Stem Cells in Pancreatic Cancers: Unveiling Clonal Diversity, Treatment, and Interactions with Microenvironment

Pancreatic cancer remains a formidable challenge in oncology, with a pressing need to comprehend the intricate interplay between pancreatic cancer stem cells (CSCs) and the tumor microenvironment. This study delves into the cloning, molecular profiling, and therapeutic targeting of patient-derived pancreatic cancer stem cells (PCSCs). Additionally, we explore the crosstalk between PCSCs and human fibroblasts, shedding light on the mechanisms driving fibrotic transformation, and on partly therapy resistance. Patient-derived PCSCs were successfully cloned using the Xian-McKeon culture system, revealing self-renewal, clonogenic, multipotency, and tumorigenic properties. RNA sequencing uncovered distinct molecular signatures, emphasizing the heterogeneity within pancreatic tumors. Single-cell cloning identified two morphologically and molecularly different PCSC clones, underscoring the diversity of this critical cancer cell subpopulation. Novel treatment combinations, particularly TP-101, demonstrated selective elimination of PCSCs in vitro and in vivo. In-depth exploration of PCSC-fibroblast interactions involved co-culture experiments and conditioned media treatments. Cancer-associated fibroblasts (CAFs) exhibited increased proliferation when co-cultured with PCSCs and myofibroblast transformation, suggesting a symbiotic relationship. Surprisingly, CAFs require PCSC-secreted factors to drive fibrosis. Normal fibroblasts showed opposition to this transformation, indicating the nuanced nature of fibroblast activation. Our findings underscore the pivotal role of PCSCs in driving pancreatic cancer progression and therapy resistance. The identification of distinct PCSC subtypes opens avenues for personalized therapies, with TP-101 showing remarkable efficacy. The symbiosis between PCSCs and fibroblasts underscores the importance of understanding the tumor microenvironment for effective therapeutic interventions to overcome therapy resistance. These insights provide a foundation for future studies and hold promise for advancing pancreatic cancer treatment strategies.