The Shulamit Katzman Endowed Postdoctoral Research Fellowship

The Katzman fellowship is a highly competitive fellowship awarded through GMTEC to an international postdoctoral researcher who has demonstrated excellence among their peers and whose work has a focus in metastasis research.

GMTEC’s current Katzman fellow is Karuna Ganesh. Dr. Ganesh is a member of Joan Massagué’s lab and is an Attending Oncologist in the Department of Medicine.

Project: Investigating and targeting L1CAM in metastatic cancer stem cells

Metastasis causes the vast majority of cancer deaths, yet most treatments for metastatic cancer offer temporary disease control at best, and are inevitably followed by resistance and lethal relapse. The residual disease that persists after therapy and drives regrowth is thought to contain metastatic cancer stem cells (MetCSCs): cells that are particularly proficient at self-renewal, slow cell cycling, tumor re-initiation and therapy resistance. Efforts to develop effective therapies capable of eliminating metastasis have been hindered by a lack of representative model systems to study MetCSCs.

To overcome this problem, I have adopted cutting-edge organoid technology to generate novel representative 3-dimensional living models from metastases of patients undergoing cancer surgery at MSK. Using these patient-derived organoids, I have identified the cell adhesion molecule L1CAM as a potential marker of MetCSCs. My current work is aimed at elucidating the mechanism by which L1CAM drives the functions of MetCSCs, and at developing innovative strategies for targeting and eliminating metastatic disease.

Past Katzman Fellows

Ekrem Er
Mentor: Joan Massagué

Project: The role of L1CAM-driven vascular co-option in metastasis

GMTEC’s Metastasis Scholars Fellowship Recipients

2017 GMTEC Fellows
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We are pleased to announce GMTEC’s 2017 fellows.  Information on their projects will be available shortly.

Francisco Barriga
Mentor: Scott Lowe

Dissecting the role of large genomic deletions in colorectal cancer metastasis.

Colorectal adenocarcinoma is the fourth most common cancer, but despite vast research efforts, it remains the second cause of cancer-related deaths. This is largely due to metastasis to the liver and lungs. These statistics stress the need to understand and develop therapies for metastatic colorectal cancer, yet the molecular basis of this disease remains ill defined.

The study of colorectal cancer genetics has given insight into the pathways required to establish this disease, but there are no gene mutations that are clearly associated with metastatic progression. Current evidence suggests that deletions affecting large regions of the genome are associated with increased metastasis rates and poor patient survival, but whether these complex lesions drive the metastatic spread of this cancer remains unknown. The overall objective of this project is to understand the functional contribution of large segmental deletions to metastasis of colorectal cancer.

To achieve this, I will characterize the genomic landscape of both primary and metastatic tumors, which will guide the selection of the most-relevant deletions to study. To model these alterations, I have developed a rapid and flexible method to engineer deletions that I will apply to 3-D cultures of mouse colorectal cancer organoids. These organoids bearing the different genomic deletions will be tested in a recently established immunocompetent transplantation model that recapitulates the cancer’s initiation and metastatic progression. Overall, the concepts and tools derived from this project will serve to decipher the contribution of large genomic deletions to the metastasis of colorectal cancer.

Zhenghan Wang
Mentor: Joan Massagué

Understanding the role of TGF- signaling in metastatic latency.

Metastasis can arise in cancer patients years after primary tumor treatment due to the ability of disseminated tumor cells to enter dormancy and become refractory to therapies. However, the mechanisms that govern metastatic latency in distant organs are poorly understood. The Massagué lab has recently isolated latency competent cancer (LCC) cells from early-stage lung and breast cancer. LCC cells are primed to enter quiescence and maintain tumor-initiating potential.

The TGF-β family of cytokines maintains tissue homeostasis and prevents tumor formation by inhibiting cell growth and promoting apoptosis. Pathological forms of TGF-β signaling elicit tumor-promoting effects by inducing epithelial-mesenchymal transition, which enhances invasiveness and facilitates tumor dissemination. Intriguingly, LCC cells exhibit increased activity of TGF-β signaling. The goal of my project is to elucidate the role of TGF-β signaling in mediating the entry and exit of latency and also to provide the rationale of targeting the TGF-β pathway with new therapies for the treatment of metastatic cancers.

Pierre-Louis Loyher
Mentor: Frederic Geissmann

Role of resident macrophages in lung metastasis development.

Tumor-associated macrophages (TAMs) make up the majority of the immune cells that infiltrate solid tumors and are known to be a key driver of cancer progression and metastasis. Therapeutic strategies targeting TAMs will benefit from an in-depth understanding of their ontogeny and the mechanisms governing their homeostasis. TAMs were considered to originate from blood monocytes and to be continuously recruited from the circulation. The relationship between the origin and function of macrophages in a cancer setting is debated, but recent development in macrophage biology makes it a promising area of research.

The Geissmann lab has contributed to the identification of resident macrophages in most tissues. These macrophages originate from embryonic precursors and self-maintain independent of hematopoietic stem cells. Distinct transcriptional programs initiated in embryonic, fetal, or adult progenitors and the exposure to specific tissue environments may explain the specialization and diversity of macrophages in healthy as well as neoplastic tissues. Our preliminary results strongly suggest that a large fraction of TAMs within pulmonary metastases are derived from embryonically seeded tissue-resident macrophages.

Our hypothesis is that tissue-resident macrophages have a specific contribution to the microenvironment of solid tumors that is different from that of recruited cells. In this project, we will combine state-of-the-art approaches (fate mapping, genetically engineered cancer models, in vivo imaging) to characterize the developmental origin, maintenance, function, and dynamics of TAMs in the context of breast cancer and lung metastasis. Our work should contribute to a better description of the mechanisms sculpting the tumor microenvironment. This project should also provide a better understanding of the cellular and molecular mechanisms driving metastasis and unveil new opportunities for developing and improving cancer therapeutics.

Alexandre Francou
Mentor: Kathryn Anderson

Regulation and quantitative dynamic analysis of EMT in vivo.

Epithelial to mesenchymal transitions (EMTs) are major events that transform tissue organization during normal animal development. They have also been implicated in cancer progression. EMTs happen repeatedly during vertebrate development and are controlled by both common and specialized mechanisms. Despite information about the transcriptional regulation of EMTs, the cellular regulation of the process is still a mystery.

My project will study EMTs during mouse gastrulation. This work provides unique opportunities for genetic and imaging studies to define and quantify the epithelial properties, the cell morphological changes, and the mechanical properties of the transition. I will analyze epithelial and cytoskeletal proteins and the pattern and cell shape in fixed embryos. Because the dynamics of mammalian EMTs have not been studied in vivo, I will use mT/mG, Lifeact-GFP, Myosin2B-GFP, and ZO1-GFP transgenic reporter lines of mice to live image and quantitate the dynamics of membranes, actin, myosin, and tight junctions during the transition.

Recent work from the Anderson lab showed that Crumbs2 is required for the gastrulation EMT and that Myosin-2B and Crumbs2 are distributed anisotropically on cells about to undergo EMT. I will generate transgenic fluorescent reporter lines for Crumbs2 to test how its localization is associated with stochastic ingression. I will analyze a set of mouse mutants affecting the gastrulation EMT to uncover the regulation of the different ingression steps. This project will use genetic, immunostaining, and cellular quantifications to define new aspects of regulation of the gastrulation EMT and provide the first quantitative dynamic analysis of this key process. Whether the cellular mechanisms of metastasis EMTs are similar to the EMT happening normally during development is still unclear. This project will provide new perspectives on tissue dynamics that can be applied to understand the regulation of epithelial tumor progression and metastasis.

Efstathios Stamatiades
Mentor: Ming Li

Immunosurveillance of Early Disseminated Tumor Cells by Innate Lymphoid Cells and Innate-like T Cells.

Metastasis arises from disseminated tumor cells (DTCs), which escape the transformed lesion before the primary tumor is diagnosed. DTCs invade the stroma and intravasate (invade blood and lymph vessels). They can be detected in the bone marrow of patients even before overt metastasis. How the immune system responds to early DTCs and how tumor cells invade the stroma is of interest for understanding not only disease mechanisms but also cancer immunotherapy. In order to address this question, I will use live imaging in a mouse model of a mammary tumor to study the interactions of innate lymphoid cells (a group of immune cells) with early DTCs and to determine how innate lymphoid cells can kill DTCs.

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Tzu‐Pei Chang
Mentor: Kitai Kim

Project: Inhibition of tumorigenesis and metastasis by NEPN

Jing Hu
Mentor: Joan Massagué

Project: Dissecting the roles of STING signaling pathway in cancer metastasis

Contantinos Zambirinis
Mentor: William Jarnagin

Project: Development of novel imaging and laboratory biomarkers to monitor the liver pre‐metastatic niche and guide treatment

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Intissar Akalay
Mentor: Filippo Giancotti

Project: Targeting noncanonical discoidin domain receptor signaling for metastasis therapy

Wytse Bruinsma
Mentor: John Petrini

Project: The tumor suppressive barrier in response to oncogenes: MRNcomplex dependent genome rearrangements to prevent tumorigenesis and metastasis

Ashley M. Laughney
Mentor: Joan Massagué

Project: Uncovering Transcriptional Vulnerabilities in Latent Metastasis

Kajan Ratnakumar
Mentor: Richard White

Project: Understanding the roles of pigmentation in melanoma metastasis

Francisco Sanchez Vega
Mentor: Nikolaus Schultz

Project: Comprehensive genomic characterization of the tissuespecific characteristics of metastasis in the MSKIMPACT cohort

Yosef Shamay
Mentor: Glenn Heller

Project: Radiation-guided drug delivery to metastases via a novel abscopallike effect

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Ekrem Er
Mentor: Joan Massagué

Project: The role of L1CAM-driven vascular co-option in metastasis

Wenjing Su
Mentor: Filippo Giancotti

Project: Identification of prometastatic genes involved in bone metastasis of prostate cancer

Lisa K. Sevenich
Mentor: Johanna Joyce

Project: Therapeutic targeting of tumorassociated macrophages/microglia in breasttobrain metastasis