NEW FINDINGS — CANCER
Engineered bacteria as a biosensor Intestinal bacteria frequently exchange fragments of DNA – a process called horizontal gene transfer. Scientists have taken advantage of this naturally occurring activity to develop a bacterial
biosensor for colon cancer. The bacteria identify specific DNA fragments shed into the gut by colon tumors. Scientists engineered the genome of Acinetobacter baylyi bacteria, adding a gene that creates resistance to the antibiotic kanamycin, together with a genetic “switch” that silences the gene. If the bacteria encounter and integrate human DNA fragments containing KRAS gene mutations (common in colon cancer), the resistance gene switches on and the bacteria can grow in the presence of the antibiotic. Scientists administered the engineered bacteria via enema to mouse models with and without KRAS- associated colon tumors. Bacteria was extracted from fecal samples of the mice and exposed to kanamycin. Only A. baylyi recovered from the gut of mice with tumors could grow in the presence of the antibiotic, meaning the biosensor was working. Colorectal cancer is one of the most common forms of cancer, with a lifetime incidence of 1 in 23 men and 1 in 25 women. While exciting, significant additional research and testing is needed before this biosensor technology can be con- sidered for humans. This includes working with bacteria better suited to live in the human gut, delivering the bacteria by mouth and ensuring the system is both effective and safe. n
Overcoming chemoresistance Treating cancer becomes more challenging when cancer cells become resistant to treatment, a phenomenon called chemoresistance. This poses a significant hur- dle, especially if only a few treatments exist for a type of cancer. Pancreatic ductal adenocarcinoma (PDAC) is especially challenging to treat because it lacks early diagnostic markers and is diagnosed at later stages. Chemoresistance is common among PDAC patients, exacerbating the difficulty of treatment. These factors make PDAC one of the most lethal forms of cancer, with an 11% survival rate five years post-diagnosis. New research identified genes associated with PDAC patient survival. High expression of the ANGPTL4 gene leads to poor survival, while low expression of this gene is associated with a better response to standard pancre- atic cancer treatment. Additional studies explored how ANGPTL4 gene ex- pression impacts cancer cell response to treatment and the development of chemoresistance. ANGPTL4 overex- pression allows cancer cells to escape the effects of can- cer drugs and ignore cell death signals. Overexpression of ANGPTL4 also enhances cell migration, increasing the likelihood of metastasis. ANGPTL4 is part of a metabolic pathway regulating the expression of genes downstream. Using CRISPR to suppress downstream factors, researchers reversed chemoresistance and reduced cell migration. These techniques made resistant cancer cells more responsive to standard PDAC drugs and reduced cell migration, limiting metastasis. This research was in vitro , but targeting ANGPTL4 or its downstream partners with a drug could be a promising strategy to counter chemoresistance in PDAC. n REFERENCE: Gordon, E.R., Wright, C.A., James, M. et al. Transcriptomic and functional analysis of ANGPTL4 overexpression in pancreatic cancer nominates targets that reverse chemoresistance. BMC Cancer 2023, 23: 524. doi.org/10.1186/s12885-023-11010-1 More details can be heard at the Tiny Expedition podcast at this link https://www.hudsonalpha.org/when-cells-kill-understanding-cancer/
REFERENCE: Cooper RM et al. Engineered bacteria detect tumor DNA. Science . 2023;381(6658):682-686. https://www.science.org/doi/10.1126/science.adf3974
Differences in colon cancer risk Men diagnosed with colorectal cancer (CRC) have poorer prognosis and increased metastasis compared to women. This is particularly true with sporadic CRC, cancer not caused by rare inherited genetic variants. The underlying molecular and biological mechanisms for this phenomenon are unknown. New research may explain these gender differences in CRC outcomes. Researchers developed a mouse model with genetic modifica- tions mirroring characteristic changes seen in CRC. In one model, mice had gene changes in the KRAS oncogene, which normally functions to prevent cells from turning cancerous. This model shows that mutant KRAS regulates a Y-chromosome gene, KDM5D , which promotes metastasis and tumor immune evasion. When this Y-chromosome gene was eliminated in the mouse model, can- cers were less invasive and did not metastasize. Researchers have generally overlooked the Y chromosome as a potential contributor to cancer hallmarks and clinical outcomes because it houses few protein-coding genes beyond sex determination. A gene on the X-chromosome exhibits structural and func- tional similarity to KDM5D . However, research shows that this X-chromosome gene is regulated differently and doesn’t play a role in the invasiveness or metastasis of CRC. Collectively, these findings establish a foundation for crafting precision medicine strategies for treating men facing metastatic CRC. n REFERENCE: Li J, et al. Histone demethylase KDM5D upregulation drives sex differences in colon cancer. Nature . (2023) 619(7970):632-639. doi: 10.1038/s41586-023-06254-7
The laboratory of HudsonAlpha faculty researcher Sara Cooper, PhD, contributed to this work.
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