MSK Researchers Uncover Pancreatic Cancer Cell Cooperation Mechanism and Demonstrate ADC Efficacy in Rare Pediatric Sarcoma
核心洞察
Memorial Sloan Kettering researchers discovered that pancreatic tumors contain two interdependent cell populations that work together through WNT (搜索) signaling to drive tumor growth and metastasis.
The study identified Porcupine (搜索) enzyme as a key therapeutic target, with blocking WNT (搜索) or Notch (搜索) signaling pathways dramatically slowing tumor progression in mouse models.
In a separate breakthrough, trastuzumab deruxtecan showed remarkable efficacy in 19 pediatric patients with desmoplastic small round cell tumor (搜索), with over half experiencing measurable tumor shrinkage.
Memorial Sloan Kettering Cancer Center researchers have unveiled critical insights into how pancreatic cancer (搜索) cells organize themselves to fuel aggressive tumor growth, while simultaneously demonstrating promising results for an antibody-drug conjugate in treating a rare pediatric sarcoma. The findings, part of multiple breakthrough studies from MSK (搜索), offer new therapeutic targets for some of the most challenging cancers.
Pancreatic Cancer Cell Cooperation Drives Tumor Growth
A groundbreaking study led by Stefan Torborg and Jung Yun Kim, PhD in the laboratory of Tuomas Tammela, MD, PhD at MSK (搜索)'s Sloan Kettering Institute has revealed that pancreatic ductal adenocarcinoma (搜索) contains two distinct, interdependent cell populations that work in concert to drive tumor progression.
Using genetically engineered mouse models, the research team identified two key cancer cell populations: WNT (搜索)-secreting cells (WNT-S) that produce critical growth signals, and WNT-responding cells (WNT-R) that receive these signals. The study showed these populations reside in close proximity and depend on each other for survival through a dynamic relationship where transient WNT-R cells emerge from basal cancer cells in response to WNT signals and eventually differentiate into WNT-S cells, creating a self-reinforcing cycle.
When researchers eliminated WNT (搜索)-S cells or blocked their signaling with drugs, the WNT-R population collapsed, dramatically slowing tumor growth and metastasis. The team identified Porcupine (搜索), an enzyme essential for WNT secretion, as a key therapeutic target. They also discovered that a subset of WNT-S cells express the Notch (搜索) signaling molecule DLL1 (搜索), which supports WNT-R cells.
"This work reveals that different cancer cell states must cooperate for pancreatic cancer (搜索) to grow and spread," Dr. Tammela explained. "Understanding these dependencies opens new therapeutic opportunities for disrupting the tumor ecosystem."
Critically, the study demonstrated that both WNT (搜索) and Notch (搜索) signaling pathways work together, with blocking either pathway suppressing tumor growth. Analysis of patient samples confirmed similar patterns exist in humans, with high Porcupine (搜索) expression linked to poor survival outcomes.
ADC Shows Promise in Rare Pediatric Sarcoma
In parallel research addressing urgent unmet medical needs, MSK (搜索) Kids physicians led by Emily Slotkin, MD, investigated the off-label use of trastuzumab deruxtecan (T-DXd, Enhertu®) in patients with desmoplastic small round cell tumor (搜索) (DSRCT (搜索)), an aggressive cancer primarily affecting teenagers and young adults.
DSRCT (搜索) often exhibits elevated HER2 (搜索) expression, making it a potential target for HER2-directed therapies. T-DXd, an antibody-drug conjugate consisting of an anti-HER2 antibody linked to a chemotherapy payload, was administered to 19 MSK (搜索) Kids patients with DSRCT.
The results proved striking: none of the patients experienced tumor growth, and more than half of those with measurable disease (9 of 17 patients) achieved measurable tumor shrinkage. Importantly, no unexpected side effects were observed, and researchers discovered that some DSRCT (搜索) diagnostic tests may underestimate HER2 (搜索) levels, potentially missing treatment opportunities.
"The efficacy of T-DXd in DSRCT (搜索) patients in this initial off-label experience is very striking and extremely promising," Dr. Slotkin noted. "It will be critical to follow up these results with a formal clinical trial, and our hope is that this approach might offer patients with this devastating disease a new and better treatment option."
AI Tool Advances Genetic Variant Identification
MSK (搜索) researchers also contributed to the development of Orthrus, an AI computational model designed to accelerate identification of disease-causing genetic variants. The tool, developed through collaboration with University of Toronto scientists, was trained on mature RNA sequences from 10 species and corresponding genes across more than 400 mammalian species.
Orthrus successfully predicted multiple RNA properties and could identify functionally distinct isoforms from sequence alone. The model correctly clustered BCL2L1 (搜索) gene isoforms with opposite effects on cell death and distinguished OAS1 (搜索) isoforms with different antiviral activities, outperforming approaches trained only on DNA or single RNA sequences.
The work was led by graduate students Philip Fradkin and Ruian (Ian) Shi of University of Toronto, and Taykhoom Dalal of MSK (搜索), under the supervision of senior authors including Quaid Morris, PhD, of MSK's Sloan Kettering Institute.
Quantum Nanosensors for Cancer Detection
Additionally, MSK (搜索) biomedical engineer Daniel Heller, PhD, developed enhanced quantum nanosensors for cancer blood tests. The laboratory created new chemistry to modify carbon nanotubes with various molecules that create surface "defects," allowing the nanotubes to trap energy-transferring packets.
These quantum nanosensors can detect subtle biological changes through measurable optical signals, expanding the sensor library for early cancer detection technologies, particularly for brain cancers (搜索).
"We now have the ability to build larger, more diverse sensor arrays that improve sensitivity and specificity for detecting cancer and other diseases at its earliest stages," explained lead author Stanislav Piletsky, PhD, a postdoctoral researcher in the Heller Lab.