He Research

EGFR inhibitors provide durable clinical responses and improvement in survival for lung cancer patients with common activating EGFR mutations; however, acquired resistance is inevitable. We have identified a novel bypass pathway S6K1/MDM2 in acquire resistance in lung cancer patients without known secondary genetic mutations (PMID: 39408794, 38397056, 33037411). Cancer-associated fibroblasts (CAFs) are the prominent component of tumor stroma that helps in tumor progression and onset of drug resistance. However, how CAFs adapt and transform under therapeutic pressure in favor of tumor relapse remains a mystery. Recent studies reveal that resistant tumors arise from a pool of cells that survive the initial therapy called drug-tolerant persister cells (DTPs). Generally defined as low proliferative and cell cycle arrest, DTPs appear at early stages of acquired resistance before cancer cells undergo irreversible genetic changes. Intervention at early stages would be more efficient in overcoming drug resistance. However, it remains largely unknown how dormant DTPs awake, causing tumor regrowth and developing drug resistance. Our ongoing project is to study the synergistic crosstalk between DTPs and CAFs in EGFR-TKI resistance in NSCLCs. This study will provide new insights into the interplay between DTP cells and the tumor microenvironment and highlight potential therapeutic strategies to overcome TKI resistance by targeting the tumor microenvironment. 

Arsenic and chromium (VI) are established lung cancer carcinogens. However, environmental and occupational exposure to arsenic and chromium is still a major public health concern. Through utilizing in vitro models, mice models, and population-based cross-sectional studies, we revealed that heavy-metal-induced epigenetic alterations contribute to arsenic or chromium - induced metabolic shift, angiogenesis, and malignant transformation (PMID: 35660107, 31170415, 24413338, 23748240). While most research into the biology of Cr (VI)-induced carcinogenesis has focused on epithelial cell transformation, few studies have addressed the effects of Cr (VI) on stromal cells for cancer initiation and development. Our ongoing research will focus on the impact of hexavalent chromium [Cr (VI)] exposure on stromal cells in lung cancer development utilizing our newly developed mouse model with chronic exposure to particulate Cr (VI) via intranasal instillation. 

Cancer cells take in higher-than-usual amounts of nutrients such as sugars and amino acids are to support rapid cell proliferation and increased energy demands. Not surprisingly, cancer cells achieve this by expressing higher levels of nutrient transporters that mediate uptake of glucose and amino acids to meet their survival needs. L-type amino acid transporter 1 (LAT1), also known as SLC7A5, is a cross-membrane transporter that functions in the uptake of large neutral amino acids into cells. Unlike glucose transporters, LAT1 exhibits high cancer-specificity in its expression, making it an ideal druggable target for cancer treatment. LAT1 is overexpressed in a vast variety of cancers and has been associated with poor survival.  Dysregulation of amino acid transporters changes intracellular amino acid levels, which leads to metabolic reprogramming that contributes to the pathogenesis of cancer. Our global metabolite analysis showed that LAT1 is strongly associated with glycolysis and nicotinate/nicotinamide metabolism. Elucidating LAT1-dependent signals in cancer metabolic rewiring highlights the potential of LAT1-targeted therapies including JPH203, a highly selective LAT1 inhibitor for clinical applications.