Foot on the gas: How RIT1 and YAP accelerate lung adenocarcinoma

Mutations in the RIT1 gene have emerged as rare, yet recurrent drivers in several human cancers, including lung adenocarcinoma. RIT1 (Ras-like in all tissues) encodes a protein that helps cells respond to growth signals from their environment. It works a bit like a rechargeable battery: when it’s loaded with energy, it sends messages that tell a cell to grow or adapt, and once that energy is spent, the signal shuts off.

In cancer, mutations in the RIT1 protein keep this signaling system stuck in the “on” position. We know this persistent growth signaling helps tumors form, but it’s been much less clear whether RIT1 mutations also change how cancer cells behave—for example, whether they can push cells to become more mobile, invasive, or adaptable as the disease progresses.

At the same time, researchers have been learning more about a different pathway that acts as a kind of cellular “context sensor.” This pathway centers on a protein called YAP, which helps cells interpret physical cues from their surroundings—like crowding, stiffness, or injury—and adjust their identity accordingly. When this system goes awry, YAP can encourage cancer cells to adopt traits linked to invasion and spread.

Both RIT1 and YAP converge on programs that promote growth, survival, and cellular plasticity, leading scientists in Dr. Alice Berger’s lab to wonder if RIT1 mutations might cooperate with YAP signaling to drive more aggressive tumor behavior. A new study recently published in Cell Reports asks whether this potential partnership is particularly relevant in lung cancer, where cells undergo epithelial–mesenchymal transition (EMT)—a shift that allows normally stationary epithelial cells to become more mobile and invasive.

“Because rare oncogenes are underrepresented in the field, relevant mouse models have historically been difficult to develop,” shares Callie Rominger, a former technician from Dr. Bergers group in the Human Biology division. “The creation of this new RIT1-driven mouse model represents a significant advancement. This autochthonous model allows us to study RIT1 in a physiologically relevant environment and discover potential therapeutic targets for RIT1-driven lung cancer."

Lung adenocarcinoma is believed to originate from alveolar type II (AT2) cells—specialized lung cells that produce surfactant to keep the air sacs open and can regenerate lung tissue after injury. To model this, the Berger lab created mice with conditional expression of a RIT1 mutant (RIT1^M90I) combined with loss of tumor suppressors p53 and Nf2 specifically in AT2 cells. By delivering Cre recombinase under the surfactant protein C promoter—which is specifically expressed by AT2 cells—into the trachea, they triggered lung tumor formation which closely mimics lung adenocarcinoma.

To better understand the comprehensive landscape of RIT1-driven lung tumors, the authors performed single-cell RNA sequencing on tumor and normal lung tissues, revealing a tumor microenvironment enriched for myeloid cells—particularly activated tumor-associated macrophages and neutrophils. Further digging identified distinct macrophage subsets exhibiting an “M2”-like, pro-tumorigenic phenotype, as well as neutrophil populations skewed towards a tumor-associated state. This shift toward a myeloid-enriched, immunosuppressive microenvironment resembles what has been observed in other aggressive lung cancer models and is linked to poorer clinical outcomes, highlighting the complex immune remodeling driven by RIT1^M90I mutations.

Mutant RIT1^M90I drives development of myeloid-rich lung tumors with some EMT-associated gene expression, but while these tumor cells lose certain markers found in healthy lung cells, they keep others, resulting in a mixed or “in-between” state rather than a full switch to a migratory phenotype. Under the microscope, tumors showed a range of appearances from more normal-like to more aggressive and invasive forms, reflecting this mix of cellular phenotypes.

“One of the major surprises with our new cancer model is that the tumors that develop have a more mesenchymal phenotype than what we would expect from human lung cancer,” shares Dr. Berger. “Part of this might be attributed to differences between mice and humans, but another explanation may be that we still have not perfectly replicated the genetic combination of mutations that occur in human cancer.”

Normally, the tumor suppressor NF2 acts like a brake pedal, keeping the growth-promoting protein YAP1 from speeding out of control. But when NF2 is lost, YAP1 hits the gas and drives unchecked. To investigate how mutant RIT1 and active YAP work together, the team used human lung cells engineered to express both RIT1^M90I and a permanently active form of YAP1. These cells grew much more aggressively than those expressing either protein alone and expressed key EMT genes—specifically the AP-1 family of transcription factors, including cJUN and FRA1.

In lung cells with both mutant RIT1 and active YAP1, cJUN was found mostly in the nucleus where it can control gene expression, and when the team blocked cJUN’s activity, tumor growth slowed down. These effects can be targeted with drugs that block two critical signaling pathways—MEK, which helps relay growth signals, and TEAD, a partner of YAP1—reducing tumor growth in cells and mice. Using both drugs together worked better than either alone, suggesting a promising combination treatment strategy for lung cancers driven by mutant RIT1.

However, to test those potential therapies, we still need better models that more closely mimic human disease. “We are currently looking at other mutations that co-occur with RIT1 mutations in human lung cancer to determine if modeling these in vivo would provide a model that better recapitulates human cancer,” shares Dr. Berger.

This study illuminates how mutant RIT1 and the YAP signaling pathway team up to push lung cancer cells into a more aggressive, adaptable state. By uncovering the molecular helpers driving this process—including key players like cJUN, ZEB1, and TEAD—and demonstrating that dual inhibition of MEK and TEAD pathways can effectively slow tumor growth, these discoveries open new doors for targeted therapies, providing hope for more precise treatments tailored to patients with RIT1-driven tumors.

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Alice Berger and Mark Headley contributed to this research.

The spotlighted research was funded by the National Institutes of Health, the Washington Research foundation, and the M.J. Murdock Charitable Trust.

Rominger MC, O'Brien S, Gupta S, Moorthi S, McSharry M, Kamlapurkar S, Lowe AR, Waldum A, Lo A, Duke F, Wu F, Headley MB, Cromwell E, Glabman R, Koehne A, Berger AH. 2025. Mutant RIT1 cooperates with YAP to drive an EMT-like lung cancer state. Cell Reports. https://doi.org/10.1016/j.celrep.2025.116185.