Metastases account for the great majority of cancer-associated deaths, in particular for Non-small cell lung cancer (NSCLC) patients, yet remain the least understood aspect of cancer biology. NSCLC comprises two histologic subtypes: lung adenocarcinoma (LAC) and squamous cell carcinoma (SCC). LAC has some preferential sites for metastases e.g. brain, bones. Interestingly, brain metastases (BM) are often seen from LAC, whereas SCC invades locally in the thoracic wall. Indeed, BM araised from LAC represent 40-60% of BM cases [1].
The influence of cellular metabolism on the selectivity of the final destination of LAC metastases is still unclear. We believe that a key contribution is given by specific microenvironments, which better meet the metabolic needs of cancer cells by providing specific metabolites and therefore can be considered "pre-metastatic niches". This would drive the development of metastases in specific sites rather than in others.
Serine/Glycine Metabolism (SGM) is a crucial factor in several cancer types. Serine hydroxymethyltransferase (SHMT), a key enzyme in SGM, catalyses the reversible interconversion of serine and tetrahydrofolate (THF) to glycine and 5,10-methylene-THF. SHMT exists in cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms. It contributes to antioxidant molecules and nucleotides biosynthesis. Our preliminary results demonstrate that A549 LAC cells sense the microenvironment and genetically cope with it by remodelling their metabolism and regulating the expression of the two SHMT isoforms. Under metabolic restrictions, Ser and Gly are able to restore the normal levels of SHMTs and of the serine synthesis pathway enzymes, to increase the energetic status of A459 cells and to boost their metastatic power. In this project, I will further investigate this process to obtain a complete picture of the metabolic reprogramming of cancer cells underlying brain metastasis formation by NSLC.
1-Patchell RA. 2003. Cancer Treat Rev 29:533-540
About 90% of cancer associated deaths are caused by metastatic disease rather than primary tumors (1). NSCLC is characterized by a high incidence of recurrence as well as distant metastasis potential in particular into the brain. Besides, the prognosis of patients with brain metastasis (BM) is particularly poor. Furthermore, these patients have a median survival of only 4-6 months (2).
In fact, BM of NSCLC represents a complex process, allowing penetration of lung cancer cells into the brain parenchyma through the blood-brain barrier (3). The latter restricts brain access and prevents the majority of diagnostic and therapeutic agents to cross into the nervous tissues until the late stages of metastatic disease. This particular process makes the brain a challenging organ for therapeutic interventions (4).
Nevertheless, during the last decades, many research efforts have been made to investigate the cellular mechanism of metastatic disease, but obviously, they have led to further open questions as well as such discrepancies. Indeed, in spite of the large findings in primary tumour study and treatment, the metastasization process remains poorly understood. Furthermore, relatively few principles have emerged that would clarify metastases markers in general and specific organ metastases homing in particular. In fact, BM from lung is not a new problem (5,6), but has gained new visions and perspectives. Therefore, a better understanding of the molecular mechanisms underlying BM from LAC is critical to provide clue bases for developing new diagnoses and therapeutic approaches. Possible strategies aiming at limiting the favourable factors for metastases may be devised by inhibiting the key metabolic genes involved in lung metastases and monitoring their small metabolites byproducts.
References
1. Seyfried T.N., Huysentruyt L.C. 2013. On the origin of cancer metastasis. Crit Rev On-cog;18:43¿73.
2 - Cheng H., Perez- Soler R. 2018. Leptomeningeal metastases in non-small-cell lung can-cer. Lancet Oncol,19 (1), e43-e55.
3 - Wenwen Liu, Jing Song, Xiaohui Du, Yang Zhou, Yang Li, Rui Li, Li Lyu, Yeting He, Junxia Hao, Jing Ben, Wei Wang, Haibin Shih, Qi Wang. 2019. Full length articleAKR1B10 (Aldo-keto reductase family 1 B10) promotes brain metastasisof lung cancer cells in a multi-organ microfluidic chip model Acta Biomaterialia 91 195-208.
4 - He Q., Liu J., Liang J., Liu x., Li W., Liu Z., Ding Z., Tuo D. 2018. Towards Improvements for Penetrating the Blood¿Brain Barrier¿Recent Progress from a Material and Pharmaceutical Perspective. Cells, 7.
5 - Jeanny B. Aragon-Ching and Jo Anne Zujewski. 2007. CNSMetastasis: An Old Problem in a New Guise. Clin Cancer Res;13(6).
6- Achrol A. S., Rennert, R. C., Anders C. R., Ahluwalia M. S., Nayak L., Peters S., Arvold N. D., Harsh G. R., Steeg P. S., Chang S. D. 2019. Brain metastases. Nature Reviews Disease Primers, 5(1).