a multi-scale model to facilitate the translation of the niche-stiffness centric myeloma model as well as experimental observations to possible clinical applications. We concluded that targeting the biophysical properties of stem cell niches is of high clinical potential since it may re-sensitize tumor initiating cells to chemotherapies and reduce risks of cancer relapse.

Conditional random pattern algorithm for LOH inference and segmentation.

MOTIVATION: Loss of heterozygosity (LOH) is one of the most important mechanisms in the tumor evolution. LOH can be detected from the genotypes of the tumor samples with or without paired normal samples. In paired sample cases, LOH detection for informative single nucleotide polymorphisms (SNPs) is straightforward if there is no genotyping error. But genotyping errors are always unavoidable, and there are about 70% non-informative SNPs whose LOH status can only be inferred from the neighboring informative SNPs. RESULTS: This article presents a novel LOH inference and segmentation algorithm based on the conditional random pattern (CRP) model. The new model explicitly considers the distance between two neighboring SNPs, as well as the genotyping error rate and the heterozygous rate. This new method is tested on the simulated and real data of the Affymetrix Human Mapping 500K SNP arrays. The experimental results show that the CRP method outperforms the conventional methods based on the hidden Markov model (HMM). AVAILABILITY: Software is available upon request.