Evaluation of SMPD3 as a quarterback for extracellular vesicle-mediated metastasis in oral carcinoma

Mouth cancer remains an under-studied and significant global cancer killer; dismal survival rates (~50% over 5 years) have not changed in decades. Potential spread to neck lymph nodes (metastasis) is the single most important prognostic factor but clinical assessment has not been very accurate. This results in insufficient surgery or over-treatment for many patients. A better understanding of mouth cancer and its way to spread is needed to improve treatment for the patients.
The SMPD3 gene is frequently dysregulated in mouth cancer it has been linked to metastasis. SMPD3 expression can impact microRNA (miRNA: small non-coding RNA molecules that regulates gene expression) cargo within extracellular vesicles (EVs). Many of these miRNAs have been linked to tumor invasion and metastasis. I hypothesize that mouth cancer cells that exhibit decreased SMPD3 expression plays a role in lymph node metastasis via specific miRNA EV content and that SMPD3 expression can be used as a biological marker for lymph node spread in mouth cancer.
We hope this project will lead to novel tools to identify the patients at highest risk for lymph node involvement, ultimately increasing survival rate and quality of life for mouth cancer patients.

Role of SASH1 in generation of hematopoietic stem cells

For many patients with a serious blood disorder or malignancy the primary treatment option is a stem cell transplant (SCT), which involves destroying the unhealthy blood cells of the patient and replacing them with healthy donor stem cells. Unfortunately, a large number of patients are unable to find a suitable donor, and die as a result. Thus, there is an urgent need to identify new sources of healthy blood stem cells for these patients.
One promising solution is to harvest other types of cells from the patient and reprogram them to become blood stem cells, which can then be reintroduced later. Key to the success of this approach is placing the cells in an environment which mimics how the first blood cells are generated during embryonic development (called endothelial to hematopoietic transition [EHT]). To date little research has focused on the external cues needed for EHT, and this presents a bottleneck to producing stem cells for SCT. Therefore, our project will use models of EHT to identify external drivers of EHT, and the mechanisms by which they program cells to transition into blood cells. The knowledge from this project will help to create protocols to reproducibly reprogram patient-derived cells into blood cells for SCT.

Cost-effective biomarker driven treatment for chronic lymphocytic leukemia in the era of precision medicine

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Ibrutinib, a new drug that works differently from chemotherapy, is a major breakthrough for CLL treatment and allows patients to live longer; however, it comes at a high cost to the BC health system.

Objective

  • Our goal is to determine which patients benefit most from ibrutinib at what point in their disease, so that ibrutinib, and other drugs like it, are given to the right patients at the right time and avoided in those who will only suffer side effects.

Methods

  • We will analyze the impact of ibrutinib on the BC CLL population including patterns of use, side effects and survival. We will perform genomic testing on samples from CLL patients on ibrutinib to find gene mutations that develop over time that may help predict who will respond well. Finally, we will combine this information to determine the overall cost of ibrutinib to the BC population, particularly when treatment is targeted to those who will benefit most.

Impact

  • This approach is crucial to ensure ibrutinib is affordable for healthcare systems and accessible for all those who need it, ultimately leading to improved quality of life and survival of CLL patients.

Cytology-based DNA measurement for oral cancer screening

Oral cancer (OC) presents a global burden on society and the healthcare system with remarkably high incidence rates and poor prognosis. Despite the oral cavity being easily accessible for visual assessment and diagnostic procedures, it remains to be detected at an advanced stage when the prognosis is poor and radical interventions are necessary. An invasive biopsy of a clinically suspicious lesion is the current standard of care for OC diagnosis and lesion monitoring; however, repeated biopsies may not be feasible.

This study aims to provide a non-invasive, objective, and accurate OC diagnostic test using high throughput DNA-based cytometry. This test incorporates the OralGetafics platform, which combines artificial intelligence software with a commercially available and affordable scanner, which has been widely used in China and India for OC screening. We recently showed that the system could detect cancer or normal cells with sensitivity of 100 percent and specificity of 86.7 percent with minimal input from the cytotechnician. Potentially, this new technique can be used in remote communities with limited access to care and provides a significant benefit in early detection of at-risk oral lesions and reduction in OC burdens.

The Impact of COVID-19 on Cancer Diagnosis and Outcomes in British Columbia (BC)

Diagnosing cancer early is critical to achieve positive patient outcomes. The COVID-19 pandemic has had an unprecedented impact on cancer diagnosis in BC, suspending screening programs and drastically reducing diagnostic services. The patient and population health impact of a prolonged reduction in these services is unknown. Further, as COVID-19 restrictions ease, the expected demand for these services will exceed the system’s capacity, significantly increasing wait times. It is now critical for BC Cancer to establish priorities for the re-introduction of services to reduce negative impacts of delays. Our research will quantify the impacts of reductions in cancer diagnostic services on patient outcomes and develop effective strategies for re-introduction.

