Kathleen McAndrews, Ph.D.

My research training began with a focus on tissue engineering, exploring the impact of tissue biophysical properties to unravel cancer pathophysiology and inform on novel designs for cancer therapeutics. I completed my Ph.D. in Chemical and Biomolecular Engineering (ChBE) at the Georgia Institute of Technology (GT) in the laboratory of Dr. Michelle Dawson. There I built my foundational training as an extracellular matrix (ECM) bioengineer, with specific focus on understanding the influence of molecular and mechanical cues provided by tissue and ECM on the properties of mesenchymal stem cells (MSCs) in tissue regeneration and cancer progression. My Ph.D. studies resulted in 4 first author and 3 co-authored peer reviewed publications and I was awarded an NIH/NIGMS T32 fellowship in Cell and Tissue Engineering Biotechnology, a GT Career, Research, and Innovation Development Conference Travel Award, and a GT ChBE Exemplary Academic Achievement Award. My research unraveled the impact of the mechanical and architectural properties of the extracellular matrix on MSC differentiation (McAndrews et al. Phys Biol 2014 and McAndrews et al. Tissue Eng Part A 2014), contributing to the design of tissue-engineered constructs and their numerous applications. I identified regulators of stromal cell interactions with cancer cells (McAndrews et al. ACS Chem Biol 2015) and deciphered the impact of transforming growth factor β-mediated directional migration of cancer cells (McAndrews et al. Sci Rep 2015). These studies elucidate how mesenchymal cells interact with their environment and offered important insight for biomaterial design and the development of cancer therapeutics targeting cancer cell mobility.

For my postdoctoral fellowship, I joined the laboratory of Dr. Raghu Kalluri at the University of Texas MD Anderson Cancer Center (MDACC) and gained additional expertise in tissue injury and damage response, regenerative biology, and tumor microenvironment as it relates to cancer progression and metastasis. During my fellowship period, I have published 15 first author and 18 co-author peer-reviewed studies, with 6 first author and one co-author manuscripts currently under review and in the submission process. Currently, my total citations are 3959 and my h-index is 26. My work strategically aligned with cancer targeting strategies with translational impact. My studies informed on novel biology associated with extracellular vesicles (EVs)/exosomes, their role in regulating tumor microenvironment to impact cancer progression and metastasis, and their utility as therapeutic delivery modalities. Collectively, my contribution in this area of research directly led to three different phase 1 clinical trials in pancreatic cancer and melanoma (NCT04827953, NCT03608631, NCT04592484). Specifically, my interest in mesenchymal cells led me to study the biogenesis and secretion of EVs/exosomes from MSCs. This work, published in JCI Insight, documented the development and characterization of clinical grade MSC exosome-based therapeutics for the targeting of oncogenic KRAS^G12D (iExosomes). I evaluated treatment responses through measurement of KRAS^G12D abundance in cfDNA for this phase 1 clinical trial (NCT03608631). I exploited exosomes as drug delivery vehicles to generate exosomes containing CRISPR/Cas9 targeting KRAS^G12D in pancreatic cancer (McAndrews et al. Life Sci Alliance 2021) and STING agonist to induce antitumor immunity in melanoma (McAndrews et al. J Biol Chem 2021, NCT04592484). During the COVID-19 pandemic, I expanded my focus to understanding and developing novel therapeutics for COVID-19. In collaboration with Dr. Huiping Liu’s lab at Northwestern University, we showed that EVs containing ACE2 are secreted with SARS-CoV-2 infection as part of the innate immune response (El-Shennawy, Hoffmann, Dashzeveg, McAndrews, et al. Nat Commun 2022). I created the first ELISA to detect both S-protein RBD domain and N-protein of SARS-CoV-2 to differentiate between antibodies that are generated via viral infection versus vaccination (McAndrews et al. JCI Insight 2020). This work further motivated me to develop an EV-based vaccine platform targeting SARS-CoV-2 S-protein and extended this strategy to target cancer antigens (Luo, McAndrews et al. J Controlled Release 2024). I received an Ergon Foundation Postdoctoral Fellowship to support my research related to immunobiology in 2021.

My long-standing interest in mesenchymal cells led me to investigate their functional role in the context of cutaneous wound healing, colon cancer, and pancreatic cancer. Solid tumors display many characteristics of abnormal tissue repair, including excessive accumulation of fibroblasts and ECM as well as infiltration of dysfunctional immune cells, suggesting that the balance of beneficial and deleterious tissue regeneration processes can impact tumor progression. Using newly generated genetically engineered mouse models (GEMMs) to selectively deplete proliferating fibroblast populations, my studies unraveled that heterogeneous markers displayed by fibroblasts are indicative of distinct, non-redundant functional subsets. These studies uncovered that aSMA⁺ fibroblasts are critical for cutaneous wound repair, whereas other subsets are largely dispensable (McAndrews et al. EMBO J 2022). We used the same fibroblast-depleting GEMMs and leveraged single-cell RNA sequencing (scRNA-seq) to study fibroblast subpopulations in spontaneously occurring colon and pancreatic cancer. In the context of colon cancer, aSMA⁺ fibroblasts restrain cancer progression through suppression of Lgr5⁺ cancer stem cells (McAndrews et al. Oncogene 2021). Depletion of αSMA compared to FAP-expressing fibroblasts in pancreatic cancer resulted in disparate effects on tumor growth, immune interactions, and chemoresistance (McAndrews, et al. Cancer Discovery 2022). This work motivated phase 1 clinical trials combining stromal cell targeting with chemotherapy and anti-CTLA-4 in advanced pancreatic cancer (NCT04827953). I am currently performing correlative studies on patient biopsies from this trial to identify stromal alterations that are associated with effective patient responses to therapy. I further elucidated the contribution of stromal cells to the efficacy of small molecule KRAS^G12D inhibition in pancreatic cancer and identified a critical role for induction of FAS expression in cancer cells in promoting CD8⁺ T cell mediated clearance of cancer cells and overall drug efficacy (Mahadevan, McAndrews, et al. Cancer Cell 2023). My recent work in collaboration with Tim Heffernan and the TRACTION platform and Anirban Maitra’s group has identified CDK8 as a mediator of resistance to KRAS^G12D inhibition through promoting immunosuppression (McAndrews et al. Under revision) and YAP1 and MYC in reprogramming the immune microenvironment to promote panKRAS inhibitor resistance (McAndrews et al. Under revision). Currently, I am using novel GEMMs to unravel the role of EVs/exosomes in pancreatic cancer progression and metastasis. Such models have enabled the evaluation of endogenous EV exchange and functional interrogation of EV transfer in spontaneously occurring cancer for the first time. I found a preferential accumulation of endogenously released cancer cell derived CD9⁺ EVs in fibroblasts and macrophages, which leads to reprogramming of fibroblasts and metabolic rewiring of macrophages to impact tumor progression. Recently, I was awarded an NCI Transition Career Development Award (K22) to support the establishment of my transition to an Assistant Professor in the Department of Cancer Biology at MDACC and further dissect the mechanisms of EV-mediated stromal reprogramming in pancreatic cancer progression and metastasis.