The Search to Identify Tumor Cells Evading Chemotherapy

For a long time, the cells within a tumor were thought to be similar to one another, like a bowl of chocolate chips. However, scientific studies have identified that a patient’s tumor cells are, in fact, highly diverse, more like different colored candies in a bowl. A direct implication of this diversity is that some cancer cells can now survive the selective pressure from chemotherapy, causing patients to have relapsed tumors.

As researchers and clinicians, we need to be able to identify these cells to target them up front along with chemotherapy in order to eliminate resistance. The real question, however, is what are we targeting?

Are we targeting a group of cells that were resistant to begin with, prior to treatment, or are we targeting an acquired physiological response that endows some cells with a survival advantage? This is a fundamental question that has remained unanswered for years, a question that I will address in the context of osteosarcoma.

Osteosarcoma (OS) is the most common primary tumor of the bone affecting children and adolescents. Unfortunately, patients who relapse have a dismal five-year survival rate – lower than 20%. We need a major change in the way we treat patients.

To get where we need to be, let’s start by looking at where we are. What do we know so far about the mechanisms of resistance to chemotherapy in OS? Our lab, the Roberts Lab in the Center for Childhood Cancer and Blood Diseases in the Abigail Wexner Research Institute at Nationwide Children’s Hospital, has previously identified specific tumor-derived factors, namely IL6 and CXCL8, that enable mechanisms of resistance to chemotherapy.

My data so far suggests that these factors are expressed by a small subset of cells and not from the majority of the tumor cells.

To definitively identify these cells, I am introducing unique molecular identifiers (or barcodes) into OS tumor cells. These barcodes will allow me to track the gene expression profile of each individual cell over the course of treatment by using a combination of single cell RNA-sequencing and lineage tracing. I can then determine the diversity of cells that survive treatment and the relative fitness or enrichment of specific groups of cells that express these known factors that enable resistance. Finally, I’ll be able to hone in on this concept of plasticity by comparing the behavior of a labelled population of OS cells post-treatment to that labelled population pre-treatment.

This study is significant because it elucidates a novel mechanism of resistance to chemotherapy in OS. The implications of the findings from this study are not only impactful to the field of OS but also as a generalizable conceptual advancement in the understanding of both intra-tumor heterogeneity and drug resistance.

References:

1. Roberts RD, Wedekind MF, Setty BA. Chemotherapy Regimens for Patients with Newly Diagnosed Malignant Bone Tumors. in Malignant Pediatric Bone Tumors – Treatment & Management (eds. Cripe TP, Yeager ND.) Springer: United States. 2015. doi:10.1007/978-3-319-18099-1
2. Gross AC. et al. IL-6 and CXCL8 mediate osteosarcoma-lung interactions critical to metastasis. JCI insight. 2018 Aug 23;3(16).