Current Projects
Research Interests in Nasser lab include unfurling of the basic biology behind the pathogenesis of breast cancer to brain metastasis (BrM) and small cell lung cancer (SCLC). We are using ex-vivo organoids and mouse models to understand the role of non-coding RNAs, immunology, metabolism, mitochondrial dynamics and tumor microenvironment in tumor initiation, progression, plasticity, and therapy resistance. We are striving to develop novel and innovative therapies that can be employed for clinical management of BrM and recalcitrant SCLC patients.
Circulating tumor cells (CTCs) or disseminated cancer cells are continuously shed from the tumor that survives in the bloodstream and can seed secondary tumors. Brain metastases (BrM) occur when cancer cells migrate from their primary site of the tumor to the brain. We are working on developing models including organoids and mice that can recapitulate the BrM.
- Brain Metastasis (BrM) occurs when extracranial circulating tumor cells invade the blood brain barrier and grow in the brain. Cancers of lung, breast and melanoma are the major contributors to BrM, which is strangely more common than primary brain tumors. In breast cancers, triple negative breast cancers (TNBCs) and epidermal growth factor receptor 2 (ErbB2 or HER2)-positive breast cancers frequently culminate into BrM. The overall survival is very poor and since it is incurable, patients are treated with palliative intent. We are focusing on the immediate challenge that is lack of suitable and reliable early detection biomarker(s) and exploiting various molecules like mucins, that have been shown to be effective in detecting cancers of pancreas, colon and other. The other area of focus is to address the limitations of treatment options for BrM patients, by searching novel therapeutic targets and identifying agents that can breach the blood-brain barrier (BBB) and prevent brain metastasis.
a. Regulation of immune cells. BrM is also not well characterized, so we are elucidating the molecular wiring that help circulating tumor cells to move towards the brain, breach the BBB and subsequently grow intracranially. For this, we are using highly sophisticated techniques to discern the attributions of chemokines in organotropism. Following the BBB breach, neuroinflammation is another factor that metastatic cancer cells need to withstand and how these cytokine and chemokine signaling can help to overcome is being investigated. BrM has significant population of immune cells infiltration, yet immune checkpoint inhibitors have not been very effective in majority of patients. Therefore, we are investigating the mechanism that are contributing to the immunosuppressive tumor microenvironment in BrM.
b. Impact of tumor microenvironment. The metabolic milieu of primary tumor and brain microenvironment is discrete so it will be interesting to understand the metabolic reprogramming (METABOR) that allow the extracranial cells survival and growth in the brain. Metabolic phenotyping of the BrM cancer cells will help to delineate the pathways that metastatic cells use to influence their metabolism to suit the metastatic environment. This will inspire to identify the metabolites that could prove to be bottlenecks for metastatic brain tumors.
c. GEMM models. BrM research is incomplete due to unavailability of spontaneous mouse model that can faithfully recapitulate the progression of BrM. The scientists are left to rely on injecting cancer cells intra-cardiac/carotid routes to study the pathogenesis of BrM which never portray the complete picture. Our lab is actively working on generation of such GEMM that can prove to be better models to study BrM.
SCLC is a highly heterogeneous disease that comprises five major subtypes SCLC-A/-N/-Y/-I/-P. Our group is working to understand the biology behind the pathogenesis and identify targeting strategies for SCLC that can enhance the chemo-immunotherapeutic response.