— College of Medicine — Department of Biochemistry and Molecular Biology — Our Faculty — Wasim Nasser, PhD — Current Projects

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.

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.

2. Novel approaches to attenuate SCLC progression and metastasis. Small cell lung cancer (SCLC) is a high-grade neuroendocrine subtype of lung cancer (LC) and remains one of the most lethal and recalcitrant solid tumors. SCLC shows poor prognosis with a 5-year survival is less than 5%. Although SCLC patients respond to platinum-based first-line therapy, most patients develop drug resistance and relapse within one year of the treatment. No effective targeted/non-targeted therapies are available for treating SCLC patients, and overall outcomes have remained unchanged for the last three decades making SCLC a ‘poster child’ disease. Our lab uses high throughput methods and genetically engineered mouse models to understand better and address a few important questions: 1) Mechanisms of SCLC progression and switching to highly metastatic and recurrent tumors, 2) what are the mechanisms that mediate subtype plasticity and/or plasticity of SCLC tumors from chemosensitive to chemoresistance tumors, 3) what are the metabolic vulnerabilities that help SCLC cells to metastasize and adapt to distant organs having metabolically different microenvironment?

a. Role of microRNAs in SCLC progression and metastasis. MicroRNAs (miRs) are endogenous short non-coding RNAs that impact the expression of a wide network of genes. It has been estimated that miRs regulate the expression of over 30% of the genes in mammalian genomes. miRs play crucial roles in the multistep processes of carcinogenesis. We are currently elucidating the role of miRs and chemokines/cytokines axis in regulating SCLC progression and metastasis. We are also developing a spontaneous mouse model for SCLC that will be used to test novel preventive and therapeutic strategies (utilizing miR mimics/anti-sense nanoparticles) against SCLC. Using serum profiling of miRs through genomic sequencing, we are trying to identify miR signatures responsible for disease progression and metastasis and evaluate their prognostic potential.

b. Novel targets (glycoproteins/mucins and immune modulatory molecules) in SCLC metastasis/brain metastasis. Most SCLC patients (30-40%) develop brain metastasis following standard therapy, and surprisingly ~10% of the patients have shown brain metastasis even at the time of diagnosis, suggesting the need for early diagnosis and better treatment strategies. Using patient samples, in vitro and preclinical mouse model systems, we are investigating the diagnostic and therapeutic potential of mucins/glycoproteins/other proteins in SCLC metastasis (in general) and brain metastasis (in particular).

c. SCLC metabolism in metastasis and subtype switching. The high metastatic and growth abilities of SCLC cells may rely on how they meet their synthetic and bioenergetic supplies. We have begun to explore the cellular metabolism of SCLC that influences metastasis/brain metastasis, recurrence, and subtype switching. Based on studying how these cells meet nutrient demands under different environments and during subtype switching, we are trying to identify metabolic vulnerabilities that can provide a future platform to develop potential therapeutic modalities for this deadly disease.