Researchers at Memorial Sloan Kettering (MSK) Cancer Center have identified the earliest cellular and molecular events that create the needed conditions for lung cancer cells to begin their growth into a tumor. The study, published in Nature, describes how cells with cancer-causing mutations initiate a coordinated chain of events to involve nearby fibroblasts and immune cells to create a microenvironment conducive to tumor growth at the very start of disease.
“We also found that this transformation of the local neighborhood is reversible, if caught early enough. This opens the door to new treatment and prevention strategies,” said senior author Joo-Hyeon Lee, PhD, an associate member in the developmental biology program at MSK.
The research focused on lung alveolar type II (AT2) stem cells that acquire mutations in the KRAS gene. Rather than simply proliferating, the mutant cells enter a regenerative-like state that resembles tissue repair. In this state, they produce amphiregulin (AREG), a signaling molecule that initiates communication with surrounding cells. AREG activates nearby fibroblasts through EGFR signaling, which prompts them to adopt a fibrotic, injury-like state which results in a remodeling of the extracellular matrix.
Within the microenvironment created, fibroblasts play a central role in shielding emerging tumor cells by producing a fibrous scaffold that supports tumor growth while also releasing signals that alter the activity of immune cells. Macrophages recruited to the site undergo reprogramming, shifting away from fighting the tumor toward phenotypes that suppress immune responses. Neutrophils and regulatory T cells are also recruited, further dampening anti-tumor immunity. This coordinated activity creates a protective niche in which the cells with the KRAS mutation can grow without being eliminated.
“These reciprocal interactions establish a self-sustaining epithelial–stromal–immune circuit that generates a tumor-permissive niche before malignant outgrowth,” the researches wrote. This loop reinforces itself: mutant cells sustain fibroblast activation, fibroblasts reshape immune responses, and immune cells further support tumor-promoting conditions.
The study builds on prior research in the Lee lab into lung injury and repair, which showed that normal regenerative programs involve temporary activation of stem cells and fibroblasts. In cancer, however, this process becomes dysregulated. Mutant cells remain locked in a regenerative state, continuously signaling to their environment. Earlier work by the same group had identified these regenerative states as a feature of early tumorigenesis.
To identify the mechanisms involved, the MSK first used mouse models of lung cancer carrying KRAS mutations. Through lineage tracing and single-cell analyses, they tracked individual cells to map how interactions with fibroblasts and immune cells evolved over time. They then used tissue samples from patients with early-stage lung adenocarcinoma and found returned the same result of cancer cells producing high levels of AREG and adjacent fibrotic fibroblasts.
Importantly, the team demonstrated that disrupting this communication network can prevent tumor formation. Blocking AREG signaling with an EGFR inhibitor kept fibroblasts and immune cells in their normal states and significantly impaired tumor development. Similarly, removing the AREG gene from mutant cells prevented the formation of the tumor-supportive niche. Even after early lesions had formed, inhibiting KRAS activity reversed many of the changes that had already occurred in the microenvironment.
The implications of this research to influence for cancer care are substantial. The identification of early signaling events and microenvironmental changes suggests new biomarkers for detecting lung cancer before it becomes advanced. High levels of AREG or evidence of fibroblast activation could indicate the presence of precancerous lesions, which could be particularly important for screening those at high risk of developing cancer, such as long-term smokers.
The findings also suggest there could be the development of new therapeutics aimed at preventing cancer development as opposed to treating it once it is established. By targeting the AREG–EGFR signaling axis or disrupting fibroblast activation, clinicians may be able to block tumor development at its earliest stages. Because the team showed these processes can be reversed, there is a window for intervention before the disease becomes resistant to treatment.
“The reversibility of these preneoplastic circuits defines a therapeutic window before progression to treatment-resistant disease,” the researchers wrote.
Next steps for the team include validating biomarkers in clinical populations, refining organoid models to study patient-specific tumor development, and testing preventive therapies that target these newly identified early signaling pathways.
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