Overview

Metastasis, the spread of cancer to a secondary site, is an inefficient process; very few cells that leave the primary tumour successfully form a distant lesion. The metastatic cascade involves detachment of cancer cells from the primary tumor and intravasation into the circulation, where it encounters new environments, physical forces and immune cells. Metastatic tumor cells that survive this migratory journey then colonize into a secondary site such as the lung or liver, where they either remain dormant or begin expansion. Successfully colonized metastatic tumor cells are more resistant to therapy and thus, more deadly. Our goal is to identify the 'seeds' of metastasis within the primary tumor (metabolic, transcriptional, translational) with the hope to catch these states for early therapeutic intervention.

Figure 1. Metabolic Flexibility and Plasticity in Metastasis. Bergers & Fendt, Nat Rev Cancer. 2021

Technologies and Tools

In our lab, we use melanoma as a tumour model to study metastasis. Melanomas are tumors that arise from melanocytes or their neural crest precursors at the dermal-epidermal junction of the skin. The lab uses the optically transparent casper zebrafish to study melanoma metastasis in vivo which allows for rapid and scalable CRISPR-Cas9 gene editing and high-resolution imaging of tumour cells at the single-cell level. We also utilize mouse syngeneic melanoma tumor models to study the tumor-immune crosstalk that is playing an important role in melanoma metastasis.

The lab will also use a diverse toolkit of molecular biology, fluorescent reporters, unbiased metabolomics, genome-wide CRISPR screening and bioinformatics approaches to tackle some exciting questions in cancer biology.

Projects

Project 1: Metabolite Scavenging and Metastasis

To meet the metabolic demand for metastasis (Figure 1), cancer cells engage in multiple processes such as ramping up metabolite synthesis, uptake from circulation and macropinocytosis of cellular fragments and biomolecules. The lab is interested in exploring a moonlighting function of cancer cells as phagocytes. Some of the questions we want to tackle are:

1) What type of meal is being foraged? Are all meals equal?

2) What cancer types engage in metabolite scavenging through this mechanism?

3) How does the meal 'talk' to the transcriptome or translatome to dictate cellular output and fate?

We currently study this in melanoma but have some exciting leads in breast cancer.

Project 2: Inter-organelle transport of cholesterol and its role in metastatic immune niche

The lab is excited to work on a newly funded project from ANRF exploring how the spatial compartmentalization of cholesterol impacts tumor metastasis and how metastatic tumor cells communicate with the immune TME in this context.

Project 3: Elucidating a non enzymatic function of CD73 in melanoma metastasis

We are studying the role of CD73, a 5' ectonucleotidase as a metastasis promoter in melanoma. Interestingly, we observed that its enzymatic activity doesn't seem to regulate its function in metastasis. Using the optically transparent zebrafish model of melanoma, human cancer cell lines and molecular biology approaches, we are exploring how this protein regulates metastasis.

Project 4: Identification of mechanisms by which cancers evade CAR-T killing

Through a CSIR funded Mission Mode project, we are delving into the domains of CD19 CAR-T therapy in the context of B Cell lymphoma wherein we hope to utilize our expertise in genome wide CRISPR screening to identify new targets that promote sensitivity to CAR-T mediated killing in B-cell lymphomas. This is particularly exciting as CAR-T therapy has exploded in India and studies that address potential resistance mechanisms are lacking and have the potential to improve CAR-T outcomes.

See Publications