Investigating noncoding RNA networks in hematopoiesis

The genetic material of cells is DNA. The popular notion in biology for a long time was that DNA makes RNA which in turn makes proteins. But over the past two decades, research has shown that not all types of RNA are converted to protein. These RNAs which do not make (or do not code for) proteins are called noncoding RNAs. Long noncoding RNAs (lncRNAs) belong to one of the classes of noncoding RNAs. Based on various studies, we know that lncRNAs are crucial during different biological contexts including embryonic development as well as disease. The importance of lncRNAs in blood stem cells and blood cancer is not yet studied in detail. We will study how lncRNAs can help blood stem cells to either remain as stem cells (maintain stemness) or convert into different blood cell types (differentiate) and how they control the blood stem cells from forming cancer.

One of the very recently studied modes of action for lncRNAs is the binding of long noncoding RNAs to other class of noncoding RNAs called microRNAs and blocking the action of microRNAs. By using several techniques, we will systematically decipher lncRNAs acting by the microRNA mechanism to the blood stem cells in maintaining stemness or differentiation. The knowledge from this project will improve our understanding of the biology of blood stem cells and can be helpful in future for treatment of disorders of the blood system, bone marrow failure and cancer.

Targeting stress granules: A novel strategy to inhibit Ewing sarcoma metastasis

Metastatic disease remains the single most powerful predictor of adverse outcomes in Ewing sarcoma (ES) and other childhood sarcomas (malignant connective tissue tumours). High risk ES appears to be characterized by uninhibited outgrowth of neoplastic clones that have acquired additional genomic or epigenomic alterations, which facilitate the spread of the cancer cells. 

Considerable research has focused on understanding the genetic and biomolecular alterations that underlie ES, including drug resistance. The challenge is to identify targetable events that can be used to characterize metastatic disease, which is widely held as an inefficient process, with only a tiny fraction of primary tumour cells surviving. 

Emerging evidence suggests that a largely overlooked component of the spread of tumour cells is the impact of stress adaptation, occurring through acute changes in mRNA translation and protein synthesis. It is likely that specific ribonucleoprotein complexes known as stress granules (SG) are intimately connected to cancer biology, and even resistance to chemotherapy. However, targeting these structures in cancer cells has not been widely pursued. Dr. El-Naggar’s research will focus on understanding the link between stress granules  and conditions that promote the spread of cancer cells. 

 

Role of allergen-experienced Group 2 Innate Lymphoid Cells in allergic lung inflammation

Allergic asthma is an incurable respiratory disease that affects more than 300 million people worldwide. Asthmatic patients first become sensitized by inhaled substances that trigger an allergic reaction (allergens). Repeated exposures to the same allergens cause allergic inflammation in the lung because allergen-specific cells of the immune system called lymphocytes acquire memory: they react when they re-encounter the same allergen.

Another set of cells, the recently identified Group 2 Innate Lymphoid Cells (ILC2s), can also trigger allergic lung inflammation. Unlike regular lymphocytes, ILC2s do not recognize specific allergens. However, experienced ILC2s can vigorously react to new allergens, causing a stronger allergic lung inflammation than they did on their first exposure to unrelated allergens. Therefore, ILC2s can acquire memory that is not specific to particular antigens.

We believe that upon allergen encounter, different subsets of memory ILC2s are generated. The goal of this research is to characterize memory ILC2s in the chronic phase of allergic lung inflammation.

The results obtained in this research would explain why sometimes the causative allergen is not identified and why asthma vaccines are not always effective. This research may lead to the development of novel therapies for chronic asthma.

Co-registered optical coherence tomography and autofluorescence imaging

Lung cancer is the most common cause of cancer death with more than 1.3 million mortalities annually. Autofluorescence (AF) bronchoscopy is an established clinical technique that has proven to be extremely effective for early detection and staging of cancer by identifying high-risk areas where biopsies should be collected.

Currently, AF imaging is the most sensitive means of lung cancer detection. However, the improved sensitivity of AF broncoscopy comes at the cost of a decrease in specificity due to false-positive fluorescence in areas of inflammation or an increase in epithelial thickness. Moreover, performing biopsies and conducting histology on the removed tissue are costly and time-consuming.

The efficacy of the treatment would be significantly enhanced by differentiating carcinoma from other non-dangerous anomalies. OCT, the optical equivalent of ultrasound, enables high resolution in vivo imaging of airway morphology to study the high-risk tissue sites without performing biopsy and removing tissue. Therefore, when used in combination, AF-OCT imaging can provide rich biochemical information. The aim of Dr. Pahlevaninezhad’s research is to combine AF imaging and optical coherence tomography (OCT) to manage this disease through earlier detection. Dr. Pahlevaninezhad’s research method begins with combining the two modalities in free space to test ex vivo samples and to calibrate the system. The next step will be to build a fibre-based system for in vivo imaging of lung and to test the system on a small number of consenting patients.

Through the combination of these imaging techniques, Pahlevaninezhad’s research will provide both architectural and biochemical information which will aid in avoiding unnecessary biopsies. Significantly, the applications of the proposed device are not just limited to lung cancer; it also could target other applications like the oral cavity, considerably enhancing the ability to detect cancers effectively and efficiently.