New cellular ‘switches’ found to fuel lung cancer growth, resistance to treatment

New cellular 'switches' fuel lung cancer growth, treatment resistance

SCLC cell lines have divergent gene regulatory networks and phenotypes. (A) Hierarchical clustering was performed using 53 SCLC cell lines. Silhouette widths were calculated, which measure the similarity within each group. j, number of clusters; nI, number of samples in each cluster; aveSi, average silhouette width for each cluster. (B) Log fold change (FC) for fate-defining TFs in the indicated cluster relative to the rest. (C) Representative cell lines, with the cluster shown in parentheses, were profiled for cluster-defining proteins by immunoblot. WCL, whole cell lysate. (D) Proportion of adherent samples for each cluster as listed in the Cancer Cell Encyclopedia (CCLE). Columns represent mean values, and the Mann-Whitney test was used for statistical analysis. *P Scientific progress (2022). DOI: 10.1126/sciadv.abp8674

Northwestern Medicine researchers have discovered new insights into how cancer cells can change their shape by undergoing phenotypic “switches” to facilitate tumor growth and resistance to treatment in small cell lung cancer, according to findings published in Scientific progress.

“This cancer can significantly shift or shape, using at least three different cell types or developmental programs. The current standard of care therapy for this tumor mainly targets the neuroendocrine subtype of cells, leaving the others to linger and rapidly repopulate the tumor when therapy is ultimately stopped. ,” said Mohamed Abazeed, MD, associate professor of radiation oncology and senior author of the study.

An estimated 15% of all lung cancer cases diagnosed worldwide are small cell lung cancers. The cancer usually develops in patients with a significant history of tobacco use and has a five-year survival rate of only 6%, with most patients dying of the disease within a year of diagnosis.

While most patients respond to first-line therapy, which often includes a combination approach of chemotherapy and radiation therapy, many will also relapse. The need for more effective targeted therapies is urgent, according to Abazeed, but progress remains slow.

“The disease is aggressive with very little progression over the last four decades. It’s also not amenable to surgical resection, so it makes collecting research samples for research studies quite difficult,” said Abazeed, who is also a Robert H. Lurie Fellow. Northwestern University Comprehensive Cancer Center.

Recently, researchers have begun to successfully develop patient-derived small cell lung cancer xenograft models that allow for further research. In the current study, Abazeed’s team studied the profiles of more than 60 of these models using multiple omics platforms.

In these samples, the researchers found that the cancer cells were significantly more heterogeneous than previously thought, suggesting that some of the more commonly used cancer cell lines had evolved into more discrete cell types.

“This suggested that we were missing a significant portion of the intratumor heterogeneity in individual samples due to these suboptimal cell systems,” Abazeed said.

The researchers also used high-resolution microscopy to observe when cancer cells turn into different types of cells. Furthermore, they found that the cells contain a high level of plasticity, allowing the cells to transform into different cell types to achieve a “cell state balance” and promote tumor growth and resistance to treatment.

“All the cancer has to do is maintain a proportion of cell types that are resistant to chemotherapy, and once the chemotherapy is no longer present, it can very quickly turn back and repopulate,” Abazeed said.

Using epigenetic targeting drugs, researchers have also identified previously unknown mechanisms that help cancer cells change their epigenetic programming. Furthermore, modulating these switches with epigenetic drugs could slow tumor growth or stop cancer from recurring, according to Abazeed.

“There is a coordinated set of events that occur during these cell-type changes, and I think that understanding the zeitgeber or time signature and the molecular cascade that leads to these transitions will reveal some fundamental insights into cell-type changes in cancer and beyond,” Abazeed said.

More information:
Priyanka Gopal et al, Multivalent state transitions shape the intratumoral composition of small cell lung cancer, Scientific progress (2022). DOI: 10.1126/sciadv.abp8674

Provided by Northwestern University

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