Christopher Schultz, assistant professor of the Department of Cancer and Cellular Biology at Temple's Lewis Katz School of Medicine, served as the lead author on the paper, which was published this fall in The Proceedings of the National Academy of Sciences, a peer reviewed journal of the National Academy of Sciences.

Small-cell lung cancer (SCLC) is one of the most aggressive, fastest-growing types of cancers, which frequently has already metastasized prior to diagnosis.  

SCLC is characterized by a high replication stress phenotype, meaning the cancer cells frequently produce DNA damage while replicating their DNA. The underlying cause for this phenotype is poorly understood. 

Gaining a stronger understanding of why exactly this happens is key for doctors and scientists as they work to combat the disease, which is why a new study from Temple University’s Lewis Katz School of Medicine could potentially be so impactful. 

Christopher W. Schultz, assistant professor of cancer and cellular biology at the Katz School, served as the lead author on “Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer,” which was recently published in The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences. PNAS is one of the world's most-cited and comprehensive multidisciplinary scientific journals, publishing more than 3,500 research papers annually. 

Lamin A/C (LMNA) is a key structural component of the nuclear envelope. While it has long been known that SCLC tumor cells frequently down-regulate LMNA, the underlying causes and consequences were not fully understood. Schultz and his colleague’s study looked at how the loss of LMNA impacts genomic stability within SCLC patients. Specifically, their findings help establish LMNA as a key regulator of nuclear transport and genome integrity, linking nuclear architecture to SCLC progression and therapeutic vulnerability. 

“What we found is that this protein is very lowly expressed in small cell lung cancer,” Schultz said. “We have determined this is primarily due to overexpression of EZH2 (enhancer of zeste homolog 2), which epigenetically silences lamin A/C in SCLC cells.” 

Importantly, Schultz and his colleagues demonstrated that loss of LMNA could be a targetable phenotype. They found that low-LMNA led to an increase in R-loops, three stranded nucleic acid structures formed when RNA binds to complimentary DNA displacing the second DNA strand. These R-loops underly the replication stress inherent to SCLC. Importantly, secondary challenges targeting replication including commonly used agents such as Topotecan can further exacerbate these complications leading to cancer cell death. 

According to Schultz, the loss of LMNA could also explain why SCLC has such a high rate of metastasis. This is part of what Schulz and colleagues explore in an additional study, “Metastatic organotropism in small cell lung cancer,” which is presently available at bioRxiv.  

Moving forward, Schultz said additional research in this area should focus on gaining a better understanding of how best to target R-loops in SCLC. 

“Future analysis should take a closer look at these R-loops and how they are a potential targetable feature of small-cell lung cancer,” he said. 

Other researchers who contributed to the recent PNAS study include Anjali Dhall, Yang Zhang, Parth Desai, Lorinc S. Pongor, David A. Scheiblin, Valentin Magidson, Ravi P. Shukla, Robin Sebastian, Umeshkumar M. Vekariya, Shahbaz Ahmed, Yilun Sun, Christophe Redon, Suresh Kumar, Manan Krishnamurthy, Henrique B. Dias, Vasilisa Aksenova, Elizabeth Giordano, Nobuyuki Takahashi, Michael Nirula, Mohit Arora, Chiori Tabe, Maria Sebastian Thomas, Rajesh Kumar, Yasuhiro Arakawa, Ukhyun Jo, Tomasz Skorski, Beverly A. Teicher, Roshan Shreshta, Mirit I. Aladjem, Stephen Lockett, Mary Dasso, Yves Pommier, Ajit K. Sharma and Anish Thomas.