Student Theses and Dissertations

Date of Award

2025

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Thesis Advisor

Sohail Tavazoie

Abstract

Most of the cancer related mortality caused by metastatic disease rather than primary tumor growth. More than 80% of gastrointestinal cancers initially metastasize to the liver first. While the prognosis of early-stage cancers is improving, a significant proportion of patients have metastatic disease at the time of diagnosis leading to poor survival outcomes. I focused on colorectal cancer and pancreatic cancer, the second and third leading causes of cancer related death in the United States, due to the lack of molecularly targeted therapies available for these cancers. Moreover, understanding the pathophysiological basis of gastrointestinal cancer liver metastasis is of great interest to the medical and scientific community. The first part of this thesis describes the establishment of multiple in vivo selected highly metastatic colorectal and pancreatic cancer models from poorly metastatic patient derive tumors and established cancer cell lines. Transcriptomic profiling of highly metastatic cancer cells identified phosphoenolpyruvate carboxykinase 1 (PCK1) in colorectal cancer and neuronal pentraxin 1 (NPTX1) in pancreatic cancer as potential metastasis promoters as they were highly differentially expressed in multiple highly metastatic models. The second part of this thesis first validates PCK1 and NPTX1 as metastasis promoters via in vivo functional assays followed by the mechanistic studies revealing PCK1’s and NPTX1’s role in promoting cancer cell growth under hypoxia, a hallmark of liver microenvironment. Metabolite profiling coupled with stable isotope tracing of highly metastatic colorectal cancer cells revealed that PCK1 reversed the TCA cycle under hypoxia to repurpose aspartate, a TCA cycle product, as a precursor of pyrimidines to promote hypoxic cell growth. On the other hand, in pancreatic cancer, NPTX1 was found to interact with adhesion molecule immunoglobulin like domain 2 (AMIGO2), newly identified cancer cell surface NPTX1 receptor in an autocrine manner that leads to nuclear retention of hypoxia inducible factor 1a (HIF1a) via phosphorylation of serine 641 and serine 643 residues. The final part of this study demonstrates therapeutic targeting of PCK1 and NPTX1-AMIGO2 pathways inhibits cancer metastasis and progression in multiple in vivo models. In collaboration with Tri-Institutional Therapeutics Discovery Institute, we developed an anti-NPTX1 therapeutic and diagnostic antibody that outperforms gemcitabine, a standard chemotherapeutic agent.

Comments

A Thesis Presented to the Faculty of The Rockefeller University In Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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