New cellular “switches” promote the growth of lung cancer

Northwestern Medicine researchers have revealed new insights into how cancer cells can change their shape by undergoing phenotypic ‘disruptions’ to facilitate tumor growth and treatment resistance in small cell lung cancer, according to findings published in this journal. The progress of science.

“This cancer can basically change shape or transform itself, using at least three distinct cell types or developmental programs. The current standard of therapies for this tumor primarily target the neuroendocrine subtype of cells, leaving others to linger and rapidly repopulate the tumor when therapy is eventually stopped,” said Mohamed Abazeed, MD, PhD, 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 typically develops in patients with a significant history of tobacco use and has a 5-year survival rate of just 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 combined approach of chemotherapy and radiation, many will also relapse. The need for more effective targeted therapies is urgent, according to Abazeed, but progress has remained slow.

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“The disease is aggressive with very little progress over the past four decades. It is also not amenable to surgical resection, which makes collecting research specimens for experimental studies quite difficult,” said Abazeed, who is also a fellow at Northwestern University’s Robert H. Lurie Comprehensive Cancer Center.

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

In these samples, the researchers found that the cancer cells were substantially more heterogeneous than previously appreciated, suggesting that some of the more commonly used cancer cell lines may have evolved into more discrete cell types.

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

The researchers also used high-resolution microscopy to see when the cancer cells converted into different cell types. Furthermore, they found that the cells contained a high level of plasticity, allowing the cells to convert into different cell types to achieve ‘cell state equilibrium’ and promote tumor growth and resistance to treatment.

“All the cancer has to do is keep a portion of the chemotherapy-resistant cell types, and once the chemotherapy is gone, it can convert back and repopulate very quickly,” Abazeed said.

Using epigenetic-targeted drugs, the researchers also identified previously unknown mechanisms that help cancer cells change their epigenetic programming. Additionally, modulating these switches with epigenetic drugs could slow tumor growth or block cancer recurrence, according to Abazeed.

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

Reference: Gopal P, Petty A, Rogacki K, et al. Multivalent state transitions shape the intratumoral composition of small cell lung cancer. Ski Adv. 2022;8(50):eabp8674. doi: 10.1126/sciadv.abp8674

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