Author ORCID Identifier

https://orcid.org/0000-0003-4709-8204

Semester

Summer

Date of Graduation

2026

Document Type

Dissertation (Campus Access)

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Brian Boone

Committee Member

Slawomir Lukomski

Committee Member

Tracy Liu

Committee Member

Jennifer Franko

Committee Member

Sharan Bobbala

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a five-year survival rate of 13.3%. This dismal prognosis can be attributed to a complex tumor microenvironment (TME) comprised of a desmoplastic stroma that renders tumors anti-immunogenic and poorly perfused. Cancer-associated fibroblasts within the stroma lay down the extracellular matrix (ECM), rich in oncofetal fibronectin (onfFn), that influences cancer growth and treatment response. Neutrophil extracellular traps (NETs) communicate with CAFs to promote ECM deposition and fibrosis which in turn enhances the immune exclusionary environment. Though immune checkpoint therapy and other anti-cancer drugs have shown profound efficacy in many malignancies, the harsh tumor environment of PDAC remains a major treatment barrier. Therefore, investigating alternative treatment strategies is necessary to combat therapeutic resistant mechanisms. Bacteriotherapy – the use of bacteria or bacterial components – has gained recognition to combat the immunosuppressive TME and reduce tumor burden across a variety of cancers. Group A Streptococcus (GAS) is considered one of the pioneer organisms of bacteriotherapy through the implementation of Coley’s Toxins in clinic up until the 1960s. Streptococcal collagen-like 1 protein (Scl1), a major adhesin of GAS, has several implications in cancer demonstrated by our group and others. Scl1 is homotrimeric collagen-like protein comprised of an N-terminal sequence-variable (V) domain and a collagen-like (CL) stalk containing repeating GXY sequences. The CL region forms a stable collagen triple-helix structure that structurally and functionally mimics mammalian collagen allowing for binding to integrin receptors on the surface of mammalian cells. The V-region is comprised of loops and a conserved acidic patch that forms the ligand binding site for onfFn which is upregulated in PDAC tumors. Scl1 has also been identified to inhibit NETs by reducing myeloperoxidase (MPO), a key regulator in NETosis, through an unknown mechanism. Our work herein focuses on exploiting these activities to generate targeted, Scl1-based therapeutic delivery systems against PDAC. Hypothesis: Scl1 hones bacteria to onfFn within the TME to generate a more immunostimulatory environment and reduce PDAC tumor burden through a NET-dependent mechanism. Results: First, we validated the anti-tumor effects of GAS and discovered this was dependent on the presence of Scl1. Using purified recombinant Scl1 (rScl1) we demonstrated that Scl1 reduces cancer-promoting NETs. Next, we discovered that Scl1 reduced tumor burden using a NET-dependent mechanism. We developed a less pathogenic Scl1 delivery system using Lactococcus lactis subsp. cremoris. Scl1-expressing Lactococcus bound to onfFn deposited by CAFs. Scl1 also altered the immune environment to be more immunostimulatory and anti-tumor indicated by increased cytotoxic T-cells and dendritic cells. These anti-tumor effects were dependent on a NET-inhibitory mechanism elicited by Scl1-expressing bacteria. Finally, we developed an avirulent strategy using Scl1-functionalized liposomes to enhance drug delivery and reduce primary and metastatic PDAC tumors. Conclusions: Scl1 binds to the CAF-deposited ECM and enhances anti-tumor immunity within the TME through a NET-dependent mechanism. This work highlights the anti-cancer capacity of Scl1 against PDAC. Moreover, these studies promote the development of Scl1-based therapeutic strategies to target cancerous tissue and reduce NETs within the PDAC TME

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