LAMP2A Protein Plays a Role in the Formation of Mesenchymal Tumors

Autophagy is the natural, conserved breakdown of the cell that eliminates unneeded or defective components. It occurs through a lysosome-dependent controlled mechanism. Autophagy enables cellular component breakdown and recycling. The importance of chaperone-mediated autophagy (CMA), one of the main autophagy routes, has come to light in recent years as it relates to several physiological and pathological situations.

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Lung Cancer

Lung Cancer

Numerous research projects have discussed a connection between CMA and cancer. CMA plays both a pro-and an anti-oncogenic role. Studies to investigate the function of CMA in cancer have been done in mice or knockdown studies. Thus, its significance in tumor growth and progression is still unknown because no CMA loss-of-function human cancer models exist.

The LAMP2A protein, which enables substrate uptake by the lysosome, is a crucial molecular component of CMA. Since its levels are strongly correlated with CMA activity, LAMP2A is the determinant and rate-limiting regulator of the CMA process. However, no human LAMP2A knockout (KO) cancer models are available.

Scientists created the first human cell isoform-specific knockout (KO) of LAMP2A to examine CMA in cancer, and their findings contradict the prevalent current theory on CMA in cancer.

The discovery by the researchers that LAMP2A helps in the formation of mesenchymal tumors suggests that CMA’s ability to inhibit tumors can influence the spread of cancer cells.

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Understanding the mechanism of action of LAMP2A in the first human cell isoform

The lack of loss-of-function cancer models for LAMP2A, the primary regulator of this process, prevents researchers from fully understanding the role of chaperone-mediated autophagy (CMA) in the development and progression of cancer. Here, researchers demonstrate that CMA deficiency enhances proliferation and tumor formation in human malignancies of mesenchymal origin by creating an isoform-specific deletion of LAMP2A. As a result, they noticed that LAMP2A levels are lower in metastatic lesions than in primary tumors from the same patients. The tumor metabolome promotes anabolic pathways and mitochondrial metabolism, meeting the metabolic needs of rapid growth. Loss of CMA increased TGF signaling in tumors.

The work demonstrates mechanisms by which TGF-R2 promotes the production of nucleotides by increasing the enzymatic activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP). Therefore, TGF-signaling is pharmacologically inhibited to restore proliferation, mitochondrial metabolism, and G6PD activity in LAMP2A-KO cells. Contrarily, pharmacological suppression of mitochondrial metabolism reduces LAMP2A-KO-driven spread.

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Researchers used CRISPR-Cas9 gene editing to produce the first isoform-specific knockout of LAMP2A in cancer cells with origins in the epithelium and mesenchyme without affecting other isoforms of the LAMP2 or LAMP1 gene.

They first examined LAMP2A levels in non-neoplastic (normal) lung tissues by RNA sequencing, contrasting three healthy lung tissues with eight primary lung tumors. Lung cancer is a cancer type with a high potential for metastasis. According to the findings, healthy tissues had higher levels of LAMP2A transcript expression than any of the malignancies evaluated. In lung cancer patients with matched pairings of primary non-small cell lung cancer (NSCLC) tumors and their corresponding brain metastases, the researchers next performed transcriptional profiling on LAMP2A. Compared to matching metastatic tumors from the same individuals, the initial tumors had a higher level of LAMP2A.

Clinical significance

The creation of the first human cell isoform-specific knockout (KO) of LAMP2A to examine CMA in cancer is clinically significant in cancer research and management. Cancer therapy, with a better understanding of LAMP2A gene, can be developed.

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Conclusion

The study scientists have developed extensive results on CMA and its actions. The groundwork for further human studies can commence with the first human cell variant of LAMP2A.

References

Chaperone-mediated Autophagy Deficiency Reprograms Cancer Metabolism Via TGFβ Signaling to drive Mesenchymal Tumor Growth

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