The tumor microenvironment (TME) is a critical regulator of cancer progression in metastatic malignancies and its biochemical composition is of prime importance for the regulation of metastases metabolism, proliferation, and motility. In fact, Metastases account for the great majority of cancer-associated deaths, in particular, Non-Small Cell Lung Cancer (NSCLC) metastases. NSCLC has some preferential sites for TME, the future metastases site, in particular the brain. In fact, Recent evidence have shown that the TME is characterized by its nutrient availability and heterogeneity in particular amino acids (1,2). Studies on such AA have gained more attention because of their key role in reprogramming metastatic cell metabolism in order to produce building blocks needed for sustaining cell survival in a foreign TME. Thereby, the high proliferative capacity of cancer cells and the increased metabolic demand/output, render up these cells dependent on continuous exogenous uptake of certain AA when intracellular synthesis is not adequate to deal with the metabolic requirements.
In fact, despite their ability to synthesize nonessential amino acids, NSCLC is unable to maintain sufficient amino acids pools by de novo synthesis under nonessential amino acids deprivation conditions in particular serine and glycine (3). Therefore, NSCLC show metabolic reliance on the exterior supply of these amino acids. At this point, the influence of the cellular metabolism on the selectivity of the favorable TME is still unclear. For these aims, we would evaluate the role of these peculiar amino acids in the motility capability and the metabolic reshaping of NSCLC during metastatization. This would clarify the development of NSCLC metastases in specific sites rather than in others.
1- Zhengtao X. et al. 2019. NATURE COMMUNICATIONS | 10:3763 |
2- Quail, D. F. & Joyce, J. A.2017. Cancer Cell 31, 326-341.
3- Sarah E., et al. 2020. Cell Metabolism 31, 339-350
Brain malignancies encompass a range of primary and metastatic cancers, including low-grade and high grade gliomas and BM, originating from diverse extracranial primary tumor sites. In light of this, our understanding of the brain TME remains limited. More precisely, BM are the most frequent cause of malignant tumor of the central nervous system, four-times higher than primary tumors. At this stage, systemic chemotherapy is rarely used in patients with BM. Because of the extreme selectivity of the BBB, these patients show a limited level of the drugs that are able to cross the BBB. The latter restricts brain access and prevents the majority of diagnostic and therapeutic agents from crossing into the nervous tissues until the late stages of metastatic disease. All these factors would drive increased resistance of the neoplastic cells to the chemotherapy accompanied with further possible curing complexity due to eventual genotypic and molecular alterations. These particular responses make the brain a challenging organ for therapeutic interventions.
In fact, most of the research efforts have been focused on studying the colonization step of the metastatization process, mainly proliferation of the metastatic cell once extravasates a brain TME (1-4), but a little is known about its initial steps during metastastatisation and the factors controlling its motility. Indeed, a deeper analyses are extremely needed to further clarifying the first leading cause of aggressive and uncured metastases by studying :
* The migration capability of NSCLC from the initial site, the lung, and once reached the metastatic niche, the brain,
* The mechanistic balance used by the cell to compensate and equilibrate between its energy demands needed to fuel two different but complementary phenomena: cell motility and cell proliferation
Therefore, a better understanding of the molecular mechanisms underlying NSCLC motility potential is critical to provide new markers of NSCLC metastases, for eventual developing of new targeted therapeutic strategies aiming to limit the favourable factors beyond metastases araisement, such as inhibiting the key metabolic genes involved in lung metastases and monitoring their small metabolites byproducts.
References
1. Frances F et al. 2019. Nature Metabolism
2. Zhang X et al. 2020. Am J Cancer Res; 10(2):545-563
3. Chunhua W ET AL. 2019. Journal of Experimental & Clinical Cancer Research; 38:95
4. Klemm F et al., 2020, Cell 181, 1-18