Lymphatic and blood vasculature are integral components of the human circulatory system. Interstitial fluid, which contains immune cells and molecules, continuously leaks out of blood capillaries into peripheral tissues. This fluid is taken up by lymphatic capillaries and transported to draining lymph nodes (dLNs), where immune surveillance occurs, before ultimately returning to the bloodstream via the thoracic duct. Within the tumor microenvironment (TME), cancer and stromal cells promote the formation of new lymphatic and blood vessels—a process known as lymphangiogenesis and angiogenesis, respectively to support tumor growth and metastasis. Historically, anti-cancer therapies have targeted the lymphatic system by inhibiting tumor lymphangiogenesis to prevent metastasis to distant draining lymph nodes (dLNs), while overlooking its critical role in initiating antitumor immune responses. In Chapter 2 and 3, I utilize organ-on-chip technology and transgenic mouse models to investigate lymphatic vessel remodeling in pancreatic cancer. Mechanistically, we found that PDAC-secreted vascular endothelial growth factor A (VEGF-A) drives junctional zippering via VEGFR-2 signaling. While VEGF-A/VEGFR-2-targeted therapies have been extensively studied in the context of tumor angiogenesis and immune cell infiltration into the TME, their effects on lymphatic vessels have largely been overlooked. This gap motivated us to establish a Kaede optogenetic system to label and track immune cell migration through lymphatic vessels in the context of VEGF-A/VEGFR-2-targeted therapies. One of the open questions I seek to pursue in the future is how to optimally target the lymphatic system while accounting for its critical role in maintaining peripheral tolerance and supporting adaptive immune responses during combinatorial cancer therapies. In Chapter 4, I present the activin receptor-like kinase (ALK7) as a novel therapeutic target to prevent PDAC metastasis in murine models. Through 3D in vitro tumor-on-chip models and in vivo orthotopic PDAC mouse models of spontaneous metastasis, we show that ALK7 enhances cancer cell invasiveness via non-canonical β-catenin signaling, promotes epithelial to mesenchymal transition (EMT). I demonstrate further that ALK7 regulates MMP secretion, facilitating basement membrane degradation and weakening vascular integrity, thereby promoting PDAC intravasation. My findings identify ALK7 as a dual modulator of metastasis, amplifying both intrinsic tumor cell mobility and extrinsic microenvironmental remodeling to drive invasive progression.