Current Projects

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The projects featured below are the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center (GMTEC)’s current funding recipients.

2021

Scott Lowe
Scott Lowe (Classic Individual)
Somatic Deletions of type I IFNs in Immune Evasion and Metastasis

Deletions of chromosome 9p21.3 are pervasive across human cancers, and strongly associated with poor prognosis, altered immune infiltration, and resistance to immune checkpoint blockade. While the contributions of these deletions to cancer biology have been broadly ascribed to the disruption of the cell cycle inhibitors CDKN2A/B, approximately half of 9p21.3 deletions include a neighboring cluster of 16 type I interferon (IFN) genes. To determine whether IFN co-deletion contributes to the phenotypes associated with 9p21.3 loss, we leveraged a new genome engineering approach developed in our group termed Molecular Alteration of Chromosomes with Engineered Tandem Elements (MACHETE), which enables the rapid and flexiblegeneration of megabase-sized chromosomal deletions. By applying MACHETE to an immunocompetent mouse model of pancreatic ductal adenocarcinoma (PDAC), we found that tumors bearing concomitant loss of Cdkn2a/b and the IFN cluster exhibit reduced immune surveillance and enhanced metastatic spread due to evasion of CD8+ T cell surveillance. Motivated by these observations, this project aims to molecularly and functionally dissect the impact of IFN signaling and its disruption on the PDAC ecosystem in tumor progression and upon immunotherapy. We propose to refine our understanding of relevant activities in the 9p21.3 locus and to interrogate the immune environment and epithelial-immune cell interactions using latest-generation single cell methods. These studies will provide novel insights and broadly applicable knowledge on what may be the most frequent genetic mechanism of immune evasion in human cancer.

Karuna Ganesh
Karuna Ganesh (Classic Individual)
Molecular Mediators of Dynamic Cell State Plasticity in Colorectal Cancer Metastasis

Metastasis is the principal cause of cancer death. Recent studies have reveal that phenotypic plasticity, the dynamic adaptation of cancer cells to the stresses of dissemination and tumor regeneration in distant sites, is an overarching hallmark of metastasis. However, the molecular mechanisms that underpin the dynamic diversification and selection of cell states during tumor progression, and the ultimate endpoint cell states that are selected for during metastasis in advanced human solid tumors remain poorly understood. We have pioneered an integrated approach for single cell profiling and organoid derivation matched trios of synchronously resected normal colon, primary colorectal cancer (CRC), and CRC liver metastasis from patients undergoing cancer surgery at MSK. Our preliminary single cell analysis reveals distinct lineage trajectories that are selected for and against in the progression from normal epithelium to primary tumor and metastasis in the same patients. In this proposal, we will leverage our patient-derived organoid and orthotopic mouse models and cutting-edge single cell, live imaging, and computational approaches to dissect the transcription factors and lineage programs that underpin metastatic plasticity. Our work will illuminate fundamental mechanisms and clinically actionable signaling pathways underlying dynamic cell state transitions and lineage plasticity in metastasis, poised for clinical translation to improve cancer outcomes.

2020

Simon Schwoerer
Simon Schwoerer (GMTEC Postdoctoral Researcher Innovation Award)
Investigating metabolism in the tumor stroma reveals an unexpected role of protein catabolism in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor characterized by nutrient-deprivation in the tumor microenvironment. How PDAC cells continue to grow despite nutrient deprivation is not fully understood. In this project, we are going to investigate whether the of uptake and degradation of extracellular proteins in non-malignant stromal cells can support PDAC progression by proving an alternative source of free amino acids.

Francisco Sanchez-Rivera
Francisco Sanchez-Rivera (GMTEC Postdoctoral Researcher Innovation Award)
Reconstructing complex cellular trajectories in vivo with single cell resolution

Cancers arise from single renegade cells that navigate complex biological trajectories that ultimately define their phenotypic identity. How individual cells navigate these unidirectional and multidirectional trajectories and whether these exhibit plasticity in vivo are fundamental questions that impact all areas of Cancer Biology. To tackle these questions, I am developing and applying a suite of CRISPR-based molecular recording tools that allow for highly precise mapping and transcriptional characterization of cellular trajectories and lineages in vivo with single cell precision